ANNEX I LIST OF THE NAMES, PHARMACEUTICAL...

ANNEX I

LIST OF THE NAMES, PHARMACEUTICAL FORMS, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTES OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS

IN THE MEMBER STATES

Member State EU/EEA

Marketing authorisation holder

Invented Name Strength Pharmaceutical form

Route of administration

Content

(concentration)

Austria

Pfizer Corporation Austria Ges.m.b.H. Floridsdorfer Hauptstrasse 1 1210 Wien Austria

Diflucan 50 mg - Kapseln

50 mg Capsule, Hard

Oral use N/A

Austria



100 mg Capsule, Hard

Oral use N/A

Austria




Oral use N/A

Austria


Fungata 150 mg - Kapsel


Oral use N/A

Austria




Oral use N/A

Austria


Diflucan 50 mg/5 ml - Trockensaft

50 mg/5ml Powder for oral Suspension

Oral use 10 mg/ml

Member State EU/EEA




Content

(concentration)

Austria


Diflucan 200 mg/5 ml - Trockensaft

200 mg/5ml Powder for oral Suspension

Oral use 40 mg/ml

Austria


Diflucan 100 mg - Infusionsflaschen

100 mg/50ml Solution for Infusion

Intravenous use 2 mg/ml

Austria





Austria





Belgium

Pfizer SA Boulevard de la Plaine 17 1050 Brussels Belgium

Diflucan 50 mg Capsule, Hard

Oral use N/A

Belgium



Oral use N/A

Belgium



Oral use N/A

Member State EU/EEA




Content

(concentration)

Belgium



Oral use N/A

Belgium


Diflucan 50 mg/5ml Powder for Suspension

Oral use 10 mg/ml

Belgium



Oral use 40 mg/ml

Belgium


Diflucan 200 mg/100ml Solution for Infusion


Belgium




Bulgaria Pfizer Europe MA EEIG Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom


Oral use N/A



Oral use N/A

Member State EU/EEA




Content

(concentration)


Diflucan 2 mg/ml Solution for Infusion


Cyprus Pfizer Hellas A. E. 243, Messoghion Ave. 154 51 Νeo Psychiko Athens Greece

Fungustatin 150 mg Capsule, Hard

Oral use N/A

Cyprus Pfizer Hellas A. E. 243, Messoghion Ave. 154 51 Νeo Psychiko Athens Greece

Fungustatin 100 mg/50ml Solution for Infusion


Czech Republic

Pfizer. s r.o. Stroupežnického 17 150 00 Prague 5 Czech Republic

Diflucan 50 mg 50 mg Capsule, Hard

Oral use N/A

Czech Republic

Pfizer. s r.o., Stroupežnického 17 150 00 Prague 5 Czech Republic


Oral use N/A

Czech Republic



Oral use N/A

Czech Republic


Diflucan I.V. 2 mg/ml Solution for Infusion


Member State EU/EEA




Content

(concentration)

Denmark

Pfizer ApS, Lautrupvang 8 2750 Ballerup Denmark


Oral use N/A

Denmark

Pfizer ApS, Lautrupvang 8 2750 Ballerup Denmark


Oral use N/A

Denmark

Pfizer ApS Lautrupvang 8 2750 Ballerup Denmark


Oral use N/A

Denmark


Diflucan 10 mg/ml Powder for Suspension

Oral use 10 mg/ml

Denmark




Estonia Pfizer Europe MA EEIG Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom


Oral use N/A

Estonia Pfizer Europe MA EEIG Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom

Diflucan 2 mg/ml 2 mg/ml Solution for Infusion


Member State EU/EEA




Content

(concentration)

Finland Pfizer Oy Tietokuja 4 00330 Helsinki Finland


Oral use N/A



Oral use N/A



Oral use N/A


Diflucan 10 mg/ml Powder for Oral Suspension

Oral use 10 mg/ml

Finland Pfizer Oy Tietokuja 4 00330 Helsinki, Finland

Diflucan 40 mg/ml Powder for Oral Suspension

Oral use 40 mg/ml

Finland Pfizer Oy, Tietokuja 4 00330 Helsinki Finland



France

Pfizer Holding France 23-25 Avenue du Docteur Lannelongue 75014 Paris France

Fluconazole Pfizer 50 mg Capsule, Hard

Oral use N/A

France

Pfizer Holding France 23-25 Avenue du Docteur Lannelongue

Triflucan 50 mg Capsule, Hard

Oral use N/A

Member State EU/EEA




Content

(concentration)

75014 Paris France

France



Oral use N/A

France



Oral use N/A

France Pfizer Holding France 23-25 Avenue du Docteur Lannelongue 75014 Paris France


Oral use N/A



Oral use N/A



Oral use N/A


Fluconazole Pfizer 50 mg/5ml Powder for Oral Suspension

Oral use 10 mg/ml

Member State EU/EEA




Content

(concentration)


Triflucan 50 mg/5ml Powder for Oral Suspension

Oral use 10 mg/ml


Triflucan 200 mg/5ml Powder for Oral Suspension

Oral use 40 mg/ml


Triflucan 2 mg/ml Solution for Infusion


Germany

Pfizer Pharma GmbH Linkstraße 10 10785 Berlin Germany


Oral use N/A

Germany


Diflucan Derm 50 mg Capsule, Hard

Oral use N/A

Germany



Oral use N/A

Germany



Oral use N/A

Member State EU/EEA




Content

(concentration)

Germany


Fungata 150 mg Capsule, Hard

Oral use N/A

Germany


Diflucan Trockensaft 50 mg/5ml Powder for Suspension

Oral use 10 mg/ml

Germany

Pfizer Pharma GmbH, Linkstraße 10 10785 Berlin Germany

Diflucan i.v.-100mg 100 mg/50 ml Solution for Infusion


Germany


Diflucan i.v.-200mg 200 mg/100ml Solution for Infusion


Germany


Diflucan i.v.-400mg 400 mg/200ml Solution for Infusion


Germany


Diflucan Derm Saft 5 mg/ml Syrup

Oral use 5 mg/ml

Germany


Diflucan Saft 5 mg/ml Syrup

Oral use 5 mg/ml

Greece

Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko Athens


Oral use N/A

Member State EU/EEA




Content

(concentration)

Greece Greece

Pfizer Hellas A. E. 243, Messoghion Ave., 154 51 Νeo Psychiko Athens Greece


Oral use N/A

Greece

Pfizer Hellas A. E. 243, Messoghion Ave. 154 51 Νeo Psychiko, Athens Greece


Oral use N/A

Greece

Pfizer Hellas A. E. 243, Messoghion Ave. 154 51 Νeo Psychiko Athens Greece


Oral use N/A

Greece


Fungustatin 50 mg/5ml Powder for Suspension

Oral use 10 mg/ml

Greece


Fungustatin 200 mg/5ml Powder for Suspension

Oral use 40 mg/ml

Greece




Greece Pfizer Hellas A. E. Fungustatin 200 mg/100ml Solution for Intravenous use 2 mg/ml

Member State EU/EEA




Content

(concentration)

243, Messoghion Ave. 154 51 Νeo Psychiko Athens Greece

Infusion

Greece




Hungary

Pfizer KFT 1123 Budapest Alkotás u. 53. Hungary

Diflucan 50 mg kemény kapszula

50 mg Capsule, Hard

Oral use N/A

Hungary




Oral use N/A

Hungary

Pfizer KFT 1123 Budapest Alkotás u. 53 Hungary



Oral use N/A

Hungary




Oral use N/A

Hungary


Diflucan 10 mg/ml por belsőleges szuszpenzióhoz

50 mg/5ml Powder for Oral suspension

Oral use 10 mg/ml

Hungary

Pfizer KFT 1123 Budapest Alkotás u. 53.

Diflucan 40 mg/ml por belsőleges szuszpenzióhoz

200 mg/5ml Powder for Oral Suspension

Oral use 40 mg/ml

Member State EU/EEA




Content

(concentration)

Hungary Hungary

Pfizer KFT 1123 Budapest, Alkotás u. 53. Hungary

Diflucan 2 mg/ml oldatos infúzió

2 mg/ml Solution for Infusion


Iceland



Oral use N/A

Iceland



Oral use N/A

Iceland



Oral use N/A

Iceland



Oral use 10 mg/ml

Iceland




Ireland Pfizer Limited Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom


Oral use N/A

Member State EU/EEA




Content

(concentration)



Oral use N/A



Oral use N/A



Oral use 10 mg/ml



Oral use 40 mg/ml




Ireland Pfizer Limited Ramsgate Road



Member State EU/EEA




Content

(concentration)

Sandwich Kent CT13 9NJ United Kingdom

Italy

Pfizer Italia S.r.l. Via Isonzo, 71 04100 Latina Italy


Oral use N/A

Italy



Oral use N/A

Italy



Oral use N/A

Italy



Oral use N/A

Italy



Oral use 10 mg/ml

Italy




Latvia

Pfizer Limited Ramsgate Road Sandwich Kent CT13 9NJ

Diflucan 50 mg kapsulas

50 mg Capsule, Hard

Oral use N/A

Member State EU/EEA




Content

(concentration)

United Kingdom Latvia

Pfizer Limited Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom

Diflucan 150 mg kapsulas


Oral use N/A

Latvia


Diflucan 2 mg/ml šķīdums infūzijām



Lithuania



Oral use N/A

Lithuania



Oral use N/A

Lithuania



Oral use N/A

Lithuania

Pfizer Limited Ramsgate Road Sandwich



Member State EU/EEA




Content

(concentration)

Kent CT13 9NJ United Kingdom

Luxembourg



Oral use N/A

Luxembourg



Oral use N/A

Luxembourg



Oral use N/A

Luxembourg



Oral use N/A

Luxembourg



Oral use 10 mg/ml

Luxembourg



Oral use 40 mg/ml

Luxembourg




Member State EU/EEA




Content

(concentration)

Luxembourg




Malta Pfizer Hellas S.A. 243, Messoghion Ave. 154 51 Νeo Psychiko Athens Greece



Malta Pfizer Hellas S.A. 243, Messoghion Ave. 154 51 Νeo Psychiko Athens Greece



Netherlands

Pfizer bv Rivium Westlaan 142 2909 LD Capelle a/d IJssel The Netherlands

Diflucan 50 50 mg Capsule

Oral use N/A

Netherlands



Oral use N/A

Netherlands



Oral use N/A

Netherlands



Oral use N/A

Netherlands

Pfizer bv Rivium Westlaan 142

Diflucan suspensie 50 50 mg/5ml Powder for Suspension

Oral use 10 mg/ml

Member State EU/EEA




Content

(concentration)

2909 LD Capelle a/d IJssel The Netherlands

Netherlands


Diflucan suspensie 200 200 mg/5ml Powder for Suspension

Oral use 40 mg/ml

Netherlands


Diflucan I.V. 2 mg/ml Solution for Infusion


Norway

Pfizer AS Pb. 3 1324 Lysaker Norway


Oral use N/A

Norway



Oral use N/A

Norway



Oral use N/A

Norway



Oral use N/A

Norway


Diflucan 50 mg/5ml Powder for Oral Suspension

Oral use 10 mg/ml

Norway Pfizer AS Diflucan 200 mg/5ml Powder for Oral Oral use 40 mg/ml

Member State EU/EEA




Content

(concentration)

Pb. 3 1324 Lysaker Norway

Suspension

Norway




Poland

Pfizer Europe MA EEIG Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom

Diflucan 50 mg Capsule,

Oral use N/A

Poland


Diflucan 150 mg Capsule,

Oral use N/A

Poland




Portugal

Laboratorios Pfizer, Lda. Lagoas Park Edifício 10 2740-271 Porto Salvo Portugal


Oral use N/A

Portugal

Laboratorios Pfizer, Lda. Lagoas Park


Oral use N/A

Member State EU/EEA




Content

(concentration)

Edifício 10 2740-271 Porto Salvo Portugal

Portugal



Oral use N/A

Portugal

Laboratorios Pfizer, Lda., Lagoas Park Edifício 10 2740-271 Porto Salvo Portugal


Oral use N/A

Portugal


Diflucan 10 mg/ml Powder for oral Suspension

Oral use 10 mg/ml

Portugal


Diflucan 40 mg/ml Powder for oral Suspension

Oral use 40 mg/ml

Portugal




Romania

Pfizer Europe MA EEIG Ramsgate Road Sandwich Kent


Oral use N/A

Member State EU/EEA




Content

(concentration)

CT13 9NJ, United Kingdom

Romania



Oral use N/A

Romania


Diflucan 50 mg/5 ml 50 mg/5ml Powder for oral Suspension

Oral use 10 mg/ml

Romania


Diflucan 2mg/ml 2 mg/ml Solution for Infusion


Slovak Republic


Diflucan 50 mg 50 mg Capsule

Oral use N/A

Slovak Republic



Oral use N/A

Member State EU/EEA




Content

(concentration)

Slovak Republic



Oral use N/A

Slovak Republic


Diflucan P.O .S. 50 mg/5ml


Oral use 10 mg/ml

Slovak Republic


Diflucan P.O .S. 200 mg/5ml


Oral use 40 mg/ml

Slovak Republic


Diflucan IV 2 mg/ml 2 mg/ml Solution for Intravenous Infusion


Slovenia

Pfizer Luxembourg SARL 51, Avenue J. F. Kennedy L-1855 Luxembourg, Luxembourg

Diflucan 50 mg trde kapsule

50 mg Capsule, Hard

Oral use N/A

Slovenia




Oral use N/A

Member State EU/EEA




Content

(concentration)

Slovenia




Oral use N/A

Slovenia


Diflucan 10 mg/ ml prašek za peroralno suspenzijo

10 mg/ml Powder for Suspension

Oral use 10 mg/ml

Slovenia


Diflucan 40 mg/ml prašek za peroralno suspenzijo

40 mg/ml Powder for Suspension

Oral use 40 mg/ml

Slovenia


Diflucan 2 mg/ml raztopina za infundiranje



Spain

Vinci Farma, S.A. (Grupo Pfizer) Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Spain

Diflucan 50 mg cápsulas duras

50 mg Capsule, Hard

Oral use N/A

Spain




Oral use N/A

Spain

Vinci Farma, S.A. (Grupo Pfizer)



Oral use N/A

Member State EU/EEA




Content

(concentration)

Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid) Spain

Spain




Oral use N/A

Spain


Diflucan 50 mg/5 ml polvo para suspensión oral

50 mg/5ml Powder for Suspension

Oral use 10 mg/ml

Spain


Diflucan 200 mg/5 ml polvo para suspensión oral

200 mg/5ml Powder for Suspension

Oral use 40 mg/ml

Spain

Vinci Farma, S.A. (Grupo Pfizer) Avda. de Europa 20B Parque Empresarial la Moraleja 28108 Alcobendas, (Madrid)

Diflucan 2 mg/ml solución para perfusión



Member State EU/EEA




Content

(concentration)

Spain Sweden

Pfizer AB 191 90 Sollentuna Sweden


Oral use N/A

Sweden



Oral use N/A

Sweden



Oral use N/A

Sweden



Oral use N/A

Sweden



Oral use 10 mg/ml

Sweden



Oral use 40 mg/ml

Sweden




United Kingdom



Oral use N/A

United Kingdom

Pfizer Limited Ramsgate Road Sandwich


Oral use N/A

Member State EU/EEA




Content

(concentration)

Kent CT13 9NJ United Kingdom

United Kingdom



Oral use N/A

United Kingdom



Oral use 10 mg/ml

United Kingdom



Oral use 40 mg/ml

United Kingdom




ANNEX II

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

PRESENTED BY THE EUROPEAN MEDICINES AGENCY

Scientific conclusions

Overall summary of the scientific evaluation of Diflucan and associated names (see Annex I)

Fluconazole is a substance belonging to the chemical class of triazole derivatives. Fluconazole specifically inhibits the fungal ergosterol synthesis and the mycotic cytochrome P-450 mediated enzymes. Fluconazole displays antifungal activity against most clinically common Candida species. Fluconazole also exhibits activity in vitro against Cryptococcus species. Fluconazole, a third generation azole, is characterised by high oral bioavailability, widespread distribution into body fluids and tissues, predictable renal clearance, and once-daily administration. The solubility characteristic allows oral as well as intravenous administration. Since the pharmacokinetic properties of orally and intravenously administered fluconazole are similar and fluconazole has good bioavailability, results obtained with oral dosing are also applicable to the intravenous formulation.

Fluconazole is available for oral use in the 50 mg, 100 mg, 150 mg and 200 mg capsule formulation, in the 5 mg/mL syrup formulation, and in the 50 mg or 200 mg/5 mL powder for oral suspension on reconstitution with water formulation. As the treatment of genital candidiasis requires a single 150 mg dose of fluconazole, a convenient presentation containing a single 150 mg fluconazole capsule is available in some Member States (MSs) only for the indication of genital candidiasis, more specifically for the treatment of acute vaginal candidiasis and candidal balanitis.

Fluconazole is available also for intravenous (IV) use in the 2 mg/mL saline solution formulation.

Furthermore, fluconazole was also available for topical use in the 0.5% gel formulation. This formulation was only approved in Italy and was indicated for the treatment of dermatomycoses due to dermatophytes, yeasts and moulds. During the time of the evaluation of the procedure the Marketing Authorisation Holder (MAH) voluntarily withdrew the gel formulation from the European Market. Thus the outcome of this referral procedure does not include any evaluation of the gel formulation.

Diflucan has been included in the list of products for Summary of Product Characteristics (SPC) harmonisation in accordance with Article 30(2) of Directive 2001/83/EC, as amended. Due to the divergent national decisions taken by Member States concerning the authorisation of the above-mentioned products (and its associated names), the European Commission notified the CHMP/EMA Secretariat of an official referral under Article 30 of Directive 2001/83/EC as amended in order to resolve divergences amongst the nationally authorised SPCs and thus to harmonise its divergent SPCs across the European Union.

Section 4.1 – Therapeutic Indications

50 mg, 100 mg, 150 mg and 200 mg capsule, 5 mg/mL syrup, 50 mg/5mL or 200 mg/5 mL powder for oral suspension, 2 mg/mL solution for infusion.

The CHMP assessed the Product Information of the product taking into account the current national ones and the existing scientific knowledge and discussed the indications for each individual medical condition. The prophylactic use of Diflucan, as distinct from the treatment indications was also discussed and justified. In addition the paediatric indications have been clarified.

In all the mycosal candidiasis studies fluconazole was efficacious and equivalent or superior to the standard agents in both adults and paediatric patients. It was also generally well tolerated and there were no changes of clinical significance at doses of up to and including 400 mg/day. The results are

supportive of fluconazole as an appropriate treatment for mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and chronic mucocutaneous candidiasis. The CHMP agreed that fluconazole should be indicated for the treatment of chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical treatment are insufficient.

The indication of relapse prevention in immunocompromised (HIV and cancer) patients was investigated. Several different dosing regimens were employed, 100 mg/day, 200 mg/day and 200 mg three times/week. In all studies fluconazole was as or more effective than placebo in preventing clinical relapse. In cancer patients it was superior to placebo in preventing mycological relapse. The CHMP concluded that continuous therapy with fluconazole at 100 mg/day and continuous or intermittent therapy at 200 mg/day are effective in preventing relapse of oropharyngeal or oesophageal candidiasis in immunocompromised patients and are well tolerated. The CHMP is in agreement in separating the treatment from the prophylaxis of the relapse on Oropharyngeal Candidiasis and presenting the posology accordingly.

Candidal infection of male and female genital areas is relatively common and responds well to an oral administration of fluconazole. Fluconazole is approved to treat acute or recurrent vulvovaginal candidiasis in women and candidal balanitis in men. Fluconazole is also used as maintenance therapy (prophylaxis) for prevention of the recurrence of vaginal candidiasis. Oral single-dose therapy with fluconazole in vaginal candidiasis and candidal balanitis has been a treatment option for around 30 years. The evidence is based on a clinical trial programme of three studies in vulvovaginal candidiasis and one in candidal balanitis. In addition, the pharmacokinetic profile of fluconazole enables its use as a single agent due to its prolonged elimination half-life of approximately 36 hours and its distribution into vaginal tissues and secretions, with concentrations above the minimum inhibitory concentration for C. albicans persisting for at least 72 hours. Overall, therefore, a single 150 mg dose of fluconazole provides a safe and effective treatment for vulvovaginal candidiasis in adult women or candidal balanitis in adult men. The CHMP concluded that fluconazole with its activity against Candida species and its pharmacokinetics offers a safe, effective, and convenient alternative to topical therapy in a single-dose regimen for both candidal vaginitis and candidal balanitis in adults as well as for the prevention of the recurrence of vaginal candidiasis. The CHMP accepted that the data presented by the MAH was satisfactory for these indications.

Endemic mycoses remain a major public health problem in several countries and they are becoming increasingly frequent with the spread of HIV infection. Coccidioidomycosis is a disease with protean manifestations. The incidences in the endemic areas of these fungal infections are increasing and the population travelling toward its specific endemic regions in the United States and Southern America is growing. Fluconazole therapy is efficacious for several deep mycoses and this is supported by clinical trial data and recommended by clinical guidelines. The CHMP concluded that the fluconazole, at 400 mg to 800 mg daily is a safe and effective primary treatment for coccidioidomycosis. It was also agreed by the CHMP that the MAH provided sufficient data on the efficacy and safety of fluconazole in invasive fungal infections (cryptococcosis, invasive candidiasis) as compared to other therapeutic options and demonstrated a favourable benefit/risk ratio. The use of fluconazole for the above indications is also supported by the Infectious Diseases Society of America (IDSA) guidelines. For the indications of paracoccidioidomycosis, histoplasmosis, lymphocutaneous sporotrichosis, where other agents have failed or are not tolerated, it was deemed by the CHMP that the submitted data on efficacy was not adequate. So these indications are no longer referred to in section 4.1 of the SPC and a warning has been added in the corresponding section.

Dermatomycoses include Tinea pedis, Tinea corporis, Tinea cruris, Tinea versicolor, Tinea unguinium (onychomycosis) and dermal Candida infections. The use of fluconazole for the treatment of fungal skin infections was examined in several comparative and non-comparative studies. These studies demonstrated that oral fluconazole is an effective and well-tolerated antimycotic agent against Tinea corporis, Tinea cruris, Tinea pedis, Tinea versicolor and onychomycosis. For Tinea unguinium

(onychomycosis) it was concluded that fluconazole is indicated only when other agents are not considered appropriate. The CHMP is in agreement on the final wording of the indication.

Cryptococcal meningitis is caused by the fungus Cryptococcus neoformans. Although C. neoformans typically infects immunocompromised persons, patients with no apparent immune system problems also develop cryptococcosis. Fluconazole has demonstrated in vitro and in vivo efficacy against Cryptococcus neoformans and providing clinicians with a treatment option that is less toxic than amphotericin B. Fluconazole has been established as a safe and effective antifungal therapy in healthy and immunocompromised patients with cryptococcal meningitis and there are clinical data supporting fluconazole as treatment in children and adults. The CHMP accepted that the supporting data were only for the indication of cryptococcal meningitis which was implemented in the SPC and not the general cryptococcosis indication.

Fluconazole has proven to be safe and efficacious for invasive candidiasis. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia; however, drug-related adverse events were more frequent with amphotericin B. The CHMP concluded that fluconazole is a safe and effective medicinal product in prophylaxis or treatment for invasive candidiasis compared to other therapies. This indication does not make any more reference to individual forms of invasive candidal infections.

Invasive Candida infections have become common and life threatening complications in patients with leukaemia, cancer, hematologic malignancies and patients with bone marrow transplantation. Neutropenic patients are at especially high risk for candidemia. Antifungal agents are being used in many prophylactic settings, but only a few studies have adequately evaluated their efficacy. The original applications for the prevention of fungal infections indication included seven comparative clinical studies in which 755 patients received oral fluconazole, 383 patients placebo and 374 patients oral comparative agents. The majority of patients began antifungal prophylaxis prior to undergoing a period of induced neutropenia through chemo- or radiotherapy for malignant disease or bone marrow transplantation. Overall, the use of fluconazole as a prophylaxis agent to prevent breakthrough fungal infections in neutropenic patients was established in the original application.

Moreover fluconazole has become established as a standard treatment for the prevention of breakthrough infections in neutropenic patients. Recently, the Infectious Diseases Society of America (IDSA: Pappas et al 2009) published updated guidance for use of antifungal agents including the prevention indication where fluconazole is recommended for prevention. The CHMP agreed with the submitted data and accepted that fluconazole is efficient for the prophylaxis of candidal infections in patients with prolonged neutropenia.

Paediatric Use An EU work sharing project-Assessment of Paediatric data took place in 2005-2006. Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-doses studies, 2 multiple-dose studies, and a study in premature neonates. Additional data were available from a compassionate use study (EU, 2006). The proposed text for the pharmokinetics in children is the wording that was agreed during the EU work sharing project.

Fluconazole is effective as a treatment against fungal infections in adults across the dose range recommended in national SPCs (50-400 mg daily). In the paediatric population fluconazole is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), systemic candidiasis and cryptococcal infections and the prevention of fungal infection in at-risk immunocompromised children following cytotoxic chemotherapy or radiotherapy.

Mucosal candidiasis (Oropharyngeal and oesophageal) in children Acute oral candidiasis may occur in up to 5% of newborn infants. It is most often associated with severe immunological impairment due to diabetes mellitus, leukaemia, lymphoma, malignancy, neutropenia and HIV infection where it presents as a predictor of clinical progression to AIDS. The use of broad-spectrum antibiotics, corticosteroids, cytotoxic drugs, and radiation therapy are also predisposing factors. Oropharyngeal candidiasis (OPC) continues to be one of the most frequent opportunistic infections in HIV-infected children during the Highly Active Anti-Retroviral Therapy (HAART) era (28% of children), with an incidence rate of 0.93 per 100 child-years.

Oesophageal candidiasis is primarily associated with HIV infection or other forms of immunosuppression in children. The incidence of oesophageal candidiasis is around 0.08 per 100 child-years after introduction of HAART in around 2001. Candida oesophagitis continues to be seen in children who are not responding to antiretroviral therapy. Risk factors for oesophageal candidiasis in children with HIV infection include low CD4 count (<100 cells/mm3), high viral load, and neutropenia (<500 cells/mm3). Systemic therapy is essential for oesophageal disease and should be initiated empirically among HIV-infected children who have OPC and oesophageal symptoms. In most patients, symptoms should resolve within days after the start of effective therapy. Oral or IV fluconazole solutions, administered for 14–21 days, are highly effective for treatment of Candida oesophagitis.

The CHMP agreed that the data available are sufficient for the safe and efficacious use of fluconazole for the treatment and prevention of the mycosal (oropharyngeal and oesophageal) candidiasis in children.

Invasive candidiasis in children Disseminated candidiasis is infrequent among HIV-infected children, but Candida can disseminate from the oesophagus particularly when co-infection with herpes simplex virus (HSV) or cytomegalovirus (CMV) is present. Candidemia occurs in up to 12% of HIV-infected children with chronically indwelling central venous catheters for total parental nutrition or intravenous antibiotics. Fluconazole has been used to treat invasive candida infections in children. Treatment of invasive candidiasis requires higher doses of fluconazole than are used for mucocutaneous disease. Alternatively, an initial course of amphotericin B therapy can be administered and then carefully followed by completion of a course of fluconazole therapy. Fluconazole administered to children at 12 mg/Kg/day provides exposure similar to standard 400 mg daily dosing in adults and higher doses are not recommended in children. The CHMP considered that the treatment of invasive candidiasis in children is sufficiently demonstrated.

Cryptococcal infections in children Cryptococcosis is a defining opportunistic infection for AIDS. Other conditions which pose an increased risk include certain lymphomas (e.g. Hodgkin's lymphoma), sarcoidosis, and patients on long-term corticosteroid therapy. Cryptococcal infections are more likely to occur in association with HIV disease, however, cryptococcal infections occur much less frequently among HIV-infected children than among adults. Fluconazole is used to treat paediatric patients with cryptococcal disease. As per the adult indication the CHMP agreed that there is sufficient evidence for the indication of treatment as well of prevention of relapse of cryptococcal meningitis in children.

Prophylaxis of candidal infections in immunocompromised children

Data supporting the indication for fluconazole prevention of fungal infection in immunocompromised patients in the paediatric International Registration Dossier (1993) were derived from three studies in

children; one study determined the efficacy of fluconazole versus nystatin therapy alone, one study versus oral polyenes (nystatin or amphotericin B) and the third study versus ketoconazole. Fluconazole, administered at doses of 1 mg/Kg/day and 3 mg/Kg/day was more effective than the active comparator at preventing fungal infections. The dose of fluconazole recommended for prevention of fungal infections in adults is 50-400 mg and using the algorithm above results in a dose recommendation in children of 3-12 mg/Kg. The CHMP agreed that fluconazole is indicated in the prophylaxis of candidal infections in immunocompromised children.

Finally and summarising here the CHMP adopted the following sets of indications for Diflucan and associated names for capsules (50mg, 100mg, 150mg, 200mg), solution for infusion (IV), syrup, powder for oral suspension.

Diflucan (fluconazole) is indicated in the following fungal infections (see section 5.1). Diflucan is indicated in adults for the treatment of: Cryptococcal meningitis (see section 4.4). Coccidioidomycosis (see section 4.4). Invasive candidiasis. Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and

chronic mucocutaneous candidiasis. Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical treatment

are insufficient. Vaginal candidiasis, acute or recurrent; when local therapy is not appropriate. Candidal balanitis when local therapy is not appropriate. Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and

dermal candida infections when systemic therapy is indicated. Tinea unguinium (onychomycosis) when other agents are not considered appropriate.

Diflucan is indicated in adults for the prophylaxis of:

Relapse of cryptococcal meningitis in patients with high risk of recurrence. Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at

high risk of experiencing relapse. To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year). Prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients

with haematological malignancies receiving chemotherapy or patients receiving Hematopoietic Stem Cell Transplantation (see section 5.1)).

Diflucan is indicated in term newborn infants, infants, toddlers, children, and adolescents aged from 0 to 17 years old: Diflucan is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in immunocompromised patients. Diflucan can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of reoccurrence (see section 4.4). Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. Consideration should be given to official guidance on the appropriate use of antifungals.

For the 150 mg, one capsule presentation

The indication of the genital candidiasis and more specifically the vulvovaginal candidiasis in adult women and the candidal balanitis in adult men was authorised in some MS for the 150 mg, one capsule presentation due to the convenience of one dose treatment. The CHMP accepted that the data presented by the MAH was satisfactory for these indications. However as the first line treatment of this candidiasis is the topical application, the one 150 mg capsule presentation is specifically indicated for the above genital candidiasis indications in adults when local therapy is not appropriate.

For the one 150 mg capsule presentation the section 4.1 of the SPC is agreed by the CHMP as follows:

Diflucan (fluconazole) is indicated in the following fungal infections in adults (see section 5.1):

Acute vaginal candidiasis when local therapy is not appropriate. Candidal balanitis when local therapy is not appropriate.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. Consideration should be given to official guidance on the appropriate use of antifungals.

Section 4.2 - Posology and method of administration In Member States there were differences in the posology of various infections, e.g. for individual mucosal candida infections. The same situation appeared for cryptococcosis/prevention of cryptococcal infections, for invasive candidiasis or vaginal candidiasis. There were also differences in the wording on the dosage recommendation for adolescents and children regarding all indications.

In order to harmonise the posology the MAH was requested to include in the posology section a table with the recommended doses regarding each indication and to distinguish between treatment and prevention. Since oral absorption is rapid and almost complete, the doses of fluconazole recommended for the treatment and/or the prophylaxis of the different indications are the same for oral (capsules, oral suspension and syrup) and IV administration. Based on the submitted data the CHMP agreed on the dosing recommendations for each indication.

Paediatric population The pharmacokinetic profile of fluconazole in children has a well understood relationship to that in adults when volume of distribution and clearance are taken into account. This results in a dosing regimen in children that is equivalent to that in adults. Doses of 3 mg/Kg in children have proved effective against fungal infections in immunocompromised children and also for the treatment of paediatric patients with serious fungal infections, such as cryptococcal meningitis.

The CHMP noted that adolescent posology had been omitted; none of the national SPCs described the posology for this age group. Following questions raised by the CHMP the MAH provided a posology for this specific age group based on the “Guideline on the role of pharmacokinetics in the development of medicinal product in the paediatric population, 2006.”

Furthermore the CHMP is of the opinion, that the safety and efficacy for indication of genital candidiasis has not been established in the paediatric population as all available data in children and adolescents are from studies in other indications rather than genital candidiasis. However in very rare

cases treatment in adolescents is imperative (i.e. no other (especially local) treatment option is appropriate) and these cases should not be totally excluded from treatment. So, the final wording in section 4.2 of the SPC regarding this indication reflects the CHMP discussion in all formulations including the 150 mg, one capsule presentation.

In the final approved text of the section 4.2 of the SPC the doses in the paediatric population have been divided in age groups of Infant, toddler and children (28 days to 11 years old), adolescents (12 years to 17 years old) and term newborn infants (0 to 27 days old).

Section 4.4 - Special warnings and precaution for use There are differences between all Member States concerning the individual paragraphs in this section. In general the Core Safety Profile, dated 2 April 2009 was considered.

A warning on tinea capitis and the fact that should not be used in children has been added.

Regarding cryptococcosis the evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited.

In the case of deep endemic mycoses the evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis was limited and they are no longer mentioned in the section 4.1 of the PI. So a warning has been added in this section.

For patients with renal impairment a warning has been added with a cross reference to the posology section of 4.2 in this patient population.

The warning on the effect on the cardiovascular system and the association with prolongation of the QT interval on the electrocardiogram has been reinforced. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated. Moreover halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended. More extensive information has been added in section 4.5 of the SPC.

A warning on hypersensitivity reactions has been added as per other azoles.

As fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor and fluconazole is also an inhibitor of CYP2C19, treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored.

All the above changes were accepted by the CHMP and apply to all formulations.

Section 4.5 - Interaction with other medicinal products and other forms of interaction

The CHMP noted the MAH proposal and adopted a harmonised text for this section. The inclusion of substances for which an involvement of CYP 3A4 and additive negative effects on QT interval prolongation is known (such as halofantrine, midazolam and triazolam) is justified.

The inclusion of the wording on the interaction of itraconazole (another triazole) in the PI of saquinavir and taking into account the recent labelling changes for saquinavir (contraindication for concomitant administration with other QTc interval prolonging drugs) was amended. Concomitant use

of fluconazole with saquinavir was contraindicated accordingly with a cross reference to section 4.3 of the PI. Concomitant use of fluconazole with saquinavir was contraindicated accordingly with a cross reference to section 4.3 of the PI. All the above changes were accepted by the CHMP and apply to all formulations.

Section 4.8 - Undesirable effects

The CHMP noted the MAH proposal and adopted a harmonised text for this section, applicable to all Diflucan formulations. The Core Safety Profile was considered when harmonising the listed adverse reactions between national SPCs of Diflucan. The general text of frequencies classification, and the adverse reaction obtained from post-marketing experience were clarified, and the frequency of a number of events was revised. The method and the statistical approach together with the data provided were reviewed and the CHMP considered the estimated frequency to be appropriate.

Section 5.1 - Pharmacodynamic properties This section was partly restructured according to guidelines. Subheadings like Mode of action, PK/PD relationship, Mechanism(s) of resistance and Breakpoints (according to European Committee of Antimicrobial Succeptibility Testing - EUCAST) were implemented.

Other Sections of the SPC The MAH was asked to evaluate all other sections of the nationally approved SPCs and suggest appropriate changes in the text where divergences exist. In addition minor typographic errors were corrected. All these changes were accepted by the CHMP.

Package Leaflet

Following all the changes in the SPC there are several corresponding changes to the Package Leaflet After the corrections were implemented a Readability Testing was performed which was submitted and assessed during the referral procedure. The final Package Leaflet wording was adopted by the CHMP.

QUALITY – MODULE 3 The MAH submitted a proposal for harmonisation of the Quality module. Information on development, manufacture and control of capsules, powder for oral suspension, syrup and solution for infusion has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics, and these in turn lead to the conclusion that the products should have a satisfactory and uniform performance in the clinic.

Based on the review of data the CHMP adopted a harmonised Module 3.

Grounds for amendment of the summary of product characteristics, labelling and package leaflet

In conclusion, based on the assessment of the MAH proposal and responses and following the discussions of the committee, the CHMP adopted harmonised sets of Product Information documents for the various presentations of Diflucan and associated names, taking into account the pharmaceutical forms. In particular, the indications and their associated posology recommendations were harmonised. A harmonised Module 3 was also adopted. Based on the above, the CHMP considers the benefit/risk ratio of Diflucan and associated names to be favourable and the harmonised Product Information documents to be approvable.

Whereas

the scope of the referral was the harmonisation of the summary of products characteristics, labelling and package leaflet

the summary of products characteristic, labelling and package leaflet proposed by the marketing authorisation holders have been assessed based on the documentation submitted and the scientific discussion within the Committee

the CHMP has recommended the amendment of the marketing authorisations for which the summary of product characteristics, labelling and package leaflet are set out in Annex III for Diflucan and associated names (see Annex I).

ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

Note: This SPC, labelling and packages leaflet is the version valid at the time of Commission decision.

After the Commission decision the Member State competent authorities, in liaison with the reference Member State, will update the product information as required. Therefore, this SPC, labelling and

package leaflet may not necessarily represent the current text.

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 150 mg hard capsules [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each hard capsule contains fluconazole 150 mg. Excipients: each hard capsule also contains 149.12 mg lactose monohydrate. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule. The 150 mg hard gelatin capsule has a turquoise blue body and turquoise blue cap overprinted with “Pfizer” and the code “FLU-150” with black ink. The capsule size is no. 1. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Diflucan is indicated in the following fungal infections in adults (see section 5.1):

Acute vaginal candidiasis when local therapy is not appropriate. Candidal balanitis when local therapy is not appropriate.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. Consideration should be given to official guidance on the appropriate use of antifungals. 4.2 Posology and method of administration Posology Adults Single dose 150 mg. Special populations Elderly Where there is no evidence of renal impairment, normal dose recommendations should be adopted. Renal impairment Fluconazole is predominantly excreted in the urine as unchanged active substance. No adjustments in single dose therapy are necessary.

Hepatic impairment Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction (see sections 4.4 and 4.8). Paediatric population Safety and efficacy for genital candidiasis indication in paediatric population has not been established. Current available data for other paediatric indications are described in section 4.8. If treatment is imperative in adolescents (from 12 to 17 years old), the posology should be the same as adults posology. Method of administration The capsules should be swallowed whole and independent of food intake. 4.3 Contraindications Hypersensitivity to the active substance, to related azole substances, or to any of the excipients (see section 6.1). Coadministration of terfenadine is contraindicated in patients receiving Diflucan at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine and erythromycin are contraindicated in patients receiving fluconazole (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Renal system Diflucan should be administered with caution to patients with renal dysfunction (see section 4.2). Hepatobiliary system Diflucan has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury. The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician. Cardiovascular system Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Diflucan. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Diflucan should be administered with caution to patients with these potentially proarrhythmic conditions. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5). Halofantrine Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5).

Dermatological reactions Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop. Hypersensitivity In rare cases anaphylaxis has been reported (see section 4.3). Cytochrome P450 Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of CYP2C19. Diflucan treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5). Terfenadine The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5). Excipients Capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of the following other medicinal products is contraindicated Cisapride: There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section 4.3). Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored. Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and astemizole is contraindicated (see section 4.3). Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsades de pointes.Coadministration of fluconazole and pimozide is contraindicated (see section 4.3).

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see section 4.3). Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3). Concomitant use of the following other medicinal products cannot be recommended: Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4). Concomitant use of the following other medicinal products lead to precautions and dose adjustments: The effect of other medicinal products on fluconazole Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered. Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs. The effect of fluconazole on other medicinal products Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see section 4.3). Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 g/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicinal products in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving

coumarin-type anticoagulants concurrently with fluconazole the prothrombin time should be carefully monitored. Dose adjustment of warfarin may be necessary. Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary. HMG CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus): Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8 fold increase in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin depending on ciclosporin concentration. Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4. Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dose adjustment of sirolimus depending on the effect/concentration measurements.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered tacrolimus should be decreased depending on tacrolimus concentration. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed. Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir with approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment of saquinavir may be necessary. Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended during coadministration. Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop.

Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Voriconazole: (CYP2C9 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole. Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. 4.6 Fertility, pregnancy and lactation

Pregnancy

Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dose in the first trimester, show no undesirable effects in the foetus. There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose mothers were treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Studies in animals have shown reproductive toxicity (see section 5.3). Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary. Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except for potentially life-threatening infections.

Breast-feeding Fluconazole passes into breast milk to reach concentrations lower than those in plasma. Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. Breast-feeding is not recommended after repeated use or after high dose fluconazole. Fertility Fluconazole did not affect the fertility of male or female rats (see section 5.3) 4.7 Effects on ability to drive and use machines No studies have been performed on the effects of Diflucan on the ability to drive or use machines. Patients should be warned about the potential for dizziness or seizures (see section 4.8) while taking Diflucan and should be advised not to drive or operate machines if any of these symptoms occur. 4.8 Undesirable effects The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash. The following adverse reactions have been observed and reported during treatment with Diflucan with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). System Organ Class Common Uncommon Rare Blood and the lymphatic system disorders

Anaemia Agranulocytosis, leukopenia, thrombocytopenia, neutropenia

Immune system disorders

Anaphylaxis

Metabolism and nutrition disorders

Decreased appetite Hypercholesterolaemia, hypertriglyceridaemia, hypokalemia

Psychiatric disorders Somnolence, insomnia Nervous system disorders

Headache Seizures, paraesthesia, dizziness, taste perversion

Tremor

Ear and labyrinth disorders

Vertigo

Cardiac disorders Torsade de pointes (see section 4.4), QT prolongation (see section 4.4)

Gastrointestinal disorders

Abdominal pain, vomiting, diarrhoea, nausea

Constipation dyspepsia, flatulence, dry mouth

Hepatobiliary disorders

Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase increased (see section 4.4), blood alkaline

Cholestasis (see section 4.4), jaundice (see section 4.4), bilirubin increased (see section 4.4)

Hepatic failure (see section 4.4), hepatocellular necrosis (see section 4.4), hepatitis (see section 4.4), hepatocellular damage (see section 4.4)

phosphatase increased (see section 4.4)

Skin and subcutaneous tissue disorders

Rash (see section 4.4)

Drug eruption (see section 4.4), urticaria (see section 4.4), pruritus, increased sweating

Toxic epidermal necrolysis, (see section 4.4), Stevens-Johnson syndrome (see section 4.4), acute generalised exanthematous-pustulosis (see section 4.4), dermatitis exfoliative, angioedema, face oedema, alopecia

Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions

Fatigue, malaise, asthenia, fever

Paediatric population The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric clinical trials, excluding the genital candidiasis indication, are comparable to those seen in adults. 4.9 Overdose There have been reports of overdose with Diflucan and hallucination and paranoid behaviour have been concomitantly reported. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties ATC classification Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01. Mode of action Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems. Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Susceptibility in vitro In vitro, fluconazole displays antifungal activity against most clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to fluconazole. Fluconazole also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis. PK/PD relationship In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candida spp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC. Mechanism(s) of resistance Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in vivo and clinically. There have been reports of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy. Breakpoints (according to EUCAST) Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below: Antifungal Species-related breakpoints (S</R>) Non-species

related breakpointsA S</R>

Candida albicans

Candida glabrata

Candida krusei

Candida parapsilosis

Candida tropicalis

Fluconazole 2/4 IE -- 2/4 2/4 2/4 S = Susceptible, R = Resistant A. = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints. -- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product. IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product. 5.2 Pharmacokinetic properties The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route.

http://217.70.33.99/Eucast2/SearchController/search.jsp?action=performSearch&BeginIndex=0&Micdif=mic&NumberIndex=50&Antib=150&Specium=-1

Absorption After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. Distribution The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%). Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels. High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g. Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy. Biotransformation Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also an inhibitor of the isozyme CYP2C19. Excretion Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Pharmacokinetics in renal impairment In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood. Pharmacokinetics in children Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study. After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 µgh/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found

after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg. Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13. Pharmacokinetics in elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µgh/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 h, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use. Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Reproductive toxicity Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg. There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. These effects on parturition are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see section 5.1). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule content: Lactose monohydrate

Maize starch Colloidal silica anhydrous Magnesium stearate Sodium laurilsulfate Capsule shell composition: Gelatin Titanium dioxide (E171) Patent blue V (E131) Printing ink: Shellac (glaze), black iron oxide, N-Butyl alcohol, dehydrated alcohol, purified water, propylene glycol, industrial methylated spirit, isopropyl alcohol, strong ammonia solution, potassium hydroxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 5 years 6.4 Special precautions for storage Store below 30°C. 6.5 Nature and contents of container 150 mg capsules: clear PVC blister packs or white opaque PVC/PVDC blister packs with aluminium foil backing. Each pack contains 1 hard capsule. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally]

10. DATE OF REVISION OF THE TEXT [To be completed nationally] Detailed information on this medicinal product is available on the website of {name of MS/Agency} [To be completed nationally]

1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 50 mg hard capsules Diflucan and associated names (see Annex I) 100 mg hard capsules Diflucan and associated names (see Annex I) 150 mg hard capsules Diflucan and associated names (see Annex I) 200 mg hard capsules [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each hard capsule contains fluconazole 50 mg Excipients: each hard capsule also contains 49.70 mg lactose monohydrate Each hard capsule contains fluconazole 100 mg Excipients: each hard capsule also contains 99.41 mg lactose monohydrate Each hard capsule contains fluconazole 150 mg Excipients: each hard capsule also contains 149.12 mg lactose monohydrate Each hard capsule contains fluconazole 200 mg Excipients: each hard capsule also contains 198.82 mg lactose monohydrate For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule. The 50 mg hard gelatin capsule has a white body and a turquoise blue cap overprinted with “Pfizer” and the code “FLU-50” with black ink. The capsule size is no. 4. The 100 mg hard gelatin capsule has a white body and blue cap overprinted with “Pfizer” and the code “FLU-100” with black ink. The capsule size is no. 2. The 150 mg hard gelatin capsule has a turquoise blue body and turquoise blue cap overprinted with “Pfizer” and the code “FLU-150” with black ink. The capsule size is no. 1. The 200 mg hard gelatin capsule has a white body and a purple cap overprinted with “Pfizer” and the code “FLU-200” with black ink. The capsule size is no. 0. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Diflucan is indicated in the following fungal infections (see section 5.1). Diflucan is indicated in adults for the treatment of:

Cryptococcal meningitis (see section 4.4). Coccidioidomycosis (see section 4.4). Invasive candidiasis. Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and

chronic mucocutaneous candidiasis.

Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical treatment are insufficient.

Vaginal candidiasis, acute or recurrent; when local therapy is not appropriate. Candidal balanitis when local therapy is not appropriate. Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and






Diflucan is indicated in term newborn infants, infants, toddlers, children, and adolescents aged from 0 to 17 years old: Diflucan is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in immunocompromised patients. Diflucan can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of reoccurrence (see section 4.4). Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. Consideration should be given to official guidance on the appropriate use of antifungals. 4.2 Posology and method of administration Posology The dose should be based on the nature and severity of the fungal infection. Treatment of infections requiring multiple dosing should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Adults Indications Posology Duration of treatment

- Treatment of cryptococcal meningitis.

Loading dose: 400 mg on Day 1 Subsequent dose: 200 mg to 400 mg daily

Usually at least 6 to 8 weeks. In life threatening infections the daily dose can be increased to 800 mg

Cryptococcosis

- Maintenance therapy to prevent relapse of cryptococcal meningitis in patients with high risk of recurrence.

200 mg daily Indefinitely at a daily dose of 200 mg

Coccidioidomycosis 200 mg to 400 mg 11 months up to 24 months or longer depending on the patient. 800 mg daily may be considered for some infections and especially for meningeal disease

Invasive candidiasis Loading dose: 800 mg on Day 1 Subsequent dose: 400 mg daily

In general, the recommended duration of therapy for candidemia is for 2 weeks after first negative blood culture result and resolution of signs and symptoms attributable to candidemia.

- Oropharyngeal candidiasis

Loading dose: 200 mg to 400 mg on Day 1 Subsequent dose: 100 mg to 200 mg daily

7 to 21 days (until oropharyngeal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function

- Oesophageal candidiasis


14 to 30 days (until oesophageal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function

- Candiduria 200 mg to 400 mg daily

7 to 21 days. Longer periods may be used in patients with severely compromised immune function.

- Chronic atrophic candidiasis

50 mg daily 14 days

Treatment of mucosal candidiasis

- Chronic mucocutaneous candidiasis

50 mg to 100 mg daily

Up to 28 days. Longer periods depending on both the severity of infection or underlying immune compromisation and infection


100 mg to 200 mg daily or 200 mg 3 times per week

An indefinite period for patients with chronic immune suppression

Prevention of relapse of mucosal candidiasis in patients infected with HIV who are at high risk of experiencing relapse




Genital candidiasis

- Acute vaginal candidiasis - Candidal balanitis

150 mg

Single dose

- Treatment and prophylaxis of recurrent vaginal candidiasis (4 or more episodes a year).

150 mg every third day for a total of 3 doses (day 1, 4, and 7) followed by 150 mg once weekly maintenance dose

Maintenance dose: 6 months.

- tinea pedis, - tinea corporis, - tinea cruris, - candida infections

150 mg once weekly or 50 mg once daily

2 to 4 weeks, tinea pedis may require treatment for up to 6 weeks

300 mg to 400 mg once weekly

1 to 3 weeks - tinea versicolor

50 mg once daily 2 to 4 weeks

Dermatomycosis

- tinea unguium (onychomycosis)

150 mg once weekly

Treatment should be continued until infected nail is replaced (uninfected nail grows in). Regrowth of fingernails and toenails normally requires 3 to 6 months and 6 to 12 months, respectively. However, growth rates may vary widely in individuals, and by age. After successful treatment of long-term chronic infections, nails occasionally remain disfigured.

Prophylaxis of candidal infections in patients with prolonged neutropenia

200 mg to 400 mg Treatment should start several days before the anticipated onset of neutropenia and continue for 7 days after recovery from neutropenia after the neutrophil count rises above 1000 cells per mm3.

Special populations Elderly Dosage should be adjusted based on the renal function (see “Renal impairment”). Renal impairment No adjustments in single dose therapy are necessary. In patients (including paediatric population) with impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to 400 mg should be given, based on the recommended daily dose for the indication. After this initial loading dose, the daily dose (according to indication) should be based on the following table: Creatinine clearance (ml/min) Percent of recommended dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.

Hepatic impairment Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction (see sections 4.4 and 4.8). Paediatric population A maximum dose of 400 mg daily should not be exceeded in paediatric population. As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Diflucan is administered as a single daily dose. For paediatric patients with impaired renal function, see dosing in “Renal impairment”. The pharmacokinetics of fluconazole has not been studied in paediatric population with renal insufficiency (for “Term newborn infants” who often exhibit primarily renal immaturity please see below). Infants, toddlers and children (from 28 days to 11 years old):

Indication Posology Recommendations - Mucosal candidiasis Initial dose: 6 mg/kg

Subsequent dose: 3 mg/kg daily Initial dose may be used on the first day to achieve steady state levels more rapidly

- Invasive candidiasis - Cryptococcal meningitis

Dose: 6 to 12 mg/kg daily Depending on the severity of the disease

- Maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of recurrence

Dose: 6 mg/kg daily Depending on the severity of the disease

- Prophylaxis of Candida in immunocompromised patients

Dose: 3 to 12 mg/kg daily Depending on the extent and duration of the induced neutropenia (see Adults posology)

Adolescents (from 12 to 17 years old): Depending on the weight and pubertal development, the prescriber would need to assess which posology (adults or children) is the most appropriate. Clinical data indicate that children have a higher fluconazole clearance than observed for adults. A dose of 100, 200 and 400 mg in adults corresponds to a 3, 6 and 12 mg/kg dose in children to obtain a comparable systemic exposure. Safety and efficacy for genital candidiasis indication in paediatric population has not been established. Current available safety data for other paediatric indications are described in section 4.8. If treatment for genital candidiasis is imperative in adolescents (from 12 to 17 years old), the posology should be the same as adults posology. Term newborn infants (0 to 27 days): Neonates excrete fluconazole slowly. There are few pharmacokinetic data to support this posology in term newborn infants (see section 5.2).

Age group Posology Recommendations Term newborn infants (0 to 14 days)

The same mg/kg dose as for infants, toddlers and children should be given every 72 hours

A maximum dose of 12 mg/kg every 72 hours should not be exceeded

Term newborn infants (from 15 to 27 days)



Method of administration Diflucan may be administered either orally or by intravenous infusion, the route being dependent on the clinical state of the patient. On transferring from the intravenous to the oral route, or vice versa, there is no need to change the daily dose. The capsules should be swallowed whole and independent of food intake. 4.3 Contraindications Hypersensitivity to the active substance, to related azole substances, or to any of the excipients (see section 6.1). Coadministration of terfenadine is contraindicated in patients receiving Diflucan at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine and erythromycin are contraindicated in patients receiving fluconazole (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Tinea capitis Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, Diflucan should not be used for tinea capitis. Cryptococcosis The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations. Deep endemic mycoses The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations. Renal system Diflucan should be administered with caution to patients with renal dysfunction (see section 4.2). Hepatobiliary system Diflucan should be administered with caution to patients with liver dysfunction. Diflucan has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury. The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician. Cardiovascular system Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Diflucan. These reports included seriously ill

patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Diflucan should be administered with caution to patients with these potentially proarrhythmic conditions. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5). Halofantrine Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5). Dermatological reactions Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop. Hypersensitivity In rare cases anaphylaxis has been reported (see section 4.3). Cytochrome P450 Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of CYP2C19. Diflucan treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5). Terfenadine The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5). Excipients Capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of the following other medicinal products is contraindicated: Cisapride: There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section 4.3). Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and astemizole is contraindicated (see section 4.3). Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and pimozide is contraindicated (see section 4.3). Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see section 4.3). Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3). Concomitant use of the following other medicinal products cannot be recommended: Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4). Concomitant use of the following other medicinal products lead to precautions and dose adjustments: The effect of other medicinal products on fluconazole Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered. Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs. The effect of fluconazole on other medicinal products Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see section 4.3). Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 g/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4.Dose adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary

Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicinal products in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type anticoagulants concurrently with fluconazole the prothrombin time should be carefully monitored. Dose adjustment of warfarin may be necessary. Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary. HMG CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus): Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin depending on ciclosporin concentration. Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4. Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dose adjustment of sirolimus depending on the effect/concentration measurements. Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered tacrolimus should be decreased depending on tacrolimus concentration. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed. Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir with approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-

glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment of saquinavir may be necessary. Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended during coadministration. Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop. Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Voriconazole: (CYP2C9 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole. Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. 4.6 Fertility, pregnancy and lactation Pregnancy Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dose in the first trimester, show no undesirable effects in the foetus. There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose mothers were

treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Studies in animals have shown reproductive toxicity (see section 5.3). Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary. Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except for potentially life-threatening infections. Breast-feeding Fluconazole passes into breast milk to reach concentrations lower than those in plasma. Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. Breast-feeding is not recommended after repeated use or after high dose fluconazole. Fertility Fluconazole did not affect the fertility of male or female rats (see section 5.3) 4.7 Effects on ability to drive and use machines No studies have been performed on the effects of Diflucan on the ability to drive or use machines. Patients should be warned about the potential for dizziness or seizures (see section 4.8) while taking Diflucan and should be advised not to drive or operate machines if any of these symptoms occur. 4.8 Undesirable effects The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash. The following adverse reactions have been observed and reported during treatment with Diflucan with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). System Organ Class Common Uncommon Rare Blood and the lymphatic system disorders



Anaphylaxis





Tremor


Vertigo


Gastrointestinal Abdominal pain, Constipation

disorders vomiting, diarrhoea, nausea

dyspepsia, flatulence, dry mouth


Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase increased (see section 4.4), blood alkaline phosphatase increased (see section 4.4)








Myalgia



Paediatric population The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric clinical trials, excluding the genital candidiasis indication, are comparable to those seen in adults. 4.9 Overdose There have been reports of overdose with Diflucan and hallucination and paranoid behaviour have been concomitantly reported. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties ATC classification Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01. Mode of action Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of

ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems. Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism. Susceptibility in vitro In vitro, fluconazole displays antifungal activity against most clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to fluconazole. Fluconazole also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus. gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis. PK/PD relationship In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candida spp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC. Mechanism(s) of resistance Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in vivo and clinically. There have been reports of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy. Breakpoints (according to EUCAST) Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below: Antifungal Species-related breakpoints (S</R>) Non-species


Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis

Fluconazole 2/4 IE -- 2/4 2/4 2/4 S = Susceptible, R = Resistant


A = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints. -- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product. IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product 5.2 Pharmacokinetic properties The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. Absorption After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. Distribution The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%). Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels. High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g. Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy. Biotransformation Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also an inhibitor of the isozyme CYP2C19. Excretion Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Pharmacokinetics in renal impairment In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser

extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood. Pharmacokinetics in children Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study. After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 µgh/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg. Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13. Pharmacokinetics in elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µgh/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 h, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use. Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 27 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Reproductive toxicity Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg. There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification.

The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. These effects on parturition are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see section 5.1). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule content: Lactose monohydrate Maize starch Colloidal silica anhydrous Magnesium stearate Sodium laurilsulfate Capsule shell composition: 50 mg capsules Gelatin Titanium dioxide (E171) Patent blue V (E131) 100 mg capsules Gelatin Titanium dioxide (E171) Erythrosin (E127) Patent blue V (E131) 150 mg capsules Gelatin Titanium dioxide (E171) Patent blue V (E131) 200 mg capsules Gelatin Titanium dioxide (E171)) Erythrosin (E127)) Indigo carmine (E132) Printing ink: Shellac (glaze), black iron oxide, N-Butyl alcohol, dehydrated alcohol, purified water, propylene glycol, industrial methylated spirit, isopropyl alcohol, strong ammonia solution, potassium hydroxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 5 years 6.4 Special precautions for storage Store below 30°C.

6.5 Nature and contents of container 50 mg and 150 mg capsules: clear PVC blister packs or white opaque PVC/PVDC blister packs with aluminium foil backing.

100 mg and 200 mg capsules: clear PVC blister packs or white opaque PVC blister packs with aluminium foil backing. Each pack contains 1, 2, 3, 4, 6, 7, 10, 12, 14, 20, 28, 30, 42, 50, 60, 100 or 500 hard capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT [To be completed nationally] Detailed information on this medicinal product is available on the website of {name of MS/Agency} [To be completed nationally].

1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 5 mg/ml oral solution [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml of oral solution contains 5 mg of fluconazole. Excipient: each 1 ml also contains 0.1334 g of sucrose and 0.9635 g of glycerol. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Oral solution A clear, colourless to slightly yellow solution with a viscosity greater than water. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Diflucan is indicated in the following fungal infections (see section 5.1). Diflucan is indicated in adults for the treatment of:









Diflucan is indicated in term newborn infants, infants, toddlers, children, and adolescents aged from 0 to 17 years old:

Diflucan is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in immunocompromised patients. Diflucan can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of reoccurrence (see section 4.4).

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. Consideration should be given to official guidance on the appropriate use of antifungals. 4.2 Posology and method of administration Posology The dose should be based on the nature and severity of the fungal infection. Treatment of infections requiring multiple dosing should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Adults: Indications Posology Duration of treatment

- Treatment of cryptococcal meningitis


Usually at least 68 weeks. In life threatening infections the daily dose can be increased to 800 mg

Cryptococcosis



Coccidioidomycosis 200 mg to 400 mg 11 months up to 24 months or longer depending on the patient. 800 mg daily may be considered for some infections and especially for meningeal disease.

Invasive candidasis

Loading dose: 800 mg on Day 1 Subsequent dose: 400 mg daily










7 to 21 days Longer periods may be used in patients with severely compromised immune function.


50 mg daily 14 days


50 to 100 mg daily



100 to 200 mg daily or 200 mg 3 times per week.




100 mg to 200 mg daily or 200 mg 3 times per week.



150 mg

Single dose

Genital candidiasis

- Treatment and prophylaxis of recurrent vaginal candidiasis (4 or more episodes a year)







1 to 3 weeks

Dermatomycosis

- tinea versicolor



150 mg once weekly




Special populations Elderly Dosage should be adjusted based on the renal function (see “Renal Impairment”). Renal impairment No adjustments in single dose therapy are necessary. In patients (including paediatric population) with impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to 400 mg should be given, based on the recommended daily dose for the indication. After this initial loading dose, the daily dose (according to indication) should be based on the following table: Creatinine clearance (ml/min) Percent of recommended dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance Hepatic impairment Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction (see sections 4.4 and 4.8). Paediatric population A maximum dose of 400 mg daily should not be exceeded in paediatric population. As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Diflucan is administered as a single daily dose.

For paediatric patients with impaired renal function, see dosing in “Renal impairment”. The pharmacokinetics of fluconazole has not been studied in paediatric population with renal insufficiency (for “Term newborn infants” who often exhibit primarily renal immaturity please see below). Infants, toddlers and children (from 28 days to 11 years old):




Dose: 6 to 12 mg/kg daily

Depending on the severity of the disease












Method of administration Diflucan may be administered either orally or by intravenous infusion, the route being dependent on the clinical state of the patient. On transferring from the intravenous to the oral route, or vice versa, there is no need to change the daily dose. Diflucan can be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance, to related azole substances, or to any of excipients (see section 6.1).

Coadministration of terfenadine is contraindicated in patients receiving Diflucan at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such ascisapride, astemizole, pimozide, quinidine and erythromycin are contraindicated in patients receiving fluconazole (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Tinea capitis Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, Diflucan should not be used for tinea capitis. Cryptococcosis The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations. Deep endemic mycoses The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations. Renal system Diflucan should be administered with caution to patients with renal dysfunction (see section 4.2). Hepatobiliary system Diflucan should be administered with caution to patients with liver dysfunction. Diflucan has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury. The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician. Cardiovascular system Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Diflucan. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Diflucan should be administered with caution to patients with these potentially proarrhythmic conditions. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5). Halofantrine Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5).

Dermatological reactions Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop. Hypersensitivity In rare cases anaphylaxis has been reported (see section 4.3). Cytochrome P450 Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of CYP2C19. Diflucan treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5). Terfenadine The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5). Excipients Diflucan oral solution contains glycerol. Glycerol may cause headache, stomach upset, and diarrhoea (see section 4.8). Diflucan oral solution contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of the following other medicinal products is contraindicated: Cisapride: There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section 4.3). Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored. Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and astemizole is contraindicated (see section 4.3). Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and pimozide is contraindicated (see section 4.3).

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see section 4.3). Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3). Concomitant use of the following other medicinal products cannot be recommended: Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4). Concomitant use of the following other medicinal products lead to precautions and dose adjustments: The effect of other medicinal products on fluconazole Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered. Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs. The effect of fluconazole on other medicinal products Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see section 4.3). Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 g/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicinal products in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During

concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type anticoagulants concurrently with fluconazole the prothrombin time should be carefully monitored. Dose adjustment of warfarin may be necessary. Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half life 3.7 fold and 2.2 fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary. HMG CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus): Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin depending on ciclosporin concentration. Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dose adjustment of sirolimus depending on the effect/concentration measurements. Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered tacrolimus should be decreased depending on tacrolimus concentration. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed. Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir with approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment of saquinavir may be necessary. Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended during coadministration. Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be

observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop. Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Voriconazole: (CYP2C9 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole. Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. 4.6 Fertility, pregnancy and lactation

Pregnancy

Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dose in the first trimester, show no undesirable effects in the foetus. There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose mothers were treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Studies in animals have shown reproductive toxicity (see section 5.3). Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary.

Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except for potentially life-threatening infections.

Breast-feeding

Fluconazole passes into breast milk to reach concentrations lower than those in plasma. Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. Breast-feeding is not recommended after repeated use or after high dose fluconazole.

Fertility

Fluconazole did not affect the fertility of male or female rats (see section 5.3).

4.7 Effects on ability to drive and use machines No studies have been performed on the effects of Diflucan on the ability to drive or use machines. Patients should be warned about the potential for dizziness or seizures (see section 4.8) while taking Diflucan and should be advised not to drive or operate machines if any of these symptoms occur. 4.8 Undesirable effects The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash. The following adverse reactions have been observed and reported during treatment with Diflucan with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). System Organ Class Common Uncommon Rare Blood and the lymphatic system disorders



Anaphylaxis





Tremor


Vertigo






Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase increased (see section 4.4), blood alkaline phosphatase increased (see section 4.4)








Myalgia



Paediatric population The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric clinical trials, excluding the genital candidiasis indication, are comparable to those seen in adults. 4.9 Overdose There have been reports of overdose with Diflucan and hallucination and paranoid behaviour have been concomitantly reported. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties ATC classification Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01. Mode of action Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of

fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems. Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism. Susceptibility in vitro In vitro, fluconazole displays antifungal activity against most clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to fluconazole. Fluconazole also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis. PK/PD relationship In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candida spp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC. Mechanism(s) of resistance Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in vivo and clinically. There have been reports of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy. Breakpoints (according to EUCAST) Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below: Antifungal Species-related breakpoints (S</R>) Non-species


Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis

Fluconazole 2/4 IE -- 2/4 2/4 2/4 S = Susceptible, R = Resistant A. = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints.


-- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product. IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product. 5.2 Pharmacokinetic properties The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. Absorption After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. Distribution The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%). Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels. High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g. Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy. Biotransformation Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also an inhibitor of the isozyme CYP2C19. Excretion Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Pharmacokinetics in renal impairment In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood.

Pharmacokinetics in children Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study. After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 µgh/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg. Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13. Pharmacokinetics in elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µgh/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use. Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Reproductive toxicity Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg. There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal

survival at these dose levels. These effects on parturation are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see section 5.1). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sucrose Glycerol 85% Purified water Citric acid monohydrate Sodium citrate Cherry liquid flavor 6.2 Incompatibilities Not applicable. 6.3 Shelf life 5 years. Once opened, Diflucan may be used for a maximum of 30 days. 6.4 Special precautions for storage The medicinal product does not require any special storage conditions. 6.5 Nature and contents of container One 180 ml amber Type III glass bottle with threaded aluminum caps. A 20 ml measuring cup is also provided. 6.6 Special precautions for disposal and other handling Do not use the medicinal product if you notice signs of deterioration such as unusual odour, product discoloration, visible particles or crystallization. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally]

10. DATE OF REVISION OF THE TEXT [To be completed nationally] Detailed information on this medicinal product is available on the website of {name of MS/Agency} [To be completed nationally].

1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 10 mg/ml powder for oral suspension Diflucan and associated names (see Annex I) 40 mg/ml powder for oral suspension [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml of reconstituted suspension contains 10 mg fluconazole. Excipient: 0.58 g sucrose per ml of reconstituted suspension. 1 ml of reconstituted suspension contains 40 mg fluconazole. Excipient: 0.55 g sucrose per ml of reconstituted suspension For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for oral suspension White to off-white powder for oral suspension providing a white to off-white orange-flavoured suspension after reconstitution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Diflucan is indicated in the following fungal infections (see section 5.1). Diflucan is indicated in adults for the treatment of: Cryptococcal meningitis (see section 4.4). Coccidioidomycosis (see section 4.4). Invasive candidiasis. Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and



dermal candida infections when systemic therapy is indicated. Tinea unguinium (onychomycosis) when other agents are not considered appropriate

Diflucan is indicated in adults for the prophylaxis of: Relapse of cryptococcal meningitis in patients with high risk of recurrence. Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at



Diflucan is indicated in term newborn infants, infants, toddlers, children, and adolescents aged from 0 to 17 years old: Diflucan is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), invasive candidiasis and cryptococcal meningitis and the prophylaxis of candidal infections in immunocompromised patients. Diflucan can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of reoccurrence (see section 4.4).





Cryptococcosis
















50 mg daily 14 days












150 mg

Single dose

Genital candidiasis

- Treatment and prophylaxis of recurrent vaginal candidiasis (4 or more episodes a year)







1 to 3 weeks

Dermatomycosis

- tinea versicolor



150 mg once weekly




Special populations Elderly Dosage should be adjusted based on the renal function (see “Renal impairment”). Renal impairment No adjustments in single dose therapy are necessary. In patients (including paediatric population) with impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to 400 mg should be given, based on the recommended daily dose for the indication. After this initial loading dose, the daily dose (according to indication) should be based on the following table: Creatinine clearance (ml/min) Percent of recommended dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance Hepatic impairment Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction (see sections 4.4 and 4.8). Paediatric population A maximum dose of 400 mg daily should not be exceeded in paediatric population. As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Diflucan is administered as a single daily dose. For paediatric patients with impaired renal function, see dosing in “Renal impairment”. The pharmacokinetics of fluconazole has not been studied in paediatric population with renal insufficiency (for “Term newborn infants” who often exhibit primarily renal immaturity please see below).

Infants, toddlers and children (from 28 days to 11 years old):

















Method of administration Diflucan may be administered either orally or by intravenous infusion, the route being dependent on the clinical state of the patient. On transferring from the intravenous to the oral route, or vice versa, there is no need to change the daily dose. Diflucan can be taken with or without food. For instructions on reconstitution of the powder for oral suspension, (see section 6.6). The reconstituted suspension will provide a white to off-white orange-flavoured suspension after reconstitution. 4.3 Contraindications Hypersensitivity to the active substance, to related azole substances, or to any of the excipients (see section 6.1).

Coadministration of terfenadine is contraindicated in patients receiving Diflucan at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine and erythromycin are contraindicated in patients receiving fluconazole (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Tinea capitis Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, Diflucan should not be used for tinea capitis. Cryptococcosis The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations. Deep endemic mycoses The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations. Renal system Diflucan should be administered with caution to patients with renal dysfunction (see section 4.2). Hepatobiliary system Diflucan should be administered with caution to patients with liver dysfunction. Diflucan has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury. The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician. Cardiovascular system Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Diflucan. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Diflucan should be administered with caution to patients with these potentially proarrhythmic conditions. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5). Halofantrine Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5).

Dermatological reactions Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop. Hypersensitivity In rare cases anaphylaxis has been reported (see section 4.3). Cytochrome P450 Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of CYP2C19. Diflucan treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5). Terfenadine The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5). Excipients Diflucan powder for oral suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose/galactose malabsorption and sucrase-isomaltase insufficiency should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of the following other medicinal products is contraindicated: Cisapride: There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section 4.3). Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored. Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and astemizole is contraindicated (see section 4.3). Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and pimozide is contraindicated (see section 4.3).

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see section 4.3). Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3). Concomitant use of the following other medicinal products cannot be recommended: Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4). Concomitant use of the following other medicinal products lead to precautions and dose adjustments: The effect of other medicinal products on fluconazole Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered. Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs. The effect of fluconazole on other medicinal products Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see section 4.3). Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 g/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicinal products in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold,

probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type anticoagulants concurrently with fluconazole the prothrombin time should be carefully monitored. Dose adjustment of warfarin may be necessary. Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2 fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary. HMG CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus): Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin depending on ciclosporin concentration. Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dose adjustment of sirolimus depending on the effect/concentration measurements. Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered tacrolimus should be decreased depending on tacrolimus concentration. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed. Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and C max of saquinavir with approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment of saquinavir may be necessary. Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended during coadministration. Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be

observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop. Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Voriconazole: (CYP2C9 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole. Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. 4.6 Fertility, pregnancy and lactation Pregnancy Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dose in the first trimester, show no undesirable effects in the foetus. There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose mothers were treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Studies in animals have shown reproductive toxicity (see section 5.3). Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary. Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except for potentially life-threatening infections.

Breast-feeding Fluconazole passes into breast milk to reach concentrations lower than those in plasma. Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. Breast-feeding is not recommended after repeated use or after high dose fluconazole. Fertility Fluconazole did not affect the fertility of male or female rats (see section 5.3) 4.7 Effects on ability to drive and use machines No studies have been performed on the effects of Diflucan on the ability to drive or use machines. Patients should be warned about the potential for dizziness or seizures (see section 4.8) while taking Diflucan and should be advised not to drive or operate machines if any of these symptoms occur. 4.8 Undesirable effects The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash. The following adverse reactions have been observed and reported during treatment with Diflucan with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated frrm the available data). System Organ Class Common Uncommon Rare Blood and the lymphatic system disorders



Anaphylaxis





Tremor


Vertigo






Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase increased (see section 4.4), blood



alkaline phosphatase increased (see section 4.4)






Myalgia



Paediatric population The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric clinical trials, excluding the genital candidiasis indication, are comparable to those seen in adults. 4.9 Overdose There have been reports of overdose with Diflucan and hallucination and paranoid behaviour have been concomitantly reported. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties ATC classification Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01. Mode of action Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems. Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Susceptibility in vitro In vitro, fluconazole displays antifungal activity against most clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to fluconazole. Fluconazole also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis. PK/PD relationship In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candida spp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC. Mechanism(s) of resistance Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in vivo and clinically. There have been reports of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy. Breakpoints (according to EUCAST) Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below: Antifungal Species-related breakpoints (S</R>) Non-species


Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis

Fluconazole 2/4 IE -- 2/4 2/4 2/4 S = Susceptible, R = Resistant A. = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints. -- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product. IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product. 5.2 Pharmacokinetic properties The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route.


Absorption After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. Distribution The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%). Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels. High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g. Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy. Biotransformation Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also an inhibitor of the isozyme CYP2C19. Excretion Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Pharmacokinetics in renal impairment In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood. Pharmacokinetics in children Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study. After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 µgh/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found

after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg. Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13. Pharmacokinetics in elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µgh/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use. Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Reproductive toxicity Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg. There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. These effects on parturation are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see section 5.1). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sucrose

Silica, colloidal anhydrous Titanium dioxide (E 171) Xanthan gum Sodium citrate Citric acid anhydrous Sodium benzoate Natural orange flavour (containing orange oil and maltodextrin) 6.2 Incompatibilities Not applicable. 6.3 Shelf life The shelf life of the powder for oral suspension is 24 months. The shelf life of the reconstituted suspension is 28 days. Reconstituted suspension: Store below 30°C, do not freeze. 6.4 Special precautions for storage Powder for oral suspension 10 mg/ml and 40 mg/ml (60 ml bottle): Store below 25°C. Powder for oral suspension 10 mg/ml (175 ml bottle): Store below 25°C. Keep the bottle tightly closed. For storage conditions of the reconstituted medicinal product, see section 6.3. 6.5 Nature and contents of container A 60 ml or a 175 ml high density polyethylene (HDPE) bottle with either a plastic child-resistant closure or continuous thread aluminum closure containing a white to off-white powder for oral suspension providing a white to off-white orange-flavoured suspension after reconstitution. Diflucan and associated names 10 mg/ml powder for oral suspension: A 60 ml bottle contains 24.4 g of powder for oral suspension. After reconstitution, the volume of the suspension is 40 ml, providing a usable volume of 35 ml. A 175 ml bottle contains 67.1 g of powder for oral suspension. After reconstitution, the volume of the suspension is 110 ml, providing a usable volume of 100 ml. Diflucan and associated names 40 mg/ml powder for oral suspension: A 60 ml bottle contains 24.4 g powder for oral suspension. After reconstitution, the volume of the suspension is 40 ml, providing a usable volume of 35 ml. Not all pack sizes may be marketed. A 5 ml measuring spoon and/or a 5 ml graduated syringe with a press-in bottle adaptor might also be provided with the 60 ml bottle. A measuring cup is provided with the 175 ml bottle. 6.6 Special precautions for disposal and other handling Reconstitution instructions: The reconstituted suspension will provide a white to off-white orange-flavoured suspension after reconstitution.

For the 60 ml bottle: 1. Tap the bottle to release the powder. 2. Add a small quantity of still water and shake it vigorously. Add water up to the level marked on the bottle (this corresponds to adding 24 ml of water) 3. Shake well for 1 to 2 minutes to obtain a homogenous suspension. 4. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days). For the 175 ml bottle: (Applicable only if marketed in your country) 1. Tap the bottle to release the powder. 2. Measure 66 ml of still water and add the water to the bottle. 3. Shake well for 1 to 2 minutes to obtain a homogenous suspension. 4. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days). Instructions for use: Shake the closed bottle of the reconstituted suspension before each use. Instructions to use the paediatric syringe: (Applicable only if marketed in your country) Shake the prepared suspension well. 1. Open the bottle (safety cap); 2. Insert the adapter fitted onto the syringe into the bottle neck (1, 2 - see Figure 1); 3. Turn the bottle with the syringe upside down and withdraw the quantity of suspension prescribed by the doctor (Figure 2). The graduations on the syringe are shown in ml. The maximum adult daily dose should not be exceeded in children (see section 4.2) 4. Remove the syringe from the bottle; 5. For younger children, the medicinal product may be given directly into the mouth from the syringe. The child should remain upright during administration. Point the syringe at the inside of the cheek; release the suspension slowly into the child's mouth (Figure 3). For older children, the suspension may be put in a spoon and drunk by the child. 6. Rinse the syringe after use. 7. Close the bottle with the safety cap; the adapter will remain on the bottle neck.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Any remaining suspension should be discarded 28 days after reconstitution.

7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT [To be completed nationally]. Detailed information on this medicinal product is available on the website of {name of MS/Agency} [To be completed nationally].

1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 2 mg/ml solution for infusion [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 25 ml solution for infusion contains 50 mg fluconazole. Each 50 ml solution for infusion contains 100 mg fluconazole. Each 100 ml solution for infusion contains 200 mg fluconazole. Each 200 ml solution for infusion contains 400 mg fluconazole. Each ml contains 2 mg of fluconazole.

Excipient: each ml also contains 9 mg sodium chloride (equivalent to 0.154 mmol sodium).

For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for infusion Clear, colourless solution with no visible particles. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Diflucan is indicated in the following fungal infections (see section 5.1). Diflucan is indicated in adults for the treatment of:


chronic mucocutaneous candidiasis. Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene topical treatment are

insufficient. Diflucan is indicated in adults for the prophylaxis of:

Relapse of crytopcoccal meningitis in patients with high risk of recurrence. Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at

high risk of experiencing relapse. Prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients


Diflucan is indicated in term newborn infants, infants, toddlers, children and adolescents aged from 0 to 17 years old: Diflucan is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in

immunocompromised patients. Diflucan can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of reoccurrence (see section 4.4).





Cryptococcosis
















50 mg daily 14 days













Special populations Elderly Dosage should be adjusted based on the renal function (see “Renal impairment”). Renal impairment Diflucan is predominantly excreted in the urine as unchanged active substance. No adjustments in single dose therapy are necessary. In patients (including paediatric population) with impaired renal function who will receive multiple doses offluconazole, an initial dose of 50 mg to 400 mg should be given, based on the recommended daily dose for the indication. After this initial loading dose, the daily dose (according to indication) should be based on the following table: Creatinine clearance (ml/min) Percent of recommended dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance Hepatic impairment Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction (see sections 4.4 and 4.8). Paediatric population: A maximum dose of 400 mg daily should not be exceeded in paediatric population.

As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Diflucan is administered as a single daily dose. For paediatric patients with impaired renal function, see dosing in “Renal impairment”. The pharmacokinetics of fluconazole has not been studied in paediatric population with renal insufficiency (for “Term newborn infants” who often exhibit primarily renal immaturity please see below). Infants, toddlers and children (from 28 days to 11 years old):










Adolescents (from 12 to 17 years old): Depending on the weight and pubertal development, the prescriber would need to assess which posology (adults or children) is the most appropriate. Clinical data indicate that children have a higher fluconazole clearance than observed for adults. A dose of 100, 200 and 400 mg in adults corresponds to a 3, 6 and 12 mg/kg dose in children to obtain a comparable systemic exposure. Term newborn infants (0 to 27 days): Neonates excrete fluconazole slowly. There are few pharmacokinetic data to support this posology in term newborn infants (see section 5.2).







Method of administration Diflucan may be administered either orally or by intravenous infusion, the route being dependent on the clinical state of the patient. On transferring from the intravenous to the oral route, or vice versa, there is no need to change the daily dose. Intravenous infusion should be administrated at a rate not exceeding 10 ml/minute. Diflucan is formulated in sodium chloride 9 mg/ml (0.9%) solution for infusion, each 200 mg (100 ml bottle) containing 15 mmol each of Na+ and C1-. Because Diflucan is available as a dilute sodium chloride solution, in patients requiring sodium or fluid restriction, consideration should be given to the rate of fluid administration. For instruction on handling of the product, see section 6.6.

4.3 Contraindications Hypersensitivity to the active substance to related azole substances, or to any of the excipients (see section 6.1). Coadministration of terfenadine is contraindicated in patients receiving Diflucan at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine and erythromycin are contraindicated in patients receiving fluconazole (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Tinea capitis Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, Diflucan should not be used for tinea capitis. Cryptococcosis The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations. Deep endemic mycoses The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations. Renal system Diflucan should be administered with caution to patients with renal dysfunction (see section 4.2). Hepatobiliary system Diflucan should be administered with caution to patients with liver dysfunction. Diflucan has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury. The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician. Cardiovascular system Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Diflucan. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Diflucan should be administered with caution to patients with these potentially proarrhythmic conditions. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5).

Halofantrine Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5). Dermatological reactions Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop. Hypersensitivity In rare cases anaphylaxis has been reported (see section 4.3). Cytochrome P450 Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of CYP2C19. Diflucan treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5). Terfenadine The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5). Excipients This medicinal product contains 0.154 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of the following other medicinal products is contraindicated: Cisapride: There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section 4.3). Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored. Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and astemizole is contraindicated (see section 4.3). Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can

lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and pimozide is contraindicated (see section 4.3). Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see section 4.3). Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3). Concomitant use of the following other medicinal products cannot be recommended: Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4). Concomitant use of the following other medicinal products lead to precautions and dose adjustments: The effect of other medicinal products on fluconazole Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered. Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs. The effect of fluconazole on other medicinal products Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see section 4.3). Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 g/kg) in healthy volunteers the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicinal products in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type anticoagulants concurrently with fluconazole the prothrombin time should be carefully monitored. Dose adjustment of warfarin may be necessary. Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary. HMG CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus): Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin depending on ciclosporin concentration.

Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4. Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dose adjustment of sirolimus depending on the effect/concentration measurements. Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered tacrolimus should be decreased depending on tacrolimus concentration. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed. Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir with approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment of saquinavir may be necessary. Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended during coadministration.

Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop. Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Voriconazole: (CYP2C9 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole. Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. 4.6 Fertility, pregnancy and lactation Pregnancy Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dose in the first trimester, show no undesirable effects in the foetus. There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose mothers were treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear. Studies in animals have shown reproductive toxicity (see section 5.3). Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary.

Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except for potentially life-threatening infections. Breast-feeding Fluconazole passes into breast milk to reach concentrations lower than those in plasma. Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. Breast-feeding is not recommended after repeated use or after high dose fluconazole. Fertility Fluconazole did not affect the fertility of male or female rats (see section 5.3) 4.7 Effects on ability to drive and use machines No studies have been performed on the effects of Diflucan on the ability to drive or use machines. Patients should be warned about the potential for dizziness or seizures (see section 4.8) while taking Diflucan and should be advised not to drive or operate machines if any of these symptoms occur. 4.8 Undesirable effects The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash. The following adverse reactions have been observed and reported during treatment with Diflucan with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). System Organ Class Common Uncommon Rare Blood and the lymphatic system disorders



Anaphylaxis





Tremor


Vertigo






Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase


Hepatic failure (see section 4.4), hepatocellular necrosis (see section 4.4), hepatitis (see section 4.4), hepatocellular

increased (see section 4.4), blood alkaline phosphatase increased (see section 4.4)

damage (see section 4.4)






Myalgia



Paediatric population The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults. 4.9 Overdose There have been reports of overdose with Diflucan and hallucination and paranoid behaviour have been concomitantly reported. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties ATC classification Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01. Mode of action Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems. Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH

stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism. Susceptibility in vitro In vitro, fluconazole displays antifungal activity against most clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to fluconazole. Fluconazole also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis. PK/PD relationship In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candida spp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC. Mechanism(s) of resistance Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in vivo and clinically. There have been reports of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy. Breakpoints (according to EUCAST) Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below: Antifungal Species-related breakpoints (S</R>) Non-species


Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis

Fluconazole 2/4 IE -- 2/4 2/4 2/4 S = Susceptible, R = Resistant A. = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints. -- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product. IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product.


5.2 Pharmacokinetic properties The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. Absorption After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. Distribution The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%). Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels. High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g. Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy. Biotransformation Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also an inhibitor of the isozyme CYP2C19. Excretion Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Pharmacokinetics in renal impairment In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood. Pharmacokinetics in children Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study.

After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 µgh/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg. Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13. Pharmacokinetics in elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µgh/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use. Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Reproductive toxicity Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg. There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. These effects on parturation are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see section 5.1).

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Water for injections Sodium hydroxide (for pH adjustment) 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Glass vials: 5 years. Plasticised PVC bags: 18 months. This medicinal product is for single use. Once opened, any unused infusion should be discarded. 6.4 Special precautions for storage Glass vials: Do not freeze. Plasticised PVC bags: Store below 30˚C. Do not freeze. From a microbiological point of view, the dilutions should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 ° C, unless dilution has taken place in controlled and validated aseptic conditions. 6.5 Nature and contents of container Clear Type I glass infusion vial sealed closed with rubber stoppers and aluminium caps. Plasticised PVC bag. Pack sizes: 30, 50, 100 or 250 ml glass vials.

1, 5, 10 or 20 plasticised PVC bags (100 or 200 ml). Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Fluconazole intravenous infusion is compatible with the following administration fluids: a) Dextrose 5% and 20% b) Ringer's solution c) Hartmann's solution d) Potassium chloride in dextrose e) Sodium bicarbonate 4.2% and 5% f) Aminosyn 3.5% g) Sodium chloride 9 mg/ml (0.9%) h) Dialaflex (interperitoneal dialysis Soln 6.36%) Fluconazole may be infused through an existing line with one of the above listed fluids. Although no specific incompatibilities have been noted, mixing with any other medicinal products prior to infusion is not recommended. The solution for infusion is for single use only.

The dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT [To be completed nationally] Detailed information on this medicinal product is available on the website of {name of MS/Agency} [To be completed nationally].

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON(capsules) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 150 mg hard capsules [See Annex I - To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains fluconazole 150 mg. 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 1 hard capsule. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store below 30°C.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Diflucan and associated names (see Annex I) 150 mg [To be completed nationally]

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS (capsules) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex 1) 150 mg hard capsule [See Annex I - To be completed nationally] Fluconazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON (capsules) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 50 mg hard capsules Diflucan and associated names (see Annex I) 100 mg hard capsules Diflucan and associated names (see Annex I) 150 mg hard capsules Diflucan and associated names (see Annex I) 200 mg hard capsules [See Annex I - To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each hard capsule contains fluconazole 50 mg Each hard capsule contains fluconazole 100 mg Each hard capsule contains fluconazole 150 mg Each hard capsule contains fluconazole 200 mg 3. LIST OF EXCIPIENTS Contains lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Hard capsule. 1, 2, 3, 4, 6, 7, 10, 12, 14, 20, 28, 30, 42, 50, 60, 100 or 500 hard capsules. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP

9. SPECIAL STORAGE CONDITIONS Store below 30°C 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and Address} <{tel}> <{fax}> <{e-mail}> 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE [To be completed nationally] 16. INFORMATION IN BRAILLE Diflucan and associated names (see Annex I) 50 mg Diflucan and associated names (see Annex I) 100 mg Diflucan and associated names (see Annex I) 150 mg Diflucan and associated names (see Annex I) 200 mg [To be completed nationally]

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS (capsules) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex 1) 50 mg hard capsules Diflucan and associated names (see Annex 1) 100 mg hard capsules Diflucan and associated names (see Annex 1) 150 mg hard capsules Diflucan and associated names (see Annex 1) 200 mg hard capsules [See Annex I – To be completed nationally] Fluconazole 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally]

3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER

PARTICULARS TO APPEAR ON THE OUTER PACKAGING PACKAGING CARTON (5 mg/ml oral solution) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 5 mg/ml oral solution [See Annex I – To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of oral solution contains 5 mg of fluconazole. 3. LIST OF EXCIPIENTS Also contains sucrose, glycerol. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Oral solution. 1 bottle - 150 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Once opened, Diflucan may be used for a maximum of 30 days. 9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Diflucan and associated names (see Annex I) 5 mg/ml [To be completed nationally]

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE LABEL(5 mg/ml oral solution) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 5 mg/ml oral solution [See Annex I - To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of oral solution contains 5 mg of fluconazole. 3. LIST OF EXCIPIENTS Contains sucrose, and glycerol. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Oral solution 1 bottle - 150 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Once opened, Diflucan may be used for a maximum of 30 days. 9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON (10 mg/ml powder for oral suspension – 60 ml and 175 ml bottles) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 10 mg/ml powder for oral suspension [See Annex I – To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of reconstituted suspension contains 10 mg fluconazole. 3. LIST OF EXCIPIENTS Also contains sucrose.See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for oral suspension. 1 bottle – 35 ml suspension after reconstitution 1 bottle – 100 ml suspension after reconstitution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use after reconstitution. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Any remaining suspension should be discarded 28 days after reconstitution. 9. SPECIAL STORAGE CONDITIONS Powder for oral suspension (60 ml bottle): Store below 25°C Powder for oral suspension (175 ml bottle): Store below 25°C. Keep the bottle tightly closed.

Reconstituted suspension: Store below 30°C, do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Diflucan and associated names (see Annex I) 10 mg/ml [To be completed nationally]

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE LABEL (10 mg/ml powder for oral suspension – 60 ml and 175 ml bottles) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 10 mg/ml powder for oral suspension [See Annex I – To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of reconstituted suspension contains 10 mg fluconazole. 3. LIST OF EXCIPIENTS Also contains sucrose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for oral suspension. 1 bottle - 35 ml suspension after reconstitution 1 bottle - 100 ml suspension after reconstitution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use after reconstitution. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Any remaining suspension should be discarded 28 days after reconstitution. 9. SPECIAL STORAGE CONDITIONS

(Powder for oral suspension (60 ml bottle): Store below 25°C no special storage conditions. (Powder for oral suspension (175 ml bottle): Store below 25°C. Keep the bottle tightly closed. Reconstituted suspension: Store below 30°C, do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON (40 mg/ml powder for oral suspension – 60 ml bottle) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 40 mg/ml powder for oral suspension [See Annex I – To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of reconstituted suspension contains 40 mg fluconazole. 3. LIST OF EXCIPIENTS Contains sucrose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for oral suspension. 1 bottle – 35 ml suspension after reconstitution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use after reconstitution. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Any remaining suspension should be discarded 28 days after reconstitution. 9. SPECIAL STORAGE CONDITIONS Powder for oral suspension: Store below 25°C. Keep the bottle tightly closed.

Reconstituted suspension: Store below 30°C, do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Diflucan and associated names (see Annex I) 40 mg/ml [To be completed nationally]

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING BOTTLE LABEL(40 mg/ml powder for oral suspension – 60 ml bottle) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 40 mg/ml powder for oral suspension [See Annex I – To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of reconstituted suspension contains 40 mg fluconazole. 3. LIST OF EXCIPIENTS Also contains sucrose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder for oral suspension. 1 bottle – 35 ml suspension after reconstitution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Oral use after reconstitution. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP Any remaining suspension should be discarded 28 days after reconstitution. 9. SPECIAL STORAGE CONDITIONS (Powder for oral suspension) Store below 25°C

Keep the bottle tightly closed. Reconstituted suspension: Store below 30°C, do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (IV 30, 50, 100 or 250 ml glass vials, 100 and 200 ml PVC bags) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 2 mg/ml solution for infusion [See Annex I – To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml contains 2 mg of fluconazole.

Each 25 ml solution for infusion contains 50 mg fluconazole Each 50 ml solution for infusion contains 100 mg fluconazole Each 100 ml solution for infusion contains 200 mg fluconazole Each 200 ml solution for infusion contains 400 mg fluconazole 3. LIST OF EXCIPIENTS Excipients: sodium chloride, water for injections and sodium hydroxide. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial – 25 ml solution 1 vial – 50 ml solution 1 vial – 100 ml solution 1 vial – 200 ml solution 5, 10, 20 PVC bags – 100 ml solution 5, 10, 20 PVC bags – 200 ml solution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. Intravenous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE

EXP 9. SPECIAL STORAGE CONDITIONS (Glass vials) Do not freeze. (PVC bags) Store below 30˚C. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING LABEL (IV- 50, 100 or 250 ml glass vials, 100 and 200 ml PVC bags) 1. NAME OF THE MEDICINAL PRODUCT Diflucan and associated names (see Annex I) 2 mg/ ml solution for infusion [See Annex I – To be completed nationally] Fluconazole 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml contains 2 mg of fluconazole. Each 50 ml solution for infusion contains 100 mg fluconazole Each 100 ml solution for infusion contains 200 mg fluconazole Each 200 ml solution for infusion contains 400 mg fluconazole 3. LIST OF EXCIPIENTS Excipients: sodium chloride, water for injections and sodium hydroxide. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial – 50 ml solution 1 vial – 100 ml solution 1 vial – 200 ml solution 1 PVC bag – 100 ml solution 1 PVC bag – 200 ml solution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Single use only. Read the package leaflet before use. Intravenous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP

9. SPECIAL STORAGE CONDITIONS (Glass vials) Do not freeze. (PVC bags) Store below 30˚C. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS LABEL (IV - 30 ml glass vial) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Diflucan and associated names (see Annex I) 2 mg/ ml solution for infusion [See Annex I – To be completed nationally] Fluconazole Intravenous use. 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBERS Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 25 ml solution 6. OTHER

PACKAGE LEAFLET

PACKAGE LEAFLET: INFORMATION FOR THE USER

Diflucan and associated names (see Annex I) 150 mg capsule [See Annex I - To be completed nationally]

fluconazole

Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even

if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist. In this leaflet: 1. What Diflucan is and what it is used for 2. Before you take Diflucan 3. How to take Diflucan 4. Possible side effects 5. How to store Diflucan 6. Further information 1. WHAT DIFLUCAN IS AND WHAT IT IS USED FOR Diflucan is one of a group of medicines called “antifungals”. The active substance is fluconazole. Diflucan is used in adults to treat infections caused by fungi. The most common cause of fungal infections is a yeast called Candida. You might be given this medicine by your doctor to treat genital thrush, infection of the vagina or penis. 2. BEFORE YOU TAKE DIFLUCAN Do not take Diflucan if you - are allergic (hypersensitive) to fluconazole, to other medicines you have taken to treat fungal

infections or to any of the other ingredients of Diflucan. The symptoms may include itching, reddening of the skin or difficulty in breathing

- are taking astemizole, terfenadine (antihistamine medicines for allergies) - are taking cisapride (used for stomach upsets) - are taking pimozide (used for treating mental illness) - are taking quinidine (used for treating heart arrhythmia) - are taking erythromycin, (an antibiotic for treating infections) Take special care with Diflucan Tell your doctor if you - have liver or kidney problems - suffer from heart disease, including heart rhythm problems - have abnormal levels of potassium, calcium or magnesium in your blood - develop severe skin reactions (itching, reddening of the skin or difficulty in breathing).

Children Although this medicine is for adults it can be used in adolescents (from 12 to 17 years old) if treatment is essential and no suitable alternative exists, and should be taken in the same way as for adults. Taking other medicines Tell your doctor immediately if you are taking astemizole, terfenadine (an antihistamine for treating allergies) or cisapride (used for stomach upsets) or pimozide (used for treating mental illness) or quinidine (used for treating heart arrhythmia) or erythromycin (an antibiotic for treating infections) as these should not be taken with Diflucan (see section: “Do not take Diflucan if you”). There are some medicines that may interact with Diflucan. Make sure your doctor knows if you are taking any of the following medicines: - rifampicin or rifabutin (antibiotics for infections) - alfentanil, fentanyl (used as anaesthetic) - amitriptyline, nortriptyline (used as anti-depressant) - amphotericin B, voriconazole (anti-fungal) - medicines that thin the blood to prevent blood clots (warfarin or similar medicines) - benzodiazepines (midazolam, triazolam or similar medicines) used to help you sleep or for

anxiety - carbamazepine, phenytoin (used for treating fits) - nifedipine, isradipine, amlodipine felodipine and losartan (for hypertension- high blood pressure) - ciclosporin, everolimus, sirolimus or tacrolimus (to prevent transplant rejection) - cyclosphosphamide, vinca alkaloids (vincristine, vinblastine or similar medicines) used for

treating cancer - halofantrine (used for treating malaria) - statins (atorvastatin, simvastatin and fluvastatin or similar medicines) used for reducing high

cholesterol levels - methadone (used for pain) - celecoxib, flurbiprofen, naproxen, ibuprofen, lornoxicam, meloxicam, diclofenac

(Non-Steroidal Anti-Inflammatory Drugs (NSAID)) - oral contraceptives - prednisone (steroid) - zidovudine, also known as AZT; saquinavir (used in HIV-infected patients) - medicines for diabetes such as chlorpropamide, glibenclamide, glipizide or tolbutamide - theophylline (used to control asthma) - vitamin A (nutritional supplement)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Taking Diflucan with food and drink You can take your medicine with or without a meal. Pregnancy and breast-feeding Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding. You should not take Diflucan while you are pregnant or breast-feeding unless your doctor has told you to. Ask your doctor or pharmacist for advice before taking any medicines.

Driving and using machines When driving vehicles or using machines, it should be taken into account that occasionally dizziness or fits may occur. Important information about some of the ingredients of Diflucan This medicine contains a small amount of lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, please contact your doctor before taking this medicine. 3. HOW TO TAKE DIFLUCAN Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Swallow the capsule whole with a glass of water. Adults 150 mg as a single dose. Doctors sometimes prescribe different doses to these. Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Elderly The usual adult dose should be given. Patients with kidney problems The usual adult dose should be given. How quickly will the treatment start to work? Vaginal thrush Your condition should start to clear up within a few days - some women notice an improvement in one day. If your condition does not clear up within a few days you should go back to your doctor. Penis thrush infection Your condition should start to clear up within a few days but it may take up to a week. If your condition has not cleared up after one week, you should go back to your doctor. If you take more Diflucan than you should Taking too many capsules at once may make you unwell. Contact your doctor or your nearest hospital casualty department at once. The symptoms of a possible overdose may include hearing, seeing, feeling and thinking things that are not real (hallucination and paranoid behaviour). Symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. If you forget to take Diflucan Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, take it as soon as you remember. If it is almost time for your next dose, do not take the dose that you missed. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS Like all medicines, Diflucan can cause side effects, although not everybody gets them A few people develop allergic reactions although serious allergic reactions are rare. If you get any of the following symptoms, tell your doctor immediately. - sudden wheezing, difficulty in breathing or tightness in the chest - swelling of eyelids, face or lips - itching all over the body reddening of the skin or itchy red spots - skin rash - severe skin reactions such as a rash that causes blistering (this can affect the mouth and tongue). Diflucan may affect your liver. The signs of liver problems include: - tiredness - loss of appetite - vomiting - yellowing of your skin or the whites of your eyes (jaundice) If any of these happen, stop taking Diflucan and tell your doctor immediately. Other side effects: Additionally, if any of the following side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Common side effects which affect 1 to 10 users in 100 are listed below: - headache - stomach discomfort, diarrhoea, feeling sick, vomiting - increases in blood tests of liver function - rash Uncommon side effects which affect 1 to 10 users in 1,000 are listed below: - reduction in red blood cells which can make skin pale and cause weakness or breathlessness - decreased appetite - inability to sleep, feeling drowsy - fit, dizziness, sensation of spinning, tingling, pricking or numbness, changes in sense of taste - constipation, difficult digestion, wind, dry mouth - muscle pain - liver damage and yellowing of the skin and eyes (jaundice) - wheals, blistering (hives), itching, increased sweating - tiredness, general feeling of being unwell, fever Rare side effects which affect 1 to 10 users in 10,000 are listed below: - lower than normal white blood cells that help defend against infections and blood cells that help

to stop bleeding - red or purple discoloration of the skin which may be caused by low platelet count, other blood

cell changes - low blood potassium - blood chemistry changes (high blood levels of cholesterol, fats) - shaking - abnormal electrocardiogram (ECG), change in heart rate or rhythm - liver failure - allergic reactions (sometimes severe), including widespread blistering rash and skin peeling,

severe skin reactions, swelling of the lips or face - hair loss

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE DIFLUCAN - Keep out of the reach and sight of children. - Do not use Diflucan after the expiry date which is stated on the pack after EXP. The expiry date

refers to the last day of the month. - Store below 30°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Diflucan contains - The active substance is fluconazole. - Each hard capsule contains fluconazole 150 mg. - The other ingredients are: Capsule content: lactose monohydrate, maize starch, colloidal silica anhydrous, magnesium stearate and sodium laurilsulfate. Capsule shell composition: Gelatin, titanium dioxide (E171) and patent blue V (E131) Printing ink: shellac (glaze), black iron oxide, N-Butyl alcohol, dehydrated alcohol, purified water, propylene glycol, industrial methylated spirit, isopropyl alcohol, strong ammonia solution, potassium hydroxide What Diflucan looks like and contents of the pack - Diflucan 150 mg hard capsules have a turquoise blue body and a turquoise blue cap. They have

“FLU-150” and “Pfizer” with black ink printed on them. - Diflucan comes in a blister pack containing one capsule. Marketing Authorisation Holderand Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in [To be completed nationally] Detailed information on this medicine is available on the web site of {MA/Agency}: [To be completed nationally]


Diflucan and associated names (see Annex I) 50 mg capsules Diflucan and associated names (see Annex I) 100 mg capsules Diflucan and associated names (see Annex I) 150 mg capsules Diflucan and associated names (see Annex I) 200 mg capsules

[See Annex I – To be completed nationally] fluconazole



please tell your doctor or pharmacist.

In this leaflet: 1. What Diflucan is and what it is used for 2. Before you take Diflucan 3. How to take Diflucan 4. Possible side effects 5. How to store Diflucan 6. Further information 1. WHAT DIFLUCAN IS AND WHAT IT IS USED FOR Diflucan is one of a group of medicines called “antifungals”. The active substance is fluconazole. Diflucan is used to treat infections caused by fungi and may also be used to stop you from getting a candidal infection. The most common cause of fungal infections is a yeast called Candida. Adults You might be given this medicine by your doctor to treat the following types of fungal infections: - Cryptococcal meningitis – a fungal infection in the brain - Coccidioidomycosis – a disease of the bronchopulmonary system - Infections caused by Candida and found in the blood stream, body organs (e.g. heart, lungs) or

urinary tract - Mucosal thrush - infection affecting the lining of the mouth, throat and denture sore mouth - Genital thrush – infection of the vagina or penis - Skin infections - e.g. athlete's foot, ringworm, jock itch, nail infection You might also be given Diflucan to: - stop cryptococcal meningitis from coming back - stop mucosal trush from coming back - reduce recurrence of vaginal trush - stop you from getting an infection caused by Candida (if your immune system is weak and not

working properly) Children and adolescents (0 to 17 years old) You might be given this medicine by your doctor to treat the following types of fungal infections: - Mucosal thrush - infection affecting the lining of the mouth, throat - Infections caused by Candida and found in the blood stream, body organs (e.g. heart, lungs) or

urinary tract - Cryptococcal meningitis – a fungal infection in the brain

You might also be given Diflucan to: - stop you from getting an infection caused by Candida (if your immune system is weak and not working properly). - stop cryptococcal meningitis from coming back 2. BEFORE YOU TAKE DIFLUCAN Do not take Diflucan if you - are allergic (hypersensitive) to fluconazole, to other medicines you have taken to treat fungal


- are taking astemizole, terfenadine (antihistamine medicines for allergies) - are taking cisapride (used for stomach upsets) - are taking pimozide (used for treating mental illness) - are taking quinidine (used for treating heart arrhythmia) - are taking erythromycin (an antibiotic for treating infections) Take special care with Diflucan Tell your doctor if you - have liver or kidney problems - suffer from heart disease, including heart rhythm problems - have abnormal levels of potassium, calcium or magnesium in your blood. - develop severe skin reactions (itching, reddening of the skin or difficulty in breathing). Taking other medicines Tell your doctor immediately if you are taking astemizole, terfenadine (an antihistamine for treating allergies) or cisapride (used for stomach upsets) or pimozide (used for treating mental illness) or quinidine (used for treating heart arrhythmia) or erythromycin (an antibiotic for treating infections) as these should not be taken with Diflucan (see section: “Do not take Diflucan if you”). There are some medicines that may interact with Diflucan. Make sure your doctor knows if you are taking any of the following medicines: - rifampicin or rifabutin (antibiotics for infections) - alfentanil, fentanyl (used as anaesthetic) - amitriptyline, nortriptyline (used as anti-depressant) - amphotericin B, voriconazole (anti-fungal) - medicines that thin the blood to prevent blood clots (warfarin or similar medicines) - benzodiazepines (midazolam, triazolam or similar medicines) used to help you sleep or for

anxiety - carbamazepine, phenytoin (used for treating fits) - nifedipine, isradipine, amlodipine felodipine and losartan (for hypertension- high blood pressure) - ciclosporin, everolimus , sirolimus or tacrolimus (to prevent transplant rejection) - cyclosphosphamide, vinca alkaloids (vincristine, vinblastine or similar medicines) used for


cholesterol levels - methadone (used for pain) - celecoxib, flurbiprofen, naproxen, ibuprofen, lornoxicam, meloxicam, diclofenac (Non-

Steroidal Anti-Inflammatory Drugs (NSAID)) - oral contraceptives

- prednisone (steroid) - zidovudine, also known as AZT; saquinavir (used in HIV-infected patients) - medicines for diabetes such as chlorpropamide, glibenclamide, glipizide or tolbutamide - theophylline (used to control asthma) - vitamin A (nutritional supplement)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Taking Diflucan with food and drink You can take your medicine with or without a meal. Pregnancy and breast-feeding Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding. You should not take Diflucan while you are pregnant or breast-feeding unless your doctor has told you to. Ask your doctor or pharmacist for advice before taking any medicines. Driving and using machines When driving vehicles or using machines, it should be taken into account that occasionally dizziness or fits may occur. Important information about some of the ingredients of Diflucan This medicine contains a small amount of lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, please contact your doctor before taking this medicine. 3. HOW TO TAKE DIFLUCAN Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Swallow the capsule whole with a glass of water. It is best to take your capsules at the same time each day. The usual doses of this medicine for different infections are below: Adults Condition Dose

To treat cryptococcal meningitis 400 mg on the first day then 200 mg to 400 mg once daily for 6 to 8 weeks or longer if needed. Sometimes doses are increased up to 800 mg

To stop cryptococcal meningitis from coming back 200 mg once daily until you are told to stop

To treat coccidioidomycosis 200 mg to 400 mg once daily from 11 months for up to 24 months or longer if needed. Sometimes doses are increased up to 800 mg

To treat internal fungal infections caused by Candida 800 mg on the first day then 400 mg once daily until you are told to stop

To treat mucosal infections affecting the lining of mouth, throat and denture sore mouth

200 mg to 400 mg on the first day then 100 mg to 200 mg until you are told to stop

To treat mucosal thrush – dose depends on where the infection is located

50 mg to 400 mg once daily for 7 to 30 days until you are told to stop

To stop mucosal infections affecting the lining of mouth, throat

100 mg to 200 mg once daily, or 200 mg 3 times a week, while you are at risk of getting an infection

To treat genital thrush 150 mg as a single dose

To reduce recurrence of vaginal trush 150 mg every third day for a total of 3 doses (day 1, 4 and 7) and then once a week for 6 months while you are at risk of getting an infection

To treat fungal skin and nail infections Depending on the site of the infection 50 mg once daily, 150 mg once weekly, 300 to 400 mg once weekly for 1 to 4 weeks (Athlete’s foot may be up to 6 weeks, for nail infection treatment until infected nail is replaced)

To stop you from getting an infection caused by Candida (if your immune system is weak and not working properly)

200 mg to 400 mg once daily while you are at risk of getting an infection

Adolescents from 12 to 17 years old Follow the dose prescribed by your doctor (either adults or children posology). Children to 11 years old The maximum dose for children is 400 mg daily. The dose will be based on the child’s weight in kilograms. Condition Daily dose

Mucosal thrush and throat infections caused by Candida – dose and duration depends on the severity of the infection and on where the infection is located

3 mg per kg of body weight (6 mg per kg of body weight might be given on the first day)

Cryptococcal meningitis or internal fungal infections caused by Candida

6 mg to 12 mg per kg of body weight

To stop children from getting an infection caused by Candida (if their immune system is not working properly)


Use in children 0 to 4 weeks of age Use in children of 3 to 4 weeks of age: The same dose as above but given once every 2 days. The maximum dose is 12 mg per kg of body weight every 48 hours. Use in children less than 2 weeks old:

The same dose as above but given once every 3 days. The maximum dose is 12 mg per kg of body weight every 72 hours. Doctors sometimes prescribe different doses to these. Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Elderly The usual adult dose should be given unless you have kidney problems. Patients with kidney problems Your doctor may change your dose, depending on your kidney function. If you take more Diflucan than you should Taking too many capsules at once may make you unwell. Contact your doctor or your nearest hospital casualty department at once. The symptoms of a possible overdose may include hearing, seeing, feeling and thinking things that are not real (hallucination and paranoid behaviour). Symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. If you forget to take Diflucan Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, take it as soon as you remember. If it is almost time for your next dose, do not take the dose that you missed. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Diflucan can cause side effects, although not everybody gets them A few people develop allergic reactions although serious allergic reactions are rare. If you get any of the following symptoms, tell your doctor immediately. - sudden wheezing, difficulty in breathing or tightness in the chest - swelling of eyelids, face or lips - itching all over the body reddening of the skin or itchy red spots - skin rash - severe skin reactions such as a rash that causes blistering (this can affect the mouth and tongue). Diflucan may affect your liver. The signs of liver problems include: - tiredness - loss of appetite - vomiting - yellowing of your skin or the whites of your eyes (jaundice) If any of these happen, stop taking Diflucan and tell your doctor immediately. Other side effects: Additionally, if any of the following side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Common side effects which affect 1 to 10 users in 100 are listed below: - headache - stomach discomfort, diarrhoea, feeling sick, vomiting - increases in blood tests of liver function - rash Uncommon side effects which affect 1 to 10 users in 1,000 are listed below: - reduction in red blood cells which can make skin pale and cause weakness or breathlessness

- decreased appetite - inability to sleep, feeling drowsy - fit, dizziness, sensation of spinning, tingling, pricking or numbness, changes in sense of taste - constipation, difficult digestion, wind, dry mouth - muscle pain - liver damage and yellowing of the skin and eyes (jaundice) - wheals, blistering (hives), itching, increased sweating - tiredness, general feeling of being unwell, fever Rare side effects which affect 1 to 10 users in 10,000 are listed below: - lower than normal white blood cells that help defend against infections and blood cells that help


cell changes - blood chemistry changes (high blood levels of cholesterol, fats) - low blood potassium - shaking - abnormal electrocardiogram (ECG), change in heart rate or rhythm - liver failure - allergic reactions (sometimes severe), including widespread blistering rash and skin peeling,

severe skin reactions, swelling of the lips or face - hair loss If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE DIFLUCAN - Keep out of the reach and sight of children. - Do not use Diflucan after the expiry date which is stated on the pack after EXP. The expiry date

refers to the last day of the month. - Store below 30°C Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Diflucan contains - The active substance is fluconazole. - Each hard capsule contains 50 mg, 100 mg, 150 mg or 200 mg of fluconazole. - The other ingredients are: Capsule content: lactose monohydrate, maize starch, colloidal silica anhydrous, magnesium stearate and sodium laurilsulfate. Capsule shell composition: 50 mg hard capsules: gelatin, titanium dioxide (E171) and patent blue V (E131) 100 mg hard capsules: gelatin, titanium dioxide (E171), erythrosin (E127) and patent blue V (E131) 150 mg hard capsules: gelatin, titanium dioxide (E171) and patent blue V (E131) 200 mg hard capsules: gelatin, titanium dioxide (E171), erythrosine (E127) and indigo carmine (E 132) Printing ink: shellac (glaze), black iron oxide, N-Butyl alcohol, dehydrated alcohol, purified water, propylene glycol, industrial methylated spirit, isopropyl alcohol, strong ammonia solution, potassium hydroxide

What Diflucan 50 mg, 100 mg, 150 mg and 200 mg hard capsules look like and contents of the pack - Diflucan 50 mg hard capsules have a white body and a turquoise blue cap. They have “FLU-50”

and “Pfizer” with black ink printed on them. - Diflucan 100 mg hard capsules have a white body and a blue cap. They have “FLU-100” and

“Pfizer” with black ink printed on them. - Diflucan 150 mg hard capsules have a turquoise blue body and a turquoise blue cap. They have

“FLU-150” and “Pfizer” with black ink printed on them. - Diflucan 200 mg hard capsules have a white body and a purple cap. They have “FLU-200” and

“Pfizer” with black ink printed on them. Diflucan 50 mg, 100 mg, 150 mg and 200 mg come in packs of 1, 2, 3, 4, 6, 7, 10, 12, 14, 20, 28, 30, 42, 50, 60, 100 or 500 hard capsules. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in. [To be completed nationally] Detailed information on this medicine is available on the web site of {MA/Agency}: [To be completed nationally]


Diflucan and associated names (see Annex I) 5 mg/ml oral solution [See Annex I – To be completed nationally]

fluconazole



please tell your doctor or pharmacist. In this leaflet: 1. What Diflucan is and what it is used for 2. Before you take Diflucan 3. How to take Diflucan 4. Possible side effects 5. How to store Diflucan 6. Further information

1. WHAT DIFLUCAN IS AND WHAT IT IS USED FOR Diflucan is one of a group of medicines called “antifungals”. The active substance is fluconazole. Diflucan is used to treat infections caused by fungi and may also be used to stop you from getting a candidal infection. The most common cause of fungal infections is a yeast called Candida. Adults You might be given this medicine by your doctor to treat the following types of fungal infections: - Cryptococcal meningitis – a fungal infection in the brain - Coccidioidomycosis – a disease of the bronchopulmonary system - Infections caused by Candida and found in the blood stream, body organs (e.g. heart, lungs) or

urinary tract - Mucosal thrush - infection affecting the lining of the mouth, throat and denture sore mouth - Genital thrush - infection of the vagina or penis - Skin infections - e.g. athlete's foot, ringworm, jock itch, nail infection

You might also be given Diflucan to: - stop cryptococcal meningitis from coming back - stop mucosal trush from coming back - reduce recurrence of vaginal trush - stop you from getting an infection caused by Candida (if your immune system is weak and not



You might also be given Diflucan to: - stop you from getting an infection caused by Candida (if your immune system is weak and not working properly) - stop cryptococcal meningitis from coming back 2. BEFORE YOU TAKE DIFLUCAN Do not take Diflucan if you - are allergic (hypersensitive) to fluconzole, to other medicines you have taken to treat fungal






Steroidal Anti-Inflammatory Drugs (NSAID)) - oral contraceptives - prednisone (steroid) - zidovudine, also known as AZT; saquinavir (used in HIV-infected patients) - medicines for diabetes such as chlorpropamide, glibenclamide, glipizide or tolbutamide

- theophylline (used to control asthma) - vitamin A (nutritional supplement)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Taking Diflucan with food and drink Diflucan can be taken with or without food. Pregnancy and breast-feeding Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding. You should not take Diflucan while you are pregnant or breast-feeding unless your doctor has told you to. Ask your doctor or pharmacist for advice before taking any medicines. Driving and using machines When driving vehicles or using machines it should be taken into account that occasionally dizziness or fits may occur. Important information about some of the ingredients of Diflucan Diflucan contains sucrose (sugar). - If you have an intolerance to some sugars, please contact your doctor before taking this

medicine. - Doses of 10 ml contain 1.3 g of sugar. This should be taken into account if you have diabetes. - May be harmful to teeth if used for periods of longer than 2 weeks. Diflucan also contains glycerol. Glycerol may cause headache, stomach upset, and diarrhoea. 3. HOW TO TAKE DIFLUCAN Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. The usual doses of this medicine for different infections are below. It is best to take medicine at the same time each day. Adults Condition Dose








50 mg to 400 mg once daily for 7 to 30 day until you are told to stop

To stop mucosal infections affecting the lining of the mouth, throat














Use in children 0 to 4 weeks of age

Use in children of 3 to 4 weeks of age: The same dose as above but given once every 2 days. The maximum dose is 12 mg per kg of body weight every 48 hours. Use in children less than 2 weeks old:

The same dose as above but given once every 3 days. The maximum dose is 12 mg per kg of body weight every 72 hours. Doctors sometimes prescribe different doses to these. Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Elderly The usual adult dose should be given unless you have kidney problems. Patients with kidney problems Your doctor may change your dose, depending on your kidney function. If you take more Diflucan than you should Taking too much Diflucan may make you unwell. Contact your doctor or your nearest hospital casualty department at once. The symptoms of a possible overdose may include hearing, seeing, feeling and thinking things that are not real (hallucination and paranoid behaviour). Symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. If you forget to take Diflucan Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, take it as soon as you remember. If it is almost time for your next dose, do not take the dose that you missed. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Diflucan can cause side effects, although not everybody gets them A few people develop allergic reactions although serious allergic reactions are rare. If you get any of the following symptoms, tell your doctor immediately. - sudden wheezing, difficulty in breathing or tightness in the chest - swelling of eyelids, face or lips - itching all over the body reddening of the skin or itchy red spots - skin rash - severe skin reactions such as a rash that causes blistering (this can affect the mouth and tongue). Diflucan may affect your liver. The signs of liver problems include: - tiredness - loss of appetite - vomiting - yellowing of your skin or the whites of your eyes (jaundice) If any of theses happen, stop taking Diflucan and tell your doctor immediately. Other side effects: Additionally, if any of the following side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Common side effects which affect 1 to 10 users in 100 are listed below: - headache - stomach discomfort, diarrhoea, feeling sick, vomiting - increases in blood tests of liver function - rash Uncommon side effects which affect 1 to 10 users in 1,000 are listed below: - reduction in red blood cells which can make skin pale and cause weakness or breathlessness

- decreased appetite - inability to sleep, feeling drowsy - fit, dizziness, sensation of spinning, tingling, pricking or numbness, changes in sense of taste - constipation, difficult digestion, wind, dry mouth - muscle pain - liver damage and yellowing of the skin and eyes (jaundice) - wheals, blistering (hives), itching, increased sweating - tiredness, general feeling of being unwell, fever Rare side effects which affect 1 to 10 users in 10,000 are listed below: - lower than normal white blood cells that help defend against infections and blood cells that help


cell changes - blood chemistry changes (high blood levels of cholesterol, fats) - low blood potassium - shaking - abnormal electrocardiogram (ECG), change in heart rate or rhythm - liver failure - allergic reactions (sometimes severe), including widespread blistering rash and skin peeling,

severe skin reactions, swelling of the lips or face - hair loss If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE DIFLUCAN - The medicinal product does not require any special storage conditions. - Keep out of the reach and sight of children. - Do not use Diflucan after the expiry date which is stated on the bottle after EXP. The expiry

date refers to the last day of that month. - Once opened, Diflucan may be used for a maximum of 30 days. - Do not use the medicine if you notice signs of deterioration such as unusual odour, product

discoloration, visible particles or crystallisation. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Diflucan contains - The active substance is fluconazole. - The other ingredients are sucrose, glycerol 85%, purified water, citric acid monohydrate, sodium

citrate and cherry Liquid Flavor. What Diflucan looks like and contents of the pack Diflucan is a clear, colourless to slightly yellow solution with a viscosity greater than water and is supplied in an amber glass bottle with a screw cap containing 750 mg fluconazole. Pack size 150 ml. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally]

This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in Detailed information on this medicine is available on the web site of {MA/Agency} [To be completed nationally]


Diflucan and associated names (see Annex I) 10 mg/ml powder for oral suspension Diflucan and associated names (see Annex I) 40 mg/ml powder for oral suspension

[See Annex I – To be completed nationally]

fluconazole



please tell your doctor or pharmacist. In this leaflet: 1. What Diflucan is and what it is used for 2. Before you take Diflucan 3. How to take Diflucan 4. Possible side effects 5. How to store Diflucan 6. Further information 1. WHAT DIFLUCAN IS AND WHAT IT IS USED FOR Diflucan is one of a group of medicines called “antifungals”. The active substance is fluconazole. Diflucan is used to treat infections caused by fungi and may also be used to stop you from getting a candidal infection. The most common cause of fungal infections is a yeast called Candida. Adults You might be given this medicine by your doctor to treat the following types of fungal infections: - Cryptococcal meningitis– a fungal infection in the brain - Coccidioidomycosis– a disease of the bronchopulmonary system - Infections caused by Candida and found in the blood stream, body organs (e.g. heart, lungs) or

urinary tract - Mucosal thrush - infection affecting the lining of the mouth, throat and denture sore mouth - Genital thrush - infection of the vagina or penis - Skin infections - e.g. athlete's foot, ringworm, jock itch, nail infection You might also be given Diflucan to: - stop cryptococcal meningitis from coming back - stop mucosal trush from coming back - reduce recurrence of vaginal trush - stop you from getting an infection caused by Candida (if your immune system is weak and not



You might also be given Diflucan to: - stop you from getting an infection caused by Candida (if your immune system is weak and not working properly). - stop cryptococcal meningitis from coming back 2. BEFORE YOU TAKE DIFLUCAN Do not take Diflucan if you - are allergic (hypersensitive) to fluconazole, to other medicines you have taken to treat fungal





cholesterol levels - methadone (used for pain) - celecoxib, flubiprofen, naproxen, ibuprofen, lornoxicam, meloxicam, diclofenac (Non-Steroidal

Anti-Inflammatory Drugs (NSAID)) - oral contraceptives - prednisone (steroid) - zidovudine, also known as AZT; saquinavir (used in HIV-infected patients) - medicines for diabetes such as chlorpropamide, glibenclamide, glipizide or tolbutamide

- theophylline (used to control asthma) - vitamin A (nutritional supplement)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Taking Diflucan with food and drink Diflucan can be taken with or without food. Pregnancy and breast-feeding Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding. You should not take Diflucan while you are pregnant or breast-feeding unless your doctor has told you to. Ask your doctor or pharmacist for advice before taking any medicines. Driving and using machines When driving vehicles or using machines it should be taken into account that occasionally dizziness or fits may occur. Important information about some of the ingredients of Diflucan Diflucan powder for oral suspension contains sucrose (sugar). - If you have an intolerance to some sugars, please contact your doctor before taking this

medicine. - Doses of 10 ml contain 5.6 g or more of sugar. This should be taken into account if you have

diabetes. - May be harmful to teeth if used for periods of longer than 2 weeks. 3. HOW TO TAKE DIFLUCAN Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. It is best to take medicine at the same time each day. The usual doses of this medicine for different infections are below: Adults Condition Dose





To treat mucosal infections affecting the lining of the mouth, throat and denture sore mouth




To stop mucosal infections of mouth and throat from coming back














Use in children 0 to 4 weeks of age Use in children of 3 to 4 weeks of age: The same dose as above but given once every 2 days. The maximum dose is 12 mg per kg of body weight every 48 hours. Use in children less than 2 weeks old: The same dose as above but given once every 3 days. The maximum dose is 12 mg per kg of body weight every 72 hours.

Doctors sometimes prescribe different doses to these. Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Elderly The usual adult dose should be given unless you have kidney problems. Patients with kidney problems Your doctor may change your dose, depending on your kidney function. Instructions to make up the suspension: It is recommended that your pharmacist makes up Diflucan powder for oral suspension before giving it to you. Instructions are provided in a section of this leaflet for healthcare professionals. Instructions for use: Shake the closed bottle of the suspension every time before using. Instructions to use the paediatric syringe: (Applicable only if marketed in your country) Shake the prepared suspension well. 1. Open the bottle (safety cap); 2. Insert the adapter fitted onto the syringe into the bottle neck (Figure 1); 3. Turn the bottle with the syringe upside down and withdraw the quantity of suspension prescribed by the doctor (Figure 2). The marks on the syringe are shown in ml. The maximum dose for children is 400 mg daily (see section “3. How to take Diflucan”). 4. Remove the syringe from the bottle; 5. For younger children, the medicinal product may be given directly into the mouth from the syringe. The child should remain upright during administration. Point the syringe at the inside of the cheek; release the suspension slowly into the child's mouth (Figure 3). For older children, the suspension may be put in a spoon and drunk by the child. 6. Rinse the syringe after use. 7. Close the bottle with the safety cap; the adapter will remain on the bottle neck.

If you take more Diflucan than you should Taking too much Diflucan may make you unwell. Contact your doctor or your nearest hospital casualty department at once. The symptoms of a possible overdose may include hearing, seeing, feeling and thinking things that are not real (hallucination and paranoid behaviour). Symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. If you forget to take Diflucan Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, take it as soon

as you remember. If it is almost time for your next dose, do not take the dose that you missed. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Diflucan can cause side effects, although not everybody gets them A few people develop allergic reactions although serious allergic reactions are rare. If you get any of the following symptoms, tell your doctor immediately. - sudden wheezing, difficulty in breathing or tightness in the chest - swelling of eyelids, face or lips - itching all over the body reddening of the skin or itchy red spots - skin rash - severe skin reactions such as a rash that causes blistering (this can affect the mouth and tongue). Diflucan may affect your liver. The signs of liver problems include: - tiredness - loss of appetite - vomiting - yellowing of your skin or the whites of your eyes (jaundice) If any of theses happen, stop taking Diflucan and tell your doctor immediately. Other side effects: Additionally, if any of the following side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Common side effects which affect 1 to 10 users in 100 are listed below: - headache - stomach discomfort, diarrhoea, feeling sick, vomiting - increases in blood tests of liver function - rash Uncommon side effects which affect 1 to 10 users in 1,000 are listed below: - reduction in red blood cells which can make skin pale and cause weakness or breathlessness - decreased appetite - inability to sleep, feeling drowsy - fit, dizziness, sensation of spinning, tingling, pricking or numbness, changes in sense of taste - constipation, difficult digestion, wind, dry mouth - muscle pain - liver damage and yellowing of the skin and eyes (jaundice) - wheals, blistering (hives), itching, increased sweating - tiredness, general feeling of being unwell, fever Rare side effects which affect 1 to 10 users in 10,000 are listed below: - lower than normal white blood cells that help defend against infections and blood cells that help

to stop bleeding

- red or purple discoloration of the skin which may be caused by low platelet count, other blood cell changes

- blood chemistry changes (high blood levels of cholesterol, fats) - low blood potassium, - shaking - abnormal electrocardiogram (ECG), change in heart rate or rhythm - liver failure - allergic reactions (sometimes severe), including widespread blistering rash and skin peeling,

severe skin reactions, swelling of the lips or face - hair loss If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE DIFLUCAN - Keep out of the reach and sight of children. - Do not use Diflucan after the expiry date which is stated on the pack after EXP. The expiry date

refers to the last day of that month. - Powder for oral suspension (60 ml bottle): - Keep the bottle tightly closed. Store below 25°C - Powder for oral suspension (175 ml bottle): - Store the powder below 25°C. Keep the bottle tightly closed. - Once reconstituted, store the suspension below 30°C, do not freeze. - The shelf life of the reconstituted suspension is 28 days. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Diflucan contains - The active substance is fluconazole. - The other ingredients are: sucrose, silica colloidal anhydrous, titanium dioxide (E 171), xanthan

gum, sodium citrate, citric acid anhydrous, sodium benzoate and natural orange flavour (containing orange oil and maltodextrin).

What Diflucan 10 mg/ml and 40 mg/ml powder for oral suspension look like and contents of the pack: For the 60 ml bottle: - Diflucan 10 mg/ml and 40 mg/ml powder for oral suspension is a dry white to off-white powder.

After adding water to the powder (as instructed in the leaflet for healthcare professionals) an orange flavoured suspension containing the equivalent of 10 mg or 40 mg of fluconazole per ml is produced.

- In each bottle the mixture of powder and water makes 35 ml of suspension. - A 5 ml measuring spoon and/or a 5 ml graduated syringe with a press-in bottle adaptor might

also be provided to measure the correct dose . For the 175 ml bottle: - Diflucan 10 mg/ml powder for oral suspension is a dry white to off-white powder. After adding

water to the powder (as instructed in the leaflet for healthcare professionals) an orange flavoured suspension containing the equivalent of 10 mg of fluconazole per ml is produced.

- In each bottle the mixture of powder and water makes 100 ml of suspension.

- A measuring cup is also provided to measure the correct dose . Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in Detailed information on this medicine is available on the web site of {MA/Agency} [To be completed nationally] --------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: Instructions to make up the suspension: The reconstituted suspension will provide a white to off-white orange-flavoured suspension after reconstitution. For the 60 ml bottle: 1. Tap the bottle to release the powder. 2. Add a small quantity of still water and shake it vigorously. Add water up to the level marked on the bottle (this corresponds to adding 24 ml of water) 3. Shake well for one to two minutes to obtain a well mixed suspension. 4. Write the expiry date of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days). Any unused suspension should be not be used after this date and should be returned to your pharmacist. For the 175 ml bottle: 1. Tap the bottle to release the powder. 2. Measure 66 ml of still water and add the water to the bottle. 3. Shake well for one to two minutes to obtain a well mixed suspension. 4. Write the expiry date of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days). Any unused suspension should be not be used after this date and should be returned to your pharmacist.


Diflucan and associated names (see Annex I) 2 mg/ml solution for infusion [See Annex I – To be completed nationally]

fluconazole



please tell your doctor or pharmacist. In this leaflet: 1. What Diflucan is and what it is used for 2. Before you are given Diflucan 3. How Diflucan is given 4. Possible side effects 5. How to store Diflucan 6. Further information 1. WHAT DIFLUCAN IS AND WHAT IT IS USED FOR Diflucan is one of a group of medicines called “antifungals”. The active substance is fluconazole. Diflucan is used to treat infections caused by fungi and may also be used to stop you from getting candidalinfection. The most common cause of fungal infections is a yeast called Candida. Adults You might be given this medicine by your doctor to treat the following types of fungal infections: - Cryptococcal meningitis – a fungal infection in the brain - Coccidioidomycosis – a disease of the bronchopulmonary system - Infections caused by Candida and found in the blood stream, body organs (e.g. heart, lungs) or

urinary tract - Mucosal thrush - infection affecting the lining of the mouth, throat and denture sore mouth You might also be given Diflucan to: - stop cryptococcal meningitis from coming back - stop mucosal trush from coming back - stop you from getting an infection caused by Candida (if your immune system is weak and not


urinary tract - Cryptococcal meningitis – a fungal infection in the brain You might also be given Diflucan to: - stop you from getting an infection caused by Candida (if your immune system is weak and not working properly) - stop cryptococcal meningitis from coming back

2. BEFORE YOU ARE GIVEN DIFLUCAN You should not be treated with Diflucan if you - are allergic (hypersensitive) to fluconazole, to other medicines you have taken to treat fungal






Steroidal Anti-Inflammatory Drugs (NSAID)) - oral contraceptives - prednisone (steroid) - zidovudine, also known as AZT; saquinavir (used in HIV-infected patients) - medicines for diabetes such as chlorpropamide, glibenclamide, glipizide or tolbutamide - theophylline (used to control asthma) - vitamin A (nutritional supplement)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Pregnancy and breast-feeding Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding and your doctor will decide whether you should be given Diflucan. Ask your doctor or pharmacist for advice before taking any medicines. Driving and using machines When driving vehicles or using machines it should be taken into account that occasionally dizziness or fits may occur. Important information about some of the ingredients of Diflucan Diflucan contains 0.154 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet. 3. HOW DIFLUCAN IS GIVEN

This medicine will be given by your doctor or nurse as a slow injection (infusion) into your vein. Diflucan is supplied as a solution. It will not be diluted further. There is more information for healthcare professionals in a section at the end of the leaflet

The usual doses of this medicine for different infections are below. Check with your doctor or nurse if you are not sure why you are being given Diflucan. Adults Condition Dose









To stop mucosal infections affecting the lining of mouth, throat




Adolescents from 12 to 17 years old Follow the dose prescribed by your doctor (either adults or children posology).

Children to 11 years old The maximum dose for children is 400 mg daily. The dose will be based on the child’s weight in kilograms.

Condition Daily dose







Use in children 0 to 4 weeks of age Use in children of 3 to 4 weeks of age: The same dose as above but given once every 2 days. The maximum dose is 12 mg per kg of body weight every 48 hours. Use in children less than 2 weeks old: The same dose as above but given once every 3 days. The maximum dose is 12 mg per kg of body weight every 72 hours. Doctors sometimes prescribe different doses to these. Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Elderly The usual adult dose should be given unless you have kidney problems. Patients with kidney problems Your doctor may change your dose, depending on your kidney function. If you receive more Diflucan than you should If you are concerned that you may have been given too much Diflucan, tell your doctor or nurse immediately. The symptoms of a possible overdose may include hearing, seeing, feeling and thinking things that are not real (hallucination and paranoid behaviour). If a dose of Diflucan has been forgotten As you will be given this medicine under close medical supervision, it is unlikely that a dose would be missed. However tell your doctor or pharmacist if you think that a dose has been forgotten. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 4. POSSIBLE SIDE EFFECTS Like all medicines, Diflucan can cause side effects, although not everybody gets them A few people develop allergic reactions although serious allergic reactions are rare. If you get any of the following symptoms, tell your doctor immediately. - sudden wheezing, difficulty in breathing or tightness in the chest - swelling of eyelids, face or lips

- itching all over the body reddening of the skin or itchy red spots - skin rash - severe skin reactions such as a rash that causes blistering (this can affect the mouth and tongue). Diflucan may affect your liver. The signs of liver problems include: - tiredness - loss of appetite - vomiting - yellowing of your skin or the whites of your eyes (jaundice) If any of theses happen, stop taking Diflucan and tell your doctor immediately. Other side effects: Additionally, if any of the following side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Common side effects which affect 1 to 10 users in 100 are listed below: - headache - stomach discomfort, diarrhoea, feeling sick, vomiting - increases in blood tests of liver function - rash Uncommon side effects which affect 1 to 10 users in 1,000 are listed below: - reduction in red blood cells which can make skin pale and cause weakness or breathlessness - decreased appetite - inability to sleep, feeling drowsy - fit, dizziness, sensation of spinning, tingling, pricking or numbness, changes in sense of taste - constipation, difficult digestion, wind, dry mouth - muscle pain - liver damage and yellowing of the skin and eyes (jaundice) - wheals, blistering (hives), itching, increased sweating - tiredness, general feeling of being unwell, fever Rare side effects which affect 1 to 10 users in 10,000 are listed below: - lower than normal white blood cells that help defend against infections and blood cells that help


cell changes - blood chemistry changes (high blood levels of cholesterol, fats) - shaking - low blood potassium - abnormal electrocardiogram (ECG), change in heart rate or rhythm - liver failure - allergic reactions (sometimes severe), including widespread blistering rash and skin peeling,

severe skin reactions, swelling of the lips or face - hair loss If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, pharmacist or nurse. 5. HOW TO STORE DIFLUCAN - Keep out of the reach and sight of children. - Do not use after the expiry date which is stated on the pack after EXP. The expiry date refers to

the last day of that month. - Glass vials: Do not freeze.

- Plasticised PVC bags: Store below 30°C. Do not freeze. This medicinal product is for single use. Once opened, any unused infusion should be discarded.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Diflucan solution for infusion contains - The active substance is fluconazole. - Each ml contains 2 mg of fluconazole. - The other ingredients are: sodium chloride, water for injections and sodium hydroxide (for pH

adjustment). What Diflucan solution for infusion looks like and contents of the pack - Diflucan is a clear, colourless solution with no visible particles. - It comes in either a glass vial containing a total of 50 mg, 100 mg, 200 mg or 400 mg

fluconazole or 1, 5, 10 and 20 plasticised PVC bag(s) containing a total of 200 mg or 400 mg fluconazole. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer [See Annex I - To be completed nationally] This medicinal product is authorised in the Member States of the EEA under the following names: [See Annex I - To be completed nationally] This leaflet was last approved in [To be completed nationally] Detailed information on this medicine is available on the web site of {MA/Agency} [To be completed nationally]

--------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: Intravenous infusion should be administrated at a rate not exceeding 10 ml/minute. Diflucan is formulated in sodium chloride 9 mg/ml (0.9%) solution for infusion, each 200 mg (100 ml bottle) containing 15 mmol each of Na+ and C1-. Because Diflucan is available as a dilute sodium chloride solution, in patients requiring sodium or fluid restriction, consideration should be given to the rate of fluid administration. Fluconazole intravenous infusion is compatible with the following administration fluids: a) Dextrose 5% and 20% b) Ringer's solution c) Hartmann's solution d) Potassium chloride in dextrose e) Sodium bicarbonate 4.2% and 5% f) Aminosyn 3.5% g) Sodium chloride 9 mg/ml (0.9%) h) Dialaflex (interperitoneal dialysis Soln 6.36%)

Fluconazole may be infused through an existing line with one of the above listed fluids. Although no specific incompatibilities have been noted, mixing with any other medicinal products prior to infusion is not recommended. The solution for infusion is for single use only. From a microbiological point of view, the dilutions should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 ° C, unless dilution has taken place in controlled and validated aseptic conditions. The dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles. Any unused medicinal product or waste material should be disposed of in accordance with local requirements

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