FLUOXETINE 20MG/5ML ORAL SOLUTION PROZEP™ … · MHRA PAR – FLUOXETINE/PROZEPTM 20MG/5ML ORAL...

MHRA PAR – FLUOXETINE/PROZEPTM 20MG/5ML ORAL SOLUTION PL 17736/0062 - 1 -

Public Assessment Report

FLUOXETINE 20MG/5ML ORAL SOLUTION PROZEP™ 20MG/5ML ORAL SOLUTION

(FLUOXETINE)

PL 17736/0062



(FLUOXETINE HYDROCHLORIDE) PL 17736/0062

UKPAR

TABLE OF CONTENTS

Lay Summary

Page 3

Scientific discussion

Page 4

Steps taken for assessment

Page 18

Steps taken after authorisation – summary

Page 19

Summary of Product Characteristics 0

Product Information Leaflet

Page 32

Labelling Page 35




LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) has granted Chemidex Pharma Limited a Marketing Authorisation (licence) for the medicinal product Fluoxetine / Prozep™ 20mg/5ml Oral Solution (PL 17736/0062). Fluoxetine is an antidepressant indicated for the treatment of depressive illness such as Major Depressive Episodes, Obsessive – Compulsive Disorder and Bulimia Nervosa. This product is an prescription only medicines [POM]. Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as α1-, α2 -, and β-adrenergic; dopaminergic; histaminergic1; muscarinic; and gamma aminobutyric acid (GABA) receptors. The data presented to the MHRA, before licensing, demonstrated that the composition of Fluoxetine / ProzepTM 20mg/5ml Oral Solution is comparable to the reference product, Prozac Oral Solution, (Eli Lilly & Company Limited - PL 00006/0272) first licensed in the UK on 28th October 1992. Based on the information provided, Fluoxetine / Prozep™ 20mg/5ml Oral Solution from Chemidex Pharma Limited is considered interchangeable with Prozac Oral Solution. No new or unexpected safety concerns arose from this application and it was decided that the benefits of using Fluoxetine / Prozep™ 20mg/5ml Oral Solution outweigh the risks, hence a Marketing Authorisation has been granted.




SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 5

Pharmaceutical assessment

Page 6

Preclinical assessment

Page 12

Clinical assessment

Page 13

Overall conclusions and risk benefit assessment Page 17


INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted marketing authorisation for the medicinal product Fluoxetine / Prozep™ 20mg/5ml Oral Solution (PL 17736/0062) to Chemidex Pharma Limited on 22nd September 2006. This product is a prescription only medicine (POM). The application was submitted as an abridged application according to Article 10.1 [formerly Article 10.1(a)(iii)] of Directive 2001/83/EC as amended, claiming essential similarity to Prozac Oral Solution (PL 00006/0272), licence granted in 1992. The product contains the drug substance fluoxetine hydrochloride. Fluoxetine hydrochloride is a synthetic aromatic derivative of propylamine and a selective serotonin re-uptake inhibitor. It is indicated for the treatment of:

Major depressive episodes Obsessive – compulsive disorder Bulimia nervosa - Fluoxetine oral solution is indicated as a complement of

psychotherapy for the reduction of binge eating and purging activity.


PHARMACEUTICAL ASSESSMENT

LICENCE NO: PL 17736/0062 PROPRIETARY NAME: Fluoxetine 20mg/5ml Oral Solution Prozep™ 20mg/5ml Oral Solution ACTIVE(S): Fluoxetine Hydrochloride COMPANY NAME: Chemidex Pharma Limited

[Trading as Chemidex Generics and / or Essential Generics] E.C. ARTICLE: Article 10.1

[formerly Article 10.1(a)(iii) of Directive 2001/83/EC] LEGAL STATUS: POM 1. INTRODUCTION & BACKGROUND This is a national abridged standard application for an oral solution containing 20mg/5ml fluoxetine (as hydrochloride), submitted under Article 10.1 [formerly Article 10.1 (a)(iii) first paragraph of EEC Directive 2001/83]. The applicant is claiming essential similarity to Prozac Oral Solution (Eli Lilly & Company Limited - PL 00006/0272), licence granted in October 1992. No clinical studies are reported. The first UK Marketing Authorisation for the use of fluoxetine hydrochloride was granted to Eli Lilly & Co in 1988 for Prozac 20mg capsules, PL 00006/0195. In 1992 the range was extended to include Prozac Oral Solution PL 00006/0272. Prozac Oral Solution has been on the market in the UK for more than 10 years and is no longer covered by data exclusivity. The active, fluoxetine, is a synthetic aromatic derivative of propylamine and a selective serotonin re-uptake inhibitor. It is administered by mouth and is not available for parenteral therapy. The UK approved therapeutic indications and doses are listed below; • Depressive illness- 20 mg daily with doses of up to 80 mg daily. • Bulimia nervosa- 60 mg daily. • Obsessive-compulsive disorder- initially 20 mg daily, maximum of 60 mg daily. • Premenstrual dysphoric disorder- 20 mg daily for 6 months. Benefit should be

assessed before continuation of therapy. The applicant has indicated that subsequent mutual recognition procedure will be considered. 2. MARKETING AUTHORISATION APPLICATION FORM 2.1 Name(s) The proposed names of the product are Fluoxetine / Prozep™ 20mg/5ml Oral Solution. The product has been named in line with current requirements.


2.2 Strength, pharmaceutical form, route of administration, container and pack sizes

The oral solution contains fluoxetine hydrochloride as active substance equivalent to 20mg of fluoxetine per 5 ml. The solution is presented in amber glass bottles containing 70ml with tamper evident child resistant closures. The UK approved shelf-life (2 years; Use within one month of first opening) and storage conditions (Do not store above 25oC, store in the original container) are supported by the data submitted. 2.3 Legal status The product will be subject to a medical prescription. 2.4 Marketing authorisation holder/Contact Persons/Company The proposed Marketing Authorisation holder is Chemidex Pharma Limited Chemidex House, Unit 7, Egham Business Village, Crabtree Road, Thorpe Industrial Estate, Egham, Surrey, TW20 8RB, United Kingdom. The Qualified Person responsible for pharmacovigilance is stated and their CV is included. 2.5 TSE A BSE/TSE risk status declarations have been included from all excipient suppliers and the drug substance manufacturer which indicates that all constituents are either synthetic or of vegetable origin and as such pose no BSE/TSE risk. DRUG SUBSTANCE One source of drug substance is approved. A Ph Eur Certificates of Suitability has been provided for this source. The certificate indicates that the quality of the drug substance is suitably controlled by the Ph Eur monograph, if supplemeneted by additional specified tests.

Analytical Procedures Analytical procedures are described.

Validation of Analytical Procedures Satisfactory validation data are provided for the analytical procedures.

Batch Analysis Results of industrial scale batches of fluoxetine hydrochloride comply with Ph. Eur and additional test limits stated in the Certificate of Suitability.

Stability A re-test period of 3 years if stored in PE bags kept in PE drums is proposed consistent with details specified in the Certificate of Suitability.


DOSAGE FORM Composition The composition is satisfactory and tabulated below. Formula Function Reference to

standards

Active

Fluoxetine (as hydrochloride) Active Ph Eur Excipients

Sorbitol Solution 70% Sweetener Ph Eur Glycerol Sweetener and solvent Ph Eur Polyoxyl 40 hydrogenated caster oil Solubilising agent Ph Eur Benzoic acid Preservative Ph Eur Peppermint flavour Flavouring agent HSE Purified Water (to volume) Solvent Ph Eur

PHARMACEUTICAL DEVELOPMENT

Drug substance A white or almost white crystalline powder, sparingly soluble in water, freely soluble in methanol and sparingly soluble in methylene chloride.

Excipients All excipients are Ph. Eur. compendial grade except for the peppermint flavouring. Typical certificates of analysis are provided from the manufacturer of the finished product for each of the excipients. The function and concentration of the excipients used is standard and accepted. A declaration has been provided by the flavour house giving the list of ingredients in the peppermint flavour and declaring that the flavour is natural or nature identical and contains ethanol. Confirmation is provided that solvents used in the preparation of the flavour comply with Ph Eur requirements.

Container Closure System Pharmaceutical grade, type III amber glass bottles with nominal fill volume of 75ml and tamper evident child resistant closures (CRC). A declaration is provided from the bottle and closure suppliers confirming suitability for food and pharmaceutical use and compliance of the closure with Directive 90/128/EEC. Bottle also comply with the Ph Eur glass type III requirements.

Microbiological Attributes The microbiological attributes are controlled in the finished product specification to Ph. Eur. 5.1.4 category 3A and accepted.


MANUFACTURE GMP Statement and Manufacturing Chain The manufacturing site of the finished product is Famar Nederland BV, Industrieweg 1, 5531 Ad Blabel, The Netherlands. This site is considered suitable. This is also the assembly, storage site and batch release site. A full copy of the licence issued to Famar Nederland BV has been provided. This document shows that the facility is approved for the manufacture of oral solutions Description of the Manufacturing Process A satisfactory formula and description of manufacture are provided. Critical phases of the manufacturing process have been satisfactorily identified and appropriate in-process controls are in place. The analytical methods and limits are the same as those used in finished product testing and comply with current guidelines and accepted. The solution is packaged with satisfactory in-process controls. In-process batch data for the validation batches is satisfactory. The validation results demonstrate homogeneity of solution and consistent manufacture. The validation protocol provided is considered adequate for the purpose. Control of Excipients The list of excipients, complying with Ph. Eur. requirements, is given under “Composition of the medicinal product” above. Satisfactory Certificates of Analysis have been provided for each excipient and are accepted. The compendial methodology is used in testing where appropriate. Specifications A satisfactory finished product specification is provided. Analytical Procedures Satisfactory validation data are provided. Batch data Satisfactory data are provided for batches manufactured at the proposed site and are considered representative of the product to be marketed. Container Closure System Satisfactory details of supplier specification, product construction, standards and compliance statements are provided. In-house specification giving details of tests performed on receipt are provided. Standard Storage Conditions Based on stability data at normal, intermediate and accelerated conditions. Satisfactory in-use stability data is also provided in line with the CPMP/QWP/2934/99 guideline. The data support the a product shelf-life of 2 years (one month once opened) and the storage conditions ‘do not store above 25°C, store in the original package’ are approved.


The samples provided for stability studies are representative of the product to be marketed in the proposed pack. Quality Overall Summary This is satisfactory. Pharmacokinetics Fluoxetine is well absorbed from the GI tract and its bioavailability is not affected by food. Published data show that following single dose administration (40-60mg) to healthy fasted volunteers, the mean time to peak plasma concentration is 6-8 hours. Fluoxetine is relatively highly bound to plasma proteins (80-95%) and has a relatively slow rate of elimination, with a half-life of 1 to 4 days. The main metabolite of fluoxetine is norfluoxetine. Norfluoxetine has similar potency and selectivity of 5-HT uptake inhibition compared with the parent compound. Norfluoxetine has a half life of ranging from 7 to 15 days. Bioequivalence Bioequivalence data are not required as the product is an aqueous solution for oral administration. The excipients used are not expected to affect gastrointestinal transit, absorption or in-vivo stability of the active substance. PRODUCT PARTICULARS Product Brand Name This is considered satisfactory. Summary of Product Characteristics Satisfactory SPC provided. Patient Information Leaflet Satisfactory coloured mock-ups are provided. The applicant has until 1st July 2008 to amend the order in which the information appears in the leaflet and provide user testing data (both parts of Article 59, Directive 2004/27/EC must be complied with at the same time). Labelling Satisfactory. MARKETING AUTHORISATION APPLICATION (MAA) form This is satisfactory. ADDITIONAL DATA REQUIREMENTS Satisfactory.


CONCLUSION A product licence may be granted for this product.


PRECLINICAL ASSESSMENT No new preclinical data have been supplied with these applications and none are required for an application of this type.


CLINICAL ASSESSMENT

1. INTRODUCTION AND BACKGROUND This is a standard abridged National Marketing Application for Fluoxetine 20mg/5ml Sugar Free Oral Solution, using the branded name ProzepTM 20mg/5ml Oral Solution made under EC Article 10.1 [Formerly 10.1 (a)(iii) of the directive 2001/83/EEC]. Essential similarity is claimed to Prozac Liquid (Eli Lilly and Company Ltd, (PL 00006/0272), which was first approved for marketing in October 1992. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI) antidepressant and was first marketed in 1988 in the UK with accumulated worldwide use for 15 years. The applicant has produced a sugar free formulation, but the drug substance and preservative remain at the same concentration as in the branded product. 2. INDICATIONS From UK approved SPC: Fluoxetine Oral Solution is indicated for the treatment of: Major depressive episodes Obsessive – compulsive disorder Bulimia nervosa - Fluoxetine oral solution is indicated as a complement of psychotherapy for the reduction of binge eating and purging activity. Two placebo-controlled studies were conducted in patients meeting Pre-Menstrual Dysphoric disorder (PMDD) diagnostic criteria according to DSM-IV. Patients were included if they had symptoms of sufficient severity to impair social and occupational function and relationships with others. Patients using oral contraceptives were excluded. In the first study of continuous 20mg daily dosing for 6 cycles, improvement was observed in the primary efficacy parameter (irritability, anxiety, and dysphoria). In the second study, with intermittent luteal phase dosing (20mg daily for 14 days) for 3 cycles, improvement was observed in the primary efficacy parameter (daily record of Severity of Problem score). However definitive conclusions on efficacy and duration of treatment cannot be drawn from these studies. Medical Assessor’s Comment: The wording and scope of the indications are in line with those of the reference product’s SPC. 3. DOSE & DOSE SCHEDULE From UK approved SPC: For oral administration in adults


Major depressive episodes (adults and the elderly): 20mg/day to 60mg/day A dose of 20mg/day is recommended as the initial dose. Although there may be an increased potential for undesirable effects at higher doses, a dose increase may be considered after three weeks if there is no response. Dosage adjustments should be made carefully, on an individual patient basis, to maintain the patients at the lowest effective dose. In agreement with the consensus statement of the World Health Organisation, antidepressant medication should be continued for at least 6 months to ensure that they are free from symptoms. Obsessive-compulsive disorder (adults and elderly): 20mg/day to 60mg/day A dose of 20mg/day is recommended initially. Although there may be an increased potential for side effects at higher doses, a dose increase may be considered after 2 weeks if there is no response. If no improvement is observed within 10 weeks, treatment with fluoxetine should be reconsidered. If a good therapeutic response has been obtained, treatment can be continued at a dosage adjusted on an individual basis. While there are no systemic studies to answer the question of how long to continue fluoxetine treatment, obsessive-compulsive disorder is a chronic condition and it is reasonable to consider continuation beyond 10 weeks in responding patients. Dosage adjustments should be made carefully, on an individual patient basis, to maintain the patient at the lowest effective dose. The need for treatment should be reassessed periodically. Some clinicians advocate concomitant behavioural psychotherapy for patients who have done well on pharmacotherapy. Long-term efficacy (more than 24 weeks) has not been demonstrated in obsessive-compulsive disorder Bulimia nervosa (adults and elderly): 60mg/day is recommended. Long-term efficacy (more than 3 months) has not been demonstrated in bulimia nervosa All indications: The recommended doses may be increased or decreased. Doses greater than 80mg/day have not been systematically evaluated. Fluoxetine may be administered as a single dose or divided doses during or between meals. When treatment with fluoxetine is stopped, active drug substances will persist in the body for weeks. This should be borne in mind when starting or stopping treatment. . The capsule and liquid dosage forms are bioequivalent. Children: Administration of Fluoxetine Oral Solution to children and adolescents (under the age of 18) is not recommended, as the efficacy and safety has not been evaluated. A lower or less frequent dose (e.g. 20mg every second day) should be considered in patients with hepatic impairment (see section 5.2, ‘Pharmacokinetic properties’), or in patients where concomitant medication has the potential for interaction with Fluoxetine Oral Solution (see section 4.5, ‘Interaction with other medicaments and other forms of interaction’)


Withdrawal symptoms seen on discontinuation of fluoxetine: Abrupt discontinuation should be avoided. When stopping treatment with fluoxetine the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and section 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate. 4. TOXICOLOGY A pharmaco-toxicological expert report has been provided by a Consultant in Pharmaceutical Medicine with appropriate experience. 5. CLINICAL PHARMACOLOGY No new pharmacological data have been submitted. 5.1 BIOEQUIVALENCE The clinical expert has provided justification for the lack of a bioequivalence study in line with the ‘Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98). The composition of this product is essentially similar to the UK branded product Prozac Liquid. The excipients present in Prozep at the recommended doses would not be expected to affect gastric transit or absorption of the drug substance. Since the compositions are similar and since both are oral solutions, there is no requirement for bioequivalence studies. 6. EFFICACY No new clinical data have been submitted with this application. None are required. A literature review has been provided. The therapeutic benefits for fluoxetine in the proposed indications are well established. 7. SAFETY The clinical safety of the product is well established. No new data has been submitted and none is required. 8. EXPERT REPORT A Clinical Overview has been provided in CTD Module 2.5. A Clinical Summary has not been provided in CTD Module 2.7. Information about the Clinical Expert is provided in CTD Module 1.4.3. 9. SUMMARY OF PRODUCT CHARACTERISTICS The SPC is considered satisfactory and are consistent with the SPC for the reference product.


10. PATIENT INFORMATION LEAFLET The PIL is considered satisfactory and is consistent with the PIL for the reference product. 11. LABELLING The labelling is considered satisfactory. 13. DISCUSSION The clinical use of fluoxetine is well established in the indications proposed. The generic and reference products are considered to be interchangeable. No new clinical efficacy and safety data has been submitted and none is required. 12. CONCLUSIONS Overall, there is no clinical objection to the grant of marketing authorisation for this application. No new or unexpected safety concerns arise from this application.


OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Fluoxetine/Prozep 20mg/5ml Oral Solution are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY Fluoxetine is a well known drug and has been used as an selective serotonin re-uptake inhibitor (SSRI) antidepressant for many years. The composition of this product is essentially similar to the UK branded product Prozac Liquid. Since the compositions are similar and since both are oral solutions, there is no requirement for bioequivalence studies. No new or unexpected safety concerns arise from these applications. The SPC, PIL and labelling are satisfactory and consistent with that for the cross-reference product. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. Extensive clinical experience with fluoxetine is considered to have demonstrated the therapeutic value of the compound. The risk benefit is therefore considered to be positive.




STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 21/07/2003.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 26/09/2003.

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 17/11/2003, 23/06/2004, 08/02/2005, 05/10/05 and 07/02/06.

4 The applicant responded to the MHRA’s requests, providing further information on 02/03/2004, 13/09/2004, 08/02/2005, 08/04/05, 21/12/05 and 28/02/06. for the quality sections.

5 The application was determined on 22/09/06.




STEPS TAKEN AFTER ASSESSMENT

Date submitted Application type Scope Outcome




SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Prozep™ 20mg/5ml Oral Solution Fluoxetine 20mg/5ml Oral Solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml of oral solution contains fluoxetine hydrochloride equivalent to 20mg of fluoxetine as drug substance Each 5ml of this medicine also contains 2.2 g sorbitol and 50mg polyoxyl 40 hydrogenated castor oil. For a full list of excipients see Section 6.1

3. PHARMACEUTICAL FORM Oral solution Clear colourless liquid with an odour of peppermint

4. CLINICAL PARTICULARS

4.1 Therapeutic indications Fluoxetine Oral Solution is indicated for the treatment of:

Major depressive episodes Obsessive – compulsive disorder Bulimia nervosa - Fluoxetine oral solution is indicated as a complement of psychotherapy for the reduction of binge eating and purging activity.


4.2 Posology and method of administration For oral administration in adults Major depressive episodes (adults and the elderly): 20mg/day to 60mg/day A dose of 20mg/day is recommended as the initial dose. Although there may be an increased potential for undesirable effects at higher doses, a dose increase may be considered after three weeks if there is no response. Dosage adjustments should be made carefully, on an individual patient basis, to maintain the patients at the lowest effective dose. In agreement with the consensus statement of the World Health Organisation, antidepressant medication should be continued for at least 6 months to ensure that they are free from symptoms. Obsessive-compulsive disorder (adults and elderly): 20mg/day to 60mg/day A dose of 20mg/day is recommended initially. Although there may be an increased potential for side effects at higher doses, a dose increase may be considered after 2 weeks if there is no response. If no improvement is observed within 10 weeks, treatment with fluoxetine should be reconsidered. If a good therapeutic response has been obtained, treatment can be continued at a dosage adjusted on an individual basis. While there are no systemic studies to answer the question of how long to continue fluoxetine treatment, obsessive-compulsive disorder is a chronic condition and it is reasonable to consider continuation beyond 10 weeks in responding patients. Dosage adjustments should be made carefully, on an individual patient basis, to maintain the patient at the lowest effective dose. The need for treatment should be reassessed periodically. Some clinicians advocate concomitant behavioural psychotherapy for patients who have done well on pharmacotherapy.

Long-term efficacy (more than 24 weeks) has not been demonstrated in obsessive-compulsive disorder Bulimia nervosa (adults and elderly): 60mg/day is recommended. Long-term efficacy (more than 3 months) has not been demonstrated in bulimia nervosa All indications: The recommended doses may be increased or decreased. Doses greater than 80mg/day have not been systematically evaluated.

Fluoxetine may be administered as a single dose or divided doses during or between meals.

When treatment with fluoxetine is stopped, active drug substances will persist in the body for weeks. This should be borne in mind when starting or stopping treatment. .

The capsule and liquid dosage forms are bioequivalent.


Children: Administration of Fluoxetine Oral Solution to children and adolescents (under the age of 18) is not recommended, as the efficacy and safety have not been evaluated. A lower or less frequent dose (e.g. 20mg every second day) should be considered in patients with hepatic impairment (see section 5.2, ‘ Pharmacokinetic properties’), or in patients where concomitant medication has the potential for interaction with Fluoxetine Oral Solution (see section 4.5, ‘Interaction with other medicaments and other forms of interaction’) Withdrawal symptoms seen on discontinuation of fluoxetine: Abrupt discontinuation should be avoided. When stopping treatment with fluoxetine the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and section 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

4.3 Contra-indications

Hypersensitivity to fluoxetine or the ingredients of the preparation.

Monoamine oxidase inhibitors: Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI selegiline and the reversible MAOI (RIMA) moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI. Treatment with fluoxetine should only be started 2 weeks after discontinuation of an irreversible MAOI and the following day after discontinuation of a reversible MAOI-A. Some cases presented with features resembling serotonin syndrome (which may resemble, and be diagnosed as, neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation, progressing to delirium and coma. Therefore, fluoxetine is contra-indicated in combination with a non-selective MAOI. At least five weeks (longer if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of therapy with an MAOI. The combination of fluoxetine with a reversible MAOI (e.g. moclobemide) is not recommended. Treatment with fluoxetine can be initiated the following day after discontinuation of a reversible MAOI.


4.4 Special warnings and special precautions for use

Warnings Rash and allergic reactions: Rash, anaphylactoid events, and progressive systemic events sometimes serious (involving skin, kidney, or lung), have been reported. Upon the appearance of rash or of other allergic phenomena for which an alternative aetiology cannot be identified, fluoxetine should be discontinued. Precautions Seizures: Seizures are a potential risk with antidepressant drugs. Therefore, as with other antidepressants, fluoxetine should be introduced cautiously in patients who have a history of seizures. Fluoxetine should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency. Fluoxetine should be avoided in patients with unstable disorders / epilepsy and patients with controlled epilepsy should be carefully monitored. Mania: Antidepressants should be used with caution in patients with a history of mania/hypomania. As with all antidepressants, fluoxetine should be discontinued in any patient entering a manic phase. Hepatic / renal function: Fluoxetine is extensively metabolized by the liver and excreted by the kidneys. A lower dose, e.g. alternate day dosing, is recommended in patients with significant hepatic dysfunction. When given fluoxetine 20mg/day for 2 months, patients with severe renal failure (GFR <10ml/min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function. Cardiac disease: No conduction abnormalities that resulted in heart block were observed in the ECG of 312 patients who received fluoxetine in double-blind trials However, clinical experience in acute cardiac disease is limited, therefore caution is advisable Weight loss: Weight loss may occur in patients taking fluoxetine but it is usually proportional to baseline body weight. Diabetes: In patients with diabetes, treatment with an SSRI may alter glycaemic control. Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may need to be adjusted. Suicide/suicidal thoughts: Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). As improvement may not occur during the first few weeks of treatment, in common with all antidepressants, patients should be closely monitored during this period. The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. It is general clinical experience with all therapies for depression that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which fluoxetine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be


co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders. Patients with a history of suicide-related events and those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal attempts, and should receive careful monitoring during treatment. In addition, there is a possibility of an increased risk of suicidal behaviour in young adults. Patients (and caregivers of patients) should be alerted about the need to monitor for the emergence of such events and to seek medical advice if these symptoms present. Akathisia/psychomotor restlessness: The use of fluoxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental. Withdrawal symptoms seen on discontinuation of SSRI treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation occurred in approximately 60% of patients in both the fluoxetine and placebo groups. Of these adverse events, 17% in the fluoxetine group and 12% in the placebo group were severe in nature. The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizzinesss, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate: however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that fluoxetine should be gradually tapered when discontinuing treatment over a period of at least one to two weeks, according to the patient’s needs (see ‘Withdrawal symptoms seen on discontinuation of fluoxetine’, section 4.2). Haemorrhage: There have been reports of cutaneous bleeding abnormalities, such as ecchymosis and purpura, with SSRIs. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other haemorrhagic manifestations (e.g. gynaecological haemorrhages, gastro-intestinal bleedings, and other cutaneous or mucous bleedings) have been reported rarely. Caution is advised in patients taking SSRIs, particularly in concomitant use with oral anticoagulants, drugs known to affect platelet function (e.g. atypical antipsychotics, such as clozapine, phenothiazines, most TCAs, aspirin, NSAIDs), or other drugs that may increase risk of bleeding, as well as in patients with a history of bleeding disorders. Electroconvulsive therapy (ECT): There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment, therefore caution is advisable.


St.John’s Wort: An increase in serotonergic effects such as serotonin syndrome may occur when selective serotonin reuptake inhibitors and herbal preparations containing St. John’s Wort (Hypericum perforatum) are used together. On rare occasions, development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of fluoxetine, particularly when given in combination with other serotonergic (among others, l-tryptophan) and/or neuroleptic drugs. As these syndromes may result in potentially life threatening conditions, treatment with fluoxetine should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes, including confusion, irritability, extreme agitation, progressing to delirium and coma) occur, and supportive symptomatic treatment should be initiated. Each 5ml spoonful of fluoxetine contains 2.2g of sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine Fluoxetine Oral Solution also contains the excipient polyoxyl 40 hydrogenated castor oil which may cause stomach upset and diarrhoea

4.5 Interaction with other medicaments and other forms of interaction

Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should be borne in mind (see section 5.2, ‘Pharmacokinetic properties’) when considering pharmacodynamic or pharmacokinetic drug interactions (e.g., when switching from fluoxetine to other antidepressants) Monoamine oxidase inhibitors (see section 4.3 contra-indications). Not recommended combinations: MAOI-A (see section 4.3, ‘Contra-indications’) Combinations requiring precautions for use; MAOI-B (selegine); risk of serotonin syndrome. Clinical monitoring is recommended. Phenytoin: Changes in blood levels have been observed when combined with fluoxetine. In some cases manifestations of toxicity have occurred. Consideration should be given to using conservative titration schedules of the concomitant drug and to monitoring clinical status. Serotonergic drugs: Co-administration with serotonergic drugs (e.g. tramadol, triptans) may increase the risk of serotonin syndrome. Use with triptans carries the risk of coronary vasoconstriction and hypertension. Lithium and tryptophan: There have been reports of serotonin syndrome when SSRIs have been given with lithium or tryptophan and, therefore, the concomitant use of fluoxetine with these drugs should be undertaken with caution. When fluoxetine is used in combination with lithium, closer and more frequent monitoring is required. CYP2D6 isoenzyme; Because fluoxetine's metabolism (like tricyclic antidepressants and other selective serotonin antidepressants) involves the hepatic cytochrome CYP2D6


isoenzyme system, concomitant therapy with drugs also metabolized by this enzyme system may lead to drug interactions, Concomitant therapy with drugs predominantly metabolised by this isoenzyme, and which have a narrow therapeutic index (such as flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants), should be initiated at or adjusted to the low end of their dose range. This will also apply if fluoxetine has been taken in the previous 5 weeks.

Oral Anticoagulants: Altered anticoagulant effects (laboratory values and/or clinical signs and symptoms), with no consistent pattern, but including increased bleeding, have been reported uncommonly when fluoxetine is co-administered with oral anti-coagulants. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. (see section 4.4, Special warnings and special precautions for use , ‘Precautions’, ‘Haemorrhage’.) Electroconvulsive therapy (ECT): There have been rare reports of prolonged seizures Alcohol: The combination of SSRI treatment and alcohol is not advisable. In formal testing, fluoxetine did not raise blood alcohol levels or enhance the effects of alcohol.

St John’s Wort: In common with other SSRIs, pharmacodynamic interactions between fluoxetine and the herbal remedy St John’s Wort (Hypericum perforatum) may occur, which may result in an increase of undesirable effects.

4.6 Pregnancy and Lactation

Pregnancy: Data on a large number of exposed pregnancies do not indicate a teratogenic effect of fluoxetine. Fluoxetine can be used during pregnancy, but caution should be exercised, especially during late pregnancy or just prior to the onset of labour, since the following effects have been reported in neonates: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or in sleeping. These symptoms may indicate either serotonergic effects or a withdrawal syndrome. The time to occur and the duration of these symptoms may be related to the long half-life of fluoxetine (4-6 days) and its active metabolite, norfluoxetine (4-16 days) Lactation: Fluoxetine and its metabolite, norfluoxetine, are known to be excreted in human breast milk. Adverse events have been reported in breast-feeding infants. If treatment with fluoxetine is considered necessary, discontinuation of breast-feeding should be considered; however, if breast-feeding is continued, the lowest effective dose of fluoxetine should be prescribed.

4.7 Effects on ability to drive and use machines

Although fluoxetine has been shown not to affect psychomotor performance in healthy volunteers, any psychoactive drug may impair judgement or skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected.


4.8 Undesirable effects Undesirable effects may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy. In common with other SSRIs, the following undesirable effects have been seen: Body as a whole: Hypersensitivity (e.g. pruritus, rash, urticaria, anaphylactoid reaction, vasculitis, serum sickness-like reaction, angioedema) (see section 4.3 ‘Contra-indications and section 4.4 ‘Special warnings and special precautions for use, ‘Warnings’), chills, photosensitivity, and, very rarely, toxic epidermal necrolysis (Lyell syndrome). Digestive system: Gastro-intestinal disorders (e.g. Nausea, diarrhoea, vomiting, dyspepsia, dysphagia, taste perversion) dry mouth. Abnormal liver function tests have been reported rarely. Very rare cases of idiosyncratic hepatitis. Nervous system: Headache, sleep abnormalities (e.g. abnormal dreams, insomnia) dizziness, fatigue (e.g. somnolence, drowsiness), euphoria, transient abnormal movement (e.g. twitching, ataxia, tremor, myoclonus) seizures and psychomotor restlessness. Hallucinations, manic reaction confusion, agitation, anxiety and associated symptoms (e.g. nervousness), impaired concentration and thought processes (e.g. depersonalization), panic attacks (these symptoms may be due to underlying disease), and, very rarely serotonin syndrome. Urinogenital system: urinary retention and frequency. Reproductive disorders: sexual dysfunction (delayed or absent ejaculation, anorgasmia), priapism, galactorrhoea Miscellaneous: Alopecia, yawn, abnormal vision (e.g. blurred vision, mydriasis), sweating, vasodilatation, arthralgia, myalgia, postural hypotension, ecchymosis. Other haemorrhagic manifestations (e.g. gynaecological haemorrhages, gastro-intestinal bleedings, and other cutaneous or mucous bleedings) have been reported rarely (see section 4.4, ‘Special warnings and special precautions for use ‘Precautions’, ’Haemorrhage’) Hyponatraemia: Hyponatraemia (including serum sodium below 110mmol/l) has been rarely reported and appeared to be reversible when fluoxetine was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients, and patients taking diuretics or otherwise volume depleted Respiratory system: Pharyngitis, dyspnoea. Pulmonary events (including inflammatory processes of varying histopathology and/or fibrosis) have been reported rarely. Dyspnoea may be the only preceding symptom.

Withdrawal symptoms seen on discontinuation of fluoxetine treatment:

Discontinuation of fluoxetine commonly leads to withdrawal symptoms.


Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and headache are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged (see section 4.4). It is therefore advised that when fluoxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 and section 4.4).

4.9 Overdose

Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias to cardiac arrest, pulmonary dysfunction, and signs of altered CNS status ranging from excitation to coma. Fatality attributed to overdose of fluoxetine alone has been extremely rare. Cardiac and vital signs monitoring are recommended, along with general symptomatic and supportive measures. No specific antidote is known.

Forced diuresis, dialysis, haemoperfusion, and exchange trnnsfusion are unlikely to be of benefit. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage. In managing overdosage, consider the possibility of multiple drug involvement. An extended time for close medical observation may be needed in patients who have taken excessive quantities of a tricyclic antidepressant if they are also taking, or have recently taken, fluoxetine.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressant ATC code: NO6A B03 Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as α1-, α2 -, and β-adrenergic; dopaminergic; histaminergic1; muscarinic; and GABA receptors. Major depressive episodes: Clinical trials in patients with major depressive episodes have been conducted versus placebo and active controls. Fluoxetine has been shown to be significantly more effective than placebo, as measured by the Hamilton Depression Rating Scale (Ham-D). In these studies, fluoxetine produced a significantly higher rate of response (defined by a 50% decrease in the HAM-D score) and remission, compared to placebo. Dose response: In the fixed dose studies of patients with major depression there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, it is clinical experience that uptitrating might be beneficial for some patients.


Obsessive-compulsive disorder: In short-term trials (under 24 weeks), fluoxetine was shown to be significantly more effective than placebo. There was a therapeutic effect at 20mg/day, but higher doses (40 or 60mg/day) showed a higher response rate. In long-term studies (three short-term studies extension phase and a relapse prevention study) efficacy has not been shown.

Bulimia nervosa: In short-term trials (under 16 weeks), in out patients fulfilling DSM-III-R-criteria for bulimia nervosa, fluoxetine 60mg/day was shown to be significantly more effective than placebo for the reduction of bingeing and purging activities. However, for long-term efficacy no conclusion can be drawn Two placebo-controlled studies were conducted in patients meeting Pre-Menstrual Dysphoric disorder (PMDD) diagnostic criteria according to DSM-IV. Patients were included if they had symptoms of sufficient severity to impair social and occupational function and relationships with others. Patients using oral contraceptives were excluded. In the first study of continuous 20mg daily dosing for 6 cycles, improvement was observed in the primary efficacy parameter (irritability, anxiety, and dysphoria). In the second study, with intermittent luteal phase dosing (20mg daily for 14 days) for 3 cycles, improvement was observed in the primary efficacy parameter (daily record of Severity of Problem score). However definitive conclusions on efficacy and duration of treatment cannot be drawn from these studies.

5.2 Pharmacokinetic properties Absorption: Fluoxetine is well absorbed from the gastro-intestinal tract after oral administration. The bioavailability is not affected by food intake. Distribution: Fluoxetine is extensively bound to plasma proteins about 95% and it is widely distributed (volume of distribution 20-40L/kg). Steady state plasma concentrations are achieved after dosing for several weeks. Steady state concentrations after prolonged dosing are similar to concentrations seen at 4 to 5 weeks. Metabolism: Fluoxetine has a non-linear pharmacokinetic profile with first pass liver effect. Maximum plasma concentration is generally achieved 6 to 8 hours after administration. Fluoxetine is extensively metabolised by the polymorphic enzyme CYP2D6. Fluoxetine is primarily metabolised by the liver to the active metabolite norfluoxetine (desmethylfluoxetine), by demethylation. Elimination: The elimination half-life of fluoxetine is 4 to 6 days and for norfluoxetine 4 to 16 days. These long half-lives are responsible for persistence of the drug for 5-6 weeks after discontinuation. Excretion is mainly (about 60%) via the kidney. Fluoxetine is secreted into breast-milk. At-risk populations Elderly: Kinetic parameters are not altered in healthy elderly when compared to younger subjects.


Hepatic insufficiency: In case of hepatic insufficiency (alcoholic cirrhosis), fluoxetine and norfluoxetine half-lives are increased to 7 and 12 days, respectively. A lower or less frequent dose should be considered. Renal insufficiency: After single–dose administration of fluoxetine in patients with mild, moderate or complete (anuria) renal insufficiency, kinetic parameters have not been altered when compared to healthy volunteers. However, after repeated administration, an increase in steady-state plateau of plasma concentrations may be observed.

5.3 Preclinical safety data There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility from in vitro or animal studies

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipient(s) Glycerol Sorbitol solution Polyoxyl 40 hydrogenated castor oil Benzoic acid Peppermint flavour Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf-life

2 years Use within one month of first opening

6.4 Special precautions for storage

Do not store above 25ºC Store in the original container

6.5 Nature and contents of container.

Amber glass bottles containing 70ml with tamper evident child resistant closures.


6.6 Instructions for use/handling There is no specific instruction for use/handling.

7. MARKETING AUTHORIZATION HOLDER

Chemidex Pharma Limited, Trading as Chemidex Generics and / or Essential Generics Egham Business Village, Crabtree Road, Egham, Surrey, TW20 8RB

8. MARKETING AUTHORIZATION NUMBER

PL 17736 / 0062

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 22/09/2006

10 DATE OF REVISION OF THE TEXT

22/09/2006




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