( DRUG INTERACTIONS

Overview No drug and substance interaction studies have been performed as part of the clinical developrnent ofVoltaren Ernulgel Joint Pain 11.6 mg/g (1.16%) gel.

From the pharmacokinetic point ofview, diclofenac is extensively (>99.7%) protein bound, mainly to alburnin (99.4%). Binding to serum albumin is characterised by 2 classes ofbinding sites: the high affinity sites are likely to be shared with benzodiazepines and the low affinity site with warfarin. Diclofenac does not modify other strongly protein bound drugs but may, in vitro, be displaced by salicylic acid (Davies and Anderson, 1997).

There is a considerable body of litera ture re garding interactions of oral NSAIDs, and diclofenac in particular, with other medicinal products. No interactions with other drugs are to be expected due to very low plasma levels observed after topical application ofVoltaren Emulgel Joint Pain.

Drug-Drug Interactions No drug-drug interactions were noted in the clinical studies presented. Isolated interaction cases have been reported for topical Voltaren Ernulgel Joint Pain from the marketplace.

Only 22 cases of possible drug interactions with Voltaren Emulgel Joint Pain over 200 million patients exposed have been made to the Novartis world-wide safety database since first marketing:

• Twelve cases with oral anticoagulant therapy (3 with acenocoumarol, 3 with warfarin, 2 with phenprocoumon, 2 with fluindione, and 2 unknown).

• Four cases with blood pressure increase (with anti-hypertensive product of different classes).

• Three case with blood glucose increase (in insulin-dependent and in non-insulin dependent diabetes mellitus).

• One case of a psychiatrie disorder ( with concomitant ofloxacin use). • One case of a rash and vascular bleeding associated with acetylsalicylic acid. The patient

was also taking heparin and a topical herbai product containing camphor, methanol and ethanol.

• One case of gastric ulcer associated with concomitant acetylsalicylic acid use.

The customary drug-drug interactions between oral NSAIDs and anticoagulants, oral antidiabetic agents and certain other classes are usually based on the high protein-binding nature of the NSAID. With significantly lower amounts of active substance in circulation following topical application compared with after oral administration, such interactions may be predicted to be very unlikely with use of Voltaren Emulgel Joint Pain.

Page Il of30

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Ad justment Adults and adolescents 16 years and older: Voltaren Emulgel Joint Pain should be rubbed gently into the skin. Depending on the size of the affected site to be treated, 2-4 g (1 g equals a strip approx. 2 cm long) should be applied 3-4 times a day. After application, the hands should be washed unless they are the site being treated.

The duration of treatment depends on the natural course of healing, rest and also on clinical response. The gel should not be used for more than 7 days for muscle and joint injuries, unless recommended by a doctor. Consumers should consult their doctor if the condition does not improve within 7 days, or if it gets worse.

Missed Dose If a dose of Voltaren Emulgel Joint Pain is missed, it should be applied when the consumer remembers and then again at the next scheduled time. A double quantity should not be applied.

OVERDOSAGE

The low systemic absorption of topical diclofenac renders overdosage extremely unlikely. In the event of accidentai ingestion, resulting in significant systemic side effects, general therapeutic measures normally adopted to treat poisoning with non-steroidal anti-inflammatory drugs should be used.

Management of overdosage with NSAIDs essentially consists of supportive and symptomatic measures. Supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastro-intestinal irritation, and respiratory depression; specifie therapies such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of prote in binding and extensive metabolism.

Twenty times the oral dose of 200 mg of diclofenac in overdose produced only somnolence with no signs of toxicity (AHFS Drug Information 1999). This would represent about 65 tubes of Voltaren Emulgel Joint Pain. In case of accidentai ingestion of one tube of product, the amount of diclofenac ingested would be less than one tablet of diclofenac 50 mg (which is the most conunon oral unit dose).

There are five cases of overdose in the paediatric population with Voltaren Emulgel Joint Pain listed on the Novartis Safety Database. A 2-year-old girl swallowed a "soup spoonful". Assuming that a spoon con tains 15 ml (or grams) and that 100% of the dose was absorbed, the amount of available diclofenac would have been approximately 150 mg. No details of the other overdose are available. A 1-year-old girl and a 3-year-old boy were also reported to have swallowed unknown quanti ti es of Voltaren Emulgel Joint Pain with no apparent adverse events.

Page 12 of30

( There are 2 cases of accidentai topical exposure to Voltaren Emulgel Joint Pain in children, one to a 2-year-old boy and another to a 2-year-old child (gender not reported). No adverse events were reported in either case.

In the adult population, there is one case of an adult swallowing an unknown quantity of Voltaren in the database. No adverse events were reported. One report of a patient applying 1.5 tubes of Voltaren Emulgel Joint Pain per day on his legs resulted in skin changes and "thin skin" (skin atrophy). Additionally, there is a consumer report of a patient with a history of cerebrovascular accident with left paralysis, hypertension, diabetes and epilepsy that used half a tube at the site of application in a single dose and experienced an increase in pain at the site. The database also includes a case report stated as serious where the patient became 'intoxicated', but there is no additional information.

The database contains a report of accidentai exposure to haemorrhoids, resulting in a buming sensation. Finally, there were 3 consumer reports of accidentai exposure in the eyes resulting in eye redness, eye discharge, eye irritation, and a feeling of increased intraocular pressure.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Diclofenac is a well characterized, patent nonsteroidal anti-inflammatory drug (NSAID) with clinically proven anti-inflammatory, analgesie and antipyretic properties (Davies & Anderson 1997). NSAIDs, including diclofenac, reduce pain principally by inhibiting formation of prostaglandins, leukotrienes and free oxygen radicals.

All non-salicylate NSAIDs reversibly black cyclooxygenase activity, which is responsible for converting arachidonic acid to prostaglandins. Diclofenac is a patent, non-selective inhibitor of COX-1 and COX-2 (preferentially COX-2), which may underlie both its therapeutic efficacy and potential side effects (Giuliano & Wamer 1999). In addition, diclofenac, when compared to NSAIDs such as ibuprofen, also blacks the lipoxygenase pathway of the arachidonic acid cascade, thereby inhibiting the formation of leukotriene B4 (LTB4), which is a known pain mediator and bas been shawn to stimulate pain receptors in the peripheral nerves. The inhibition of lipoxygenase also prevents the pro-inflammatory and gastrointestinal damaging effects of leukotrienes (Bertolini, Ottani & Sandrini 2001). Prostaglandins, along with thromboxanes and L TB4, are responsible for several inflammatory effects. The lipoxygenase inhibition produced by diclofenac may therefore play a significant role in its efficacy as an analgesie and anti-inflammatory agent (Amadia, Cummings & Amadia, 1993; Todd & Sorkin 1988).

Pharmacodynamies

As with other NSAIDs, the ability of diclofenac to inhibit prostaglandin synthesis is instrumental in the anti-inflammatory response. Data from in vitro studies show that most topical NSAIDs are able to inhibit prostaglandin synthesis to a significant degree. In this respect, diclofenac has a high intrinsic activity, as demonstrated in vitro in human rheumatoid synovial microsomes (Dreiser 1994).

Page 13 of30

The pharmacodynamie properties of diclofenac have been demonstrated for each of the sodium, potassium and diethylamine salts administered either orally or topically in standard animal models of acute and chronic inflammation (Hiramatsu et a/1990, Kyuki et al 1983).

It has also been reported that topically applied diclofenac diethylamine 1.16% actively inhibited methyl nicotinate induced skin inflammation, which is known to involve prostaglandins and free arachidonic acid. Topical diclofenac was shown to exhibit a prolonged potent anti-inflammatory effect, even 48 hours after application (Duteil et al 1990).

The anti-inflammatory properties ofVoltaren Emulgel Joint Pain were demonstrated in two placebo-controlled, double-blind, randomized trials, one in healthy volunteers using the urate crystal induced inflammation model (NGB5) and the other in patients with chronic synovitis of the knee (NGB 8855). Voltaren Emulgel Joint Pain proved to be superior to placebo in significantly reducing the diameter of erythema at 24 hours in study NGB 5 (p

Special Populations and Conditions

There are no gender differences in the pharmacokinetics of diclofenac. No safety or efficacy concems relating to ethnicity have been identified from the marketplace. Davies and Anderson ( 1997) discuss the influence of age on diclofenac pharmacokinetics with relevance in the very young and elderly. Also, changes to the skin in the elderly will affect absorption in sorne patients. However, as plasma levels will be very low after topical application these factors are not a clinical concem. For similar reasons, any effect ofhepatic or renal impairment on the pharmacokinetics of diclofenac is unlikely to be clinically significant.

STORAGE AND ST ABILITY Voltaren Emulgel Joint Pain should be stored between 15 and 30°C.

SPECIAL HANDLING INSTRUCTIONS There are no special handling instructions for Voltaren Emulgel Joint Pain.

DOSAGE FORMS, COMPOSITION AND PACKAGING Voltaren Emulgel Joint Pain is a white to practically white, soft, homogenous, cream-like oil-in-water topical emulsion available in one strength ( diclofenac diethylamine 1.16% w/w) and packaged in either:

• An aluminium tube with a sealing membrane, coated intemally with a phenol-epoxy lacquer. The tube is closed with a polypropylene screw cap, incorporating a point to pierce the aluminium sealing membrane before first use; or

• An aluminium laminated tube [low density polyethylene 1 aluminium 1 high density polyethylene (intemallayer)] fitted with a high density polyethylene shoulder and closed by a moulded seal. The tube is closed with a polypropylene screw cap, incorporating a llioulded feature used to insert, twist and remove the seal before first use.

Pack sizes: 75 g tubes.

Voltaren Emulgel Joint Pain contains the following nonmedicinal ingredients: Carbomer, cocoyl caprylocaprate, diethylamine, isopropyl alcohol, liquid paraffin, macrogol cetostearyl ether, perfume, propylene glycol, purified water.

Page 15 of30

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Diclofenac diethylamine

Chemical name: Diethylammonium { o-[ (2,6-dichlorophenyl)-amino ]-phenyl} acetate

Structural formula:

Physicochemical properties: Diclofenac diethylamine is a white to light beige crystalline powder. No polymorphie forms of diclofenac diethylamine have been observed. The solubility ofdiclofenac diethylamine in water is 15.8 giL at a pH of7.8 and a temperature of l8°C, 17.4 g/L at a pH of 7.6 and a temperature of 25°C, and 22.8 g/L at a pH of 7.6 and a temperature of 37°C. Diclofenac diethylamine has a pH range of 6.5-8.3 in a 1% solution in 10% ethanol. Diclofenac diethylamine has a pKa value of3.9 ± 0.2 in water at 25°C.

Page 16 of30

CLINICAL TRIALS

For the indication "pain in muscles and joints injuries", the studies NF 113 and D458 L7/D141 are considered pivotai. Study demographies and trial design for these studies are presented in Table 4.

Study demographies and trial design

Table 4- Summary of patient demographies for clinicat trials in muscle and joint injuries

Study # Trial design Dosage, route of Study Mean age Gender administration and subjects (Range) duration (n=number)

NF113 Multicentre, parallel- Gel was applied n=254 Voltaren: Men group, randomised, topically 4 times 34.1 (7-88) Voltaren: 72 double-blind, placebo- daily at a mean dose Placebo: 35.5 (57%) controlled of 2.2 g (ac tuai dose (12-84) Placebo: 83 Subjects had soft tissue was determined by (65%) trauma resulting in a physician) Women minor sprain, Voltaren: 54 dislocation, tear of (43%) muscle or tendon, or Placebo: 45 pulled muscle/ (35%) contusion

D458 Single-centre parallel- Voltaren Emulgel n= 80 Voltaren: Ali 80 subjects L7/Dl41 group, randomised Joint Pain or placebo 22.4 (19-29) were male

double-blind, placebo- was applied 3 times Placebo: 22.2 controlled daily for up to 14 (19-31) Subjects were soldiers da ys with acutely sprained ankles

Study results - Soft tissue trauma

Study NF113

There was a significant difference in favour ofVoltaren Emulgel Joint Pain 1.16% gel for spontaneous pain on delibera te movement on day 7 with 44% (51) of the active treatment group having no pain, 43% (50) having only moderate pain and 13% (15) marked pain compared with 35% (41), 38% (44) and 24% (28) of the subjects in the placebo group respectively. Three (3) subjects (3%) of the placebo group had very marked pain at 7 days whereas no active treatment subject had marked pain (p=0.05 for day 7 evaluation) and similar results were found for pain on pressing, also on day 7 (p=0.02). The need for rescue medication was lower in the active treatment group, and of significantly shorter duration i.e., those in the active treatment group stopped using rescue medication before those receiving placebo (p=0.02). The regression of haematoma was also faster in the active treatment group (p=0.04). These data concur with the investigator's general assessments rating the results on day 7 as 'excellent' in 64% of patients receiving active treatment and 52% in those receiving placebo.

Page 17 of30

Study D458 L7/D141

There was a significant difference for articular pain at rest and on movement ( 100 mm V AS) and joint swelling at days 3 and 4 in the Voltaren Emulgel Joint Pain treated group compared to the placebo group (p

concentration of the drug is higher in the dennis and subcutaneous tissue below the application site than at greater depths where the drug concentration becomes less than the corresponding plasma concentration. Thus, anti-inflammatory effects at deeper tissue levels may be influenced by both direct and systemic drug concentrations (Singh & Roberts 1994).

When Voltaren Emulgel Joint Pain is applied topically, the amount of diclofenac absorbed through intact skin is proportional to the contact time and skin area covered and depends on the total topical dose and the hydration of the skin.

Systemic absorption amounts to approximately 3-7% of the dose of diclofenac after topical application of2.5g Voltaren Emulgel Joint Pain per 500 cm2 skin, left for 12 hours on non-occluded skin (Riess et al 1986, Davies & Anderson 1997). Plasma drug concentrations are weil below those observed after a standard oral or intramuscular dose and below the range at which systemic AEs usually occur. Maximum plasma concentrations of diclofenac after topical administration ofVoltaren Emulgel Joint Pain are between 50 (repeated dose) and 100 (single dose) times lower than a fier oral administration of Voltaren tablets (Riess et a/1986). The steady state is reached after 2 da ys of twice-daily administration and the low plasma levels remain in the same range over the full day indicating prolonged absorption from the application site (Sioufi et a/1994). Absorption of diclofenac through the skin can be increased by 3-10 times after application of an occlusive dressing.

Report 17727B-510.20-02-01-B describes a single and multiple dose (7 days), open, randomized, three-way cross-over, comparative bioavailability trial ofVoltaren Emulgel Joint Pain, diclofenac enteric coated tablet and a diclofenac patch formulation that was in development in the Company, in 24 healthy volunteers. The main pharmacokinetic findings are summarized in Table 5.

Table 5- Summary ofpharmacokinetic data for Study NCH 177278-510.20-02-018

Parameter Voltaren Emulgel Joint Pain 4g Voltaren tablet (40 mg diclofenac-Na equivalent) 25 mg t.i.d

t.i.d

After first administràtion {day 1}

Cmu (nglml) 5.36 (0.502- 42.6) 370 (92.0- 984)

lm•• {h) 20.00 (10.00- 23.95) 4.00 ( 1.00 - 18.00)

AUCo-24 (ng.hlml) 43.6 (0.502- 240) 1190 (231 - 3800)

After last morning administration {day 7}

Cm•• (ng/ml) 12.0 (2.54- 45.1) 380 (51.0 - 1330)

'=· (h) 18.00 (0.00- 20.00) 4.00 (1.00- 20.00) AUCo-24 (ng.h/ml) 179 (51.8 - 332) 1360 (327- 4690)

Cmin (nglml) 4.07 ( 1.19- 8.06) 2.11 (

As expected, these data demonstrate that the relative bioavailability ofVoltaren Emulgel Joint Pain versus tablets remained low (Cmax 99.7%), mainly to albumin (99.4%) (Reiss et al 1978). The Ii ver is the primary site of metabolism for diclofenac (Da vies & Anderson 1997) to virtually inactive metabolites (Stierlin, Faigle & Colombi 1978, Stierlin et a/1979, Faigle et a/1988). The total systemic clearance of diclofenac from plasma is 263±56 ml/min (mean value ± SD). The terminal plasma half-life is 1 to 2 hours. Diclofenac and its metabolites are excreted mainly in urine (60%).

Diclofenac in target tissues

After topical administration ofVoltaren Emulgel Joint Pain to band and knee joints in patients, diclofenac can be measured in the synovial tissue and synovial fluid with concentrations as high as 20 times the plasma concentration (Riess et al 1986). In study C.R.B. R8/1986 plasma concentrations of diclofenac recorded on the fourth day in 7 patients ranged from 6 to 52 ng/ml with one extreme value of 698 ng/ml. In synovial fluid, the concentrations of diclofenac ranged from 119 to larger than 3320 ng/ml and in synovial tissue ranged from 131 to 1740 ng/ml. In the other patient study Tl3/1987 diclofenac could not be detected in plasma samples. In synovial fluid from k.nee joints the diclofenac concentrations were in the range of 6.5-22.1 ng/g sample. These patient studies confirm that topically applied diclofenac will reach the target tissues (soft tissue/joint) at sufficient concentrations to exert a therapeutic response. Relevant publications in elude Radermacher et al ( 1991 ), Gondolph-Zink & Gron wald ( 1996), Day et al ( 1999), Kurowski & Dunky (1992), Chlud & Wagener (1987, 1991), Chlud (1999), Dreiser (1994), and Giuliano & Warner ( 1999).

Drug and substance interactions

The customary drug-drug interactions between oral NSAIDs and anticoagulants and oral antidiabetic agents, for example, are usually consequent to the high protein-binding of the NSAID. With a significantly lower amount of active substance in circulation following topical application than after oral administration, such interactions may be predicted to be very unlikely with Voltaren Emulgel Joi~t Pain.

Pharmacokinetics in special patient populations

There are no gender differences in the pharmacokinetics of diclofenac. No safety or efficacy concerns relating to ethnicity have been identified from the marketplace. Davies and Anderson ( 1997) discuss the influence of age on diclofenac pharmacokinetics with ~el evan ce in the very young and elderly. Also, changes to the skin in the elderly will affect absorption in sorne patients. However, as plasma levels will be very low after topical application these factors are not a clinical concern. For similar reasons, any effect ofhepatic or renal impairment on the pharmacokinetics of diclofenac is unlikely to be clinically significant.

Page20of30

Pharmacodynamies

Phannacodynamics studies- anti-inflammatory activity

As with other NSAIDs, the ability of diclofenac to inhibit prostaglandin synthesis is instrumental in the anti-inflammatory response. Data from in vitro studies show that most topical NSAIDs are able to inhibit prostaglandin synthesis to a significant degree. In this respect, diolofenac bas a high intrinsic activity, as demonstrated in vitro in human rheumatoid synovial microsomes (Dreiser 1994 ).

Prostaglandins, along with thromboxanes and leukotriene B4 (LTB4), are responsible for several inflammatory effects such as vasodilatation, increased vascular penneability, hyperalgesia and increased platelet aggregation. Free oxygen radicals, also mediators of inflammation, are by-products of prostaglandin synthesis. Diclofenac non-specifically inhibits the cyclo-oxygenase pathway with a subsequent reduction in prostaglandin, prostacyclin and thromboxane production. Although non specifie, diclofenac inhibits preferentially COX-2 pathway (Giuliano & Wamer 1999). The production of leukotrienes is also decreased following the administration of diclofenac, suggesting an inhibitory effect on the lipoxygenase pathway with direct impact on LTB4 and inhibition ofpain (Amadio, Cummings & Amadio 1993).

The phannacodynamic properties of diclofenac have been demonstrated for each of the sodium, potassium and diethylamine salts administered either orally or topically in standard animal models ofacute and chronic inflammation (Hiramatsu et a/1990, Kyuki et a/1983).

lt bas also been reported that topically applied diclofenac diethylamine 1.16% actively inhibited methyl nicotinate induced skin inflammation, which is known to involve prostaglandins and free arachidonic acid. Topical diclofenac was shown to exhibit a prolonged potent anti-inflammatory effect, even 48 hours after application (Duteil et a/1990).

The anti-inflammatory properties ofVoltaren Emulgel Joint Pain were demonstrated in two placebo-controlled, double-blind, randomized trials (refer to Table 6), one in healthy volunteers using the urate crystal induced inflammation model (NGB5) and the other in patients with chronic synovitis of the knee (NGB 8855). Voltaren Emulgel Joint Pain proved to be superior to placebo in significantly reducing the diameter of erythema at 24 hours in study NGB 5 (p

Table 6- Summary of Studies NGB 5 and NGB 8855

Study Regi men lnvestigator Design Condition Population Criteria Efficacy

Country Comparator

NGB5 5 applications Urate crystal Total: 19 Lesion diameter, VE vs. Placebo: P.A. Dieppe in 48 hours induced (healthy tendemess, intensity significantly reduced UK (every 12 hr) inflammation volunteers) of erythema, subject erythema diameter at 24

DB, CO Mode! Age range: and investigator hours. lnvestigator's and Placebo 18-50 years preference. volunteer's preference at

48 hours (p

(

TOXICOLOGY

The toxicology ofVoltaren Emulgel Joint Pain 11.6 mg/g Gel was investigated in a series of in vivo studies, including acute and three-month repeat dose toxicity, but concentrating particularly on potentiallocal tolerance and photo-safety issues, as outlined in Table 7 below.

Table 7- Diclofenac Diethylamine Toxicology Program

Study type and duration Route of Species Compound administered administration

Single-dose toxicity Topical, occluded Rat Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Single-dose toxicity Oral Rat Diclofenac diethylamine

Repeat-dose toxicity: 3 months Topical, occluded Rabbit Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Local tolerance 1 photo-safety Phototoxicity, single dose Topical Mo use Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Phototoxicity, single dose Topical Guinea pig Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Photo-allergenicity Topical Guinea pig Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Skin sensitization Topical, occluded Guinea pig Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Skin irritation, 5 days Topical, occluded Rab bit Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Skin irritation, 5 days Topical, occluded Rab bit Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Eye irritation, single dose Ocular Rab bit Voltaren Emulgel Joint Pain 11.6 mg/g Gel

Voltaren Emulgel Joint Pain 11.6 mg/g Gel was generally well tolerated. The acute toxicity of diclofenac diethylamine was essentially the same as that of diclofenac sodium when expressed in terms of the base. The re was no evidence of any significant local irritancy, unexpected toxicity or of any photo-safety concems.

There have been no ether studies specifically designed to investi gate toxicity of the drug substance, diclofenac diethylamine, or of the drug product, Voltaren Emulgel Joint Pain 11.6 mg/g Gel. The non-clinical toxicology of diclofenac sodium is directly relevant to diclofenac diethylamine and is summarized below.

Single dose experiments in mice, rats, rabbits and dogs indicate an acute intravenous LD50 in the region of 100 mg/kg and an oral LD50 nearer 200 mg/kg with little evidence to suggest any significant influence of age or sex on the outcome. An oral study in baboons suggests significantly greater tolerance with a probable LD50 of more than 600 mg/kg. Death following intravenous administration was usually attributed to respiratory or cardiac failure, those following oral administration to gastrointestinal problems.

Repeat dose oral gavage studies of up to 6 months dura ti on in rats indicate a no observed adverse effect level (NOAEL) of 1 to 2 mg/kg/day. A similar result was obtained in a one-month meuse study by dietary administration. At doses greater than 4 mg/kg/day, deaths were common and usually associated with mild anaemia, neutrophilia, disturbance of plasma pro teins, increased extramedullary haematopoiesis and, most prominently, ulceration ofthe gastrointestinal tract with accompanying peritonitis. These latter were commonly associated with hypertrophy or reactive hyperplasia of the mesenteric lymph nodes.

Page23 of30

In a series ofbaboon studies, similar changes were apparent with deaths consistently seen within 3 months oftreatment at 20 mg/kg/day or more. In a 1-year study, 5 of 14 animais treated at 15 mg/kg/day bad died by 8.5 months when this dosage was reduced to 10 mg/kg/day. Bath constipation and diarrhoea were apparent and there was a high incidence of skin ulcers the severity ofwhich was treatment-related. In bath three-month studies, but not in the one-year study, there was evidence of nephropathy at the high dose with increased blood urea nitrogen and disturbance of plasma electrolytes in one study. In the one-year study only and at the high dose only (where 13 of 14 animais died despite a dosage reduction) adrenal cortical hyperplasia was noted in severa} animais. Other changes seen in baboons were essentially similar to those in rats and the deaths were ali associated with gastrointestinal changes. Gastrointestinal changes were seen at the lowest dosages studied in baboons (around 3-5 mg/kg/day) but were generally considered to reflect an exacerbation of pre-existing conditions rather than a primary effect of treatment with diclofenac.

The potential genetic toxicology of diclofenac sodium bas been studied in a wide variety of in vitro and in vivo studies. Most of these studies were carried out many years a go and in elude:

• Ames tests of the drug, of urine and bile concentrates, and of the major hydroxy-metabolites of diclofenac.

• In vitro mammalian cell mutation studies of diclofenac sodium and its hydroxy-metabolites.

• In vivo chromosome aberration and nucleus anomaly tests in Chinese hamsters after bath short-term treatment and repeated administration for 12 weeks.

• Metaphase analyses of spermatogonia and spermatocytes following five administrations.

• A dominant lethal study in mice.

None of these studies gave any indication of a positive outcome. Recently full y GLP compliant in vitro photo-mutagenicity and photo-chromosome aberration studies have been carried out. The photo-mutagenicity study (Ames test) was also negative. Chromosome aberrations were seen in the other study at 25 1-1g/ml and with 16 minutes of UV radiation. These conditions were associated with a reduced mitotic index and the apparently positive result is attributed to cytotoxicity. No chromosome aberrations were seen at lower doses of UV or at lower concentrations of diclofenac. An additional conventional in vivo GLP compliant chromosome aberration study bas also been completed with diclofenac sodium and was also negative.

One mouse and two rat carcinogenicity studies have been conducted. Exposure levels, as judged from plasma concentration data obtained during the more recent of these studies, were 12-45 ng/g in mice at the NOAEL (0.3 mg/kg/day) and l 0-48 ng/ml in rats at the lowest dosage (0.25 mg/kg/day). In ali 3 studies there was a dosage-related increase in mortality at l and 2 mg/kg/day with only isolated animais surviving at the high dose. Most deaths were associated with gastrointestinal ulceration and peritonitis. There were few changes that could be ascribed to treatment at lower dosages (0.1 to 0.5 mg/kg/day) and there was no treatment-related increase in the incidences ofbenign or malignant tumours in any ofthese studies.

Reproduction toxicity bas been assessed in a series of pre-ICH design studies, including Segment I and III studies in rats and a variety of Segment II studies in mice, rats and rabbits. Almost aU studies included treatment at taxie dosages and dea th of the dams, usually attributed to peritonitis, was a common finding. Treatment with diclofenac sodium in the Segment I and III

Page24 of JO

(

studies was generally associated with a slight increase in gestation and occasional dystocia resulting in increased peri-natal mortality. Even discounting this, there was usually an increase in embryo-foetal and/or perinatallosses. Birth weight was reduced. Foetal changes extended to the lowest dosage examined, 2 mg/kg/day, in both studies. Other than deaths associated with dystocia, post-natal survival was not affected.

In the Segment II studies in mi ce, there was no clear effect of treatment at 2 or 4 mg/kg/day wh en given orally, even wh en administered through da ys 0-17 of gestation. Reductions in foetal numbers and reduced ossification at higher dosages were associated with severe maternai toxicity. In oral rat studies a similar picture emerged. There were sorne minor contradictory findings at 4 mg/kg/day but none at 2 mg/kg/day and clear effects at higher dosages, including reduced ossification, that were attributed to maternai toxicity. An intramuscular study indicated no changes in the foetuses at 10 mg/kg/day, despite maternai sedation and local injection site responses. In a GLP compliant subcutaneous rat study, however, minimally reduced ossification was identified at 1.2 mg/kg/day; 0.4 mg/kg/day was a NOAEL. In an oral rabbit Segment II study, 5 mg/kg/day was a clear NOAEL, changes at 10 mg/kg/day included increased embryonic and foetal resorptions and reduced foetal ossification in three foetuses. An intramuscular rabbit study identified 3 mg/kg/day as the NOAEL with increased abortions and dead foetuses, reduced number of full y formed foetuses and reduced ossification, and reduced foetal viability at higher dosages, associated with maternai toxicity.

Page 25 of30

REFERENCES

American Hospital Formulary Service. AHFS Drug Information; 1671, 1679-84, 1700, 1705, 1715, 1718-9, 1731, 1736, 1826, 1828-9. American Society ofHealth System Pharmacists (1999). The most comprehensive authoritative source of eva1uative drug information.

Amadio P, Cummings DM and Amadio P (1993) Nonsteroida1 anti-inflammatory drugs. Tai1oring therapy to achieve results and avoid toxicity. Postgrad Med; 93(4): 73-6, 79-81, 85-6, 88, 93-6

Bertolini A, Ottani A and Sandrini M (200 1) Dual acting anti-inflammatory drugs: a reappraisal. Pharmacol Res; 44(6): 437-50

Chlud K, Wagener HH (1987) Perkutane Therapie mit NSAID (Non-steroidal Anti-Inflammatory Drugs) unter besonderer Berücksichtigung kinetischer Fragen. EULAR Bull; 2: 41-45.

Chlud K and Wagener HH ( 1991) Perkutane Therapie mit nichtsteroidalen Antiphlogistika. Fortschr Med; 1 09(2): 29-32

Ch1ud K (1999) Zur Anwendung von NSAR-Topika bei irritierten und dekompensierten Arthrosen. Wien Med Wochenschr; 149: 546-7

Davies NM, Anderson KE (1997) Clinicat pharmacokinetics of diclofenac.Therapeutic insights and pitfalls. Clin Pharmacokinet; 3(3): 184-213.

Day RO, McLachlan AJ, Graham GG, et al ( 1999) Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid. Clin Pharmacokinet; 36(3): 191-210

Dreiser RL (1994) Topical antirheumatic drug therapy: current practice and future trends. Eur J Rheumatol Inflamm; 14(4): 3-8.

Duteil L, Que ille C, Poncet M, et al (1990) Objective assessment of topical corticosteroids and non-steroidal anti-inflammatory drugs in methyl-nicotinate-induced skin inflammation. Clin Exp Dermatol; 15: 195-9

Faigle JW, Bottcher I, Godbillon J, et al ( 1988) A new metabolite of diclofenac sodium in human plasma. Xenobiotica; 18( 1 0): 1191-7

Giuliano F and Wamer TD (1999) Ex Vivo assay to determine the cyclooxygenase selectivity of non-steroidal anti-inflammatory drugs. Br J Pharmacol; 126: 1824-30

Gondolph-Zink B, Gronwald U (1996) Wirkstoffk.onzentrationen in artikularen und periartikularen Geweben des Kniegelenkes nach kutaner Anwendung von Diclofenac-Diethylammonium Emulgel. Akt Rheumatol; 21: 298-304

Page26of30

Grahame R (1995) Transdermal non-steroidal anti-inflammatory agents. Br J Clin Pract; 49 (1): 33-35.

Hiramatsu Y, Akita S, Salamin PA, et al (1990) Assessment oftopical non-steroidal anti-inflammatory drugs in animal models. Arzneim. Forsch; 40: 1117-1124.

Kurowski M, Dunky A (1992) Transdermal absorption ofnonsteroidal anti-inflammatory drugs in rheumatoid arthritis patients; 1. diclofenac. Int J Pharm Ther Toxicol; 30(11): 479

Kyuki K, Shibuya T, Tsurumi K, et al (1983) Anti-inflammatory effect of diclofenac sodium ointment (cream) in topical application. Japan J Pharmacol; 33: 121-132.

Martin H, Basbaum A, Goetzl J, et al (1988) Leukotriene B4 Decreases the Mechanical and Thermal Thresholds ofC-FiberNociceptors in the Hairy Skin ofthe Rat. Journal of Neurophysiology; 60: 438-445.

Radermacher J, Jentsch D, Scholl MA, et al (1991) Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol; 31:537-41

Riess W, Schmid K, Botta L, et al ( 1986) Percutaneous absorption of diclofenac. Arzneim Forsch; 36 (2): 1092-1096.

Singh P, Roberts MS (1994) Skin permeability and local tissue concentrations ofnon-steroidal anti-inflammatory drugs after topical application. J Pharm Exp Ther; 268: 144-151.

Sioufi A, Pommier F, Boschet F, et al (1994) Percutaneous absorption of diclofenac in healthy volunteers after single and repeated application of diclofenac emulgel. Biopharm Drug Disp; 15: 441-449.

Stierlin H, Faigle JW, Colombi A (1978) Pharmacokinetics of diclofenac sodium (Voltaren) and metabolites in patients with impaired renal function. Scand J Rheumatol; Suppl 22: 30-5.

Stierlin H, Faigle JW, Sallmann A, et al ( 1979) Biotransformation of diclofenac sodium (Voltaren®) in animais and in man. Isolation and identification of principal metabolites. Xenobiotica; 9( 1 0): 601-1 0

Todd PA and Sorkin EM (1988) Diclofenac sodium: A reappraisal ofits pharmacodynamie and pharmacokinetic properties, and therapeutic efficacy. Drugs; 35:244-85

V aile JH, Davis P (1998) Topical NSAIDs for musculoskeletal conditions. A review of the literature. Drugs; 56 (5): 783-799.

Page27 of30

PART III: CONSUMER INFORMATION

VOLT AREN® EMULGEL™ - JOINT PAIN (Diclofenac diethylamine gel)

..

This leaflet is part III of a three-part "Product Monograph" published when Voltaren Emulgel - Joint Pain was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Voltaren Emulgel - Joint Pain. Contact your doc tor or pharmacist if you have any questions about the drug.

ABOUT TIIIS :\IEDICATIO~

What the medication is used for:

For the relief of aches and pain associated with acute, localized joint or muscle injuries such as sprains, strains or sports injuries (e.g. sore ankles, knees, bands or shoulder). Rest may a Iso be helpful to assist the relief of associated discomfort.

What it does: Voltaren Emulgel - Joint Pain is specially formulated for rubbing into the skin to relieve acute pain affecting the joints and muscles. The active substance, diclofenac, is one of the group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs) that work within the body by blocking the production of particular substances, ca lied prostaglandins, which are involved in the development of pain and inflammation.

Whcn it should not be used:

• If y ou are currently taking diclofenac or any other oral non-steroidal anti-inflammatory drug (NSAID) which are used to treat pain, fever or inflammation, such as ibuprofen or acetylsalicylic acid (ASA). If you are not sure, ask your doctor or pharmacist.

• If in the past you have bad allergie reactions to diclofenac or any other NSAIDs such as ibuprofen or ASA.

• If y ou have attacks of asthma, urticaria (hives), or acute rhinitis (nasal inflammation, irritation or stuffy nose that lasts less than 6 weeks) after taking ASA or other NSAIDs.

• If you are allergie to any of the non medicinal ingredients in the gel (see list of non medicinal ingredients).

What the medicinal ingredient is: Diclofenac diethylamine

What the nonmedicinal ingredients are: Carbomer, cocoyl caprylocaprate, diethylamine, isopropyl alcohol, liquid paraffin, macrogol cetostearyl ether, perfume, propylene glycol, purified water.

What dosage forms it cornes in: The product co mes in tubes of 75 g. The strength of medicinal ingredient in ali tubes is 11.6 mg/g (1.16% w/w).

WAR~INGS A:'I:D PRECAl'TJO:\S

BEFORE you use Voltaren Emulgel- Joint Pain talk to your doctor or pharmacist if:

If you have a history of stomach ulcers or take medication for such gastrointestinal disorders.

• Y ou are pregnant or breast-feeding.

This product is not intended for use in children under the age of 16.

Do not apply to cuts or open wounds or to skin that has a rash or eczema.

Do not wrap the skin with an airtight or occlusive dressing when using Voltaren Emulgel- Joint Pain.

ln very rare cases, your skin may be more sensitive to sunlight while using this product. Use caution during sun exposure or when using tanning booths/sun lamps. Possible signs are sunburn with itching, swelling and blistering.

Be careful not to get it in your eyes. If this happens, rinse your eyes weil with clean water and tell a doctor or a pharmacist.

Voltaren Emulgel - Joint Pain is for EXTERNAL USE ONLY.

Do not use it in the mouth, vaginal or anal areas.

Never swallow it.

JNTERACTJOi'IS WITII TIIIS ;\IEDICATIO~

Check with your doctor or pharmacist if you are taking any other NSAIDs (ibuprofen or acetylsalicylic acid) or anticoagulants (blood thinners), high blood pressure medication, oral anti-diabetic agents, fluoroquinolone antibiotics (i.e., ofloxacin) or are taking medication for peptic ulcers, gastroesophageal disease orto control excess acidity. If you suspect a drug interaction, notify your doctor or pharmacist.

Page 28of30

Usual dose: For adults and adolescents 16 years and older: apply Voltaren Emulgel- Joint Pain 3 to 4 times a day. Before first use, unscrew and remove the cap. Use the reverse side of the cap to remove the seal from the tube. Gently rub a small amount of Voltaren Emulgel- Joint Pain into the skin where you have pain or swelling. The amount needed will vary depending upon the size of the pain fui or swollen area. Usually, a strip approximately 2 cm long will be sufficient to cover a 200 cm1

area. Wash your bands after rubbing in Voltaren Emulgei-Joint Pain, unless of course they are the site being treated.

The gel should not be used for more than 7 days for muscle and joint injuries, unless recommended by a doctor. Talk to your doctor if your condition does not improve within 7 da ys, or if it gets worse.

Overdose Management Information: In case of accidentai drug overdose, contact a health ca re practitioner, hospital emergency department or regional poison control centre immediately, even ifthere are no symptoms.

Missed Dose: If you miss applying Voltaren Emulgel- Joint Pain at the correct time, apply it when you remember and then next apply it at the usual time. Do not apply a double quantity.

SIDE EFFECTS A~D \\liAT TO DO .\BOLT TIIE:\1

Itching, reddening or slight irritation of the skin are corn mon after use of Voltaren Emulgel - Joint Pai~. These symptoms are usually mild, passing and harmless. If you are concerned, tell a doctor or pharmacist.

SERIOLS SIDE EFFECTS, 110\\ OFTE;'I; THEY HAPPE:\ A:\D \\"11.\T TO DO ABOU' TIIEi\1

Symptom 1 effect Talk with Stop taking your doctor or drug and cali pharmacist if your doctor or

severe pharmacist

Common None

Uncommon allergy to the product (hives or skin rash "' which may coverlarge parts of your body, wheezing or shortness of breath, swelling of the face or ton gue)

blistering of the skin where the "' gel bas been applied

the skin may be more sensitive "' to sunlight Gastro-intestinal · "' discomfort, dyspepsia

This is not a complete list of side effects. For any unexpected effects wh ile taking Voltaren Emu/ge/- Joint Pain, contact your doctor or pharmacist.

Page 29of30

HO\\' TO STORE IT

Voltaren Emulgel - Joint Pain should be stored between 15 and 30°C.

Voltaren Emulgel - Joint Pain should not be stored after the expiry date shown on the carton and tube.

Keep Voltaren Emulgel - Joint Pain out of the rea ch and sight of children.

RErORTI:\'G SUSPECTEO SIDE EFFECTS

Y ou cao report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Pro gram by one of the following three ways:

• Report online at www.healthcanada.gc.ca/medeffect • Cali toll-free at: 866-234-2345 • Complete a Canada Vigilance Reporting Form and:

- Fax toll-free to: 866-678-6789, or - Mail to: Canada Vigilance Program

Health Canada, Postal Locator 0701C Ottawa, ON, KIA OK9

Postage paid labels, Canada Vigilance Reporting Form, and the adverse reaction reporting guidelines are available in the MedEffect™ Canada website at www .healthcanada.gc.ca/medeffect

NOTE: Shouldyou require information related to the management of the si de effect, contact y our hea/th professional. The Canada Vigilance Program does not provide medical advice ..

i\IORE l;\ FORi\IATION

This document plus the full product monograph, prepared for health professionals, can be received by contacting the sponsor, Novartis Consumer Health Canada lnc., at: 1-888-788-8181

This leaflet was prepared by Novartis Consumer Health Canada Inc.

Last revised: Nov. 27, 2009

Page 30of30

Objet:

Rapport d'expert

Reclassement de la formulation de diclofenac topique 1%

(Voltaren Emulgel) de l'Annexe Il à l'Annexe Ill.

Questions : L'innocuité de la formulation Voltaren Emulgel est-elle

suffisamment documentée pour que ce produit puisse être

disponible dorénavant au Québec sous surveillance du

pharmacien et non plus sous contrôle de celui-ci?

Quels sont les risques d'interactions médicamenteuses avec le

Voltaren Emulgel?

. B.Pharm., Ph.D., FCAHS

16 juin 2014

2

Sommaire

Les informations détaillées dans les paragraphes suivants m'amènent à conclure que l'inscription du diclofenac en Annexe Ill favoriserait l'accès aux patients à une médication active sans pour autant augmenter le risque de toxicité. Cette conclusion est basée sur les données de la littérature qui démontrent :

1) Que l'hépatotoxicité reliée à l'exposition systémique 'de diclofenac est un phénomène rare s'observant chez 11/100 000 à 23/100 000 patients;

2) Qu'un monitoring des transaminases (ALT/AST) ne permet pas d'établir le risque temporel d'hépatotoxicité lors d'un traitement avec le diclofenac;

3) Que le mécanisme sous-jacent à l'hépatotoxicité induite par le diclofenac est fort probablement lié à la formation de métabolites réactifs;

4) Que l'apparition d'hépatotoxicité peut être rapide mais en lien avec la durée

d'exposition totale. Conséquemment, que l'hypothèse d'une réaction immunitaire non prévisible peut être rejetée, l'augmentation des marqueurs inflammatoires étant probablement secondaire à la production de métabolites réactifs;

5) Que les polymorphismes associés au CYP2C9, une enzyme reliée à la formation du métabolite majeur, ne permettent pas d'identifier les patients à risque;

6) Que plusieurs isoenzymes sont impliquées dans la formation de plusieurs métabolites mineurs dont au moins 4 dérivés iminés possèdent des caractéristiques physico-chimiques propres à des substances réactives;

7) Qu'une diminution en activité fonctionnelle pour une enzyme de conjugaison

(UGT2B7) ou pour un transporteur d'efflux (MRP2; ABCC2) impliqués dans la formation ou le transport des métabolites toxiques serait reliée au risque accrue d'hépatotoxicité au diclofenac;

8) Que des analyses de génotypage pour UGT287 ou ABCC2 ne font pas partie de

standards de pratique actuels, ni recommandées par des organismes comme PharmKBG;

9) Qu'une plus grande exposition (concentration plasmatique élevée) du diclofenac au

sein des hépatocytes augmenterait le risque de toxicité;

10) Que la formulation de Voltaren Emulgel ne produit que de très faibles concentrations plasmatiques et hépatiques par rapport à la forme orale.

11) Que les formulations topiques de diclofenac présentent un excellent profil thérapeutique tant au niveau de l'efficacité que des effets secondaires systémiques;

12) Que pour le Voltaren Emulgel, une plus faible exposition systémique malgré des concentrations tissulaires locales supérieures permet d'observer une excellente efficacité en diminuant les risques de toxicité systémique.

Enfin, je démontrerai que le risque d'interactions médicamenteuses avec le Voltaren Emu/gel est très faible justifiant ainsi son inscription à l'Annexe Ill.

Question 1

L'innocuité de la formulation Voltaren Emulgel est-elle suffisamment documentée pour que ce produit puisse être disponible dorénavant au Québec sous surveillance du pharmacien et non plus sous contrôle de celui-ci?

3

Le diclofenac sodique est un agent anti-inflammatoire approuvé depuis 1988 pour

le traitement de patients souffrant d'ostéoarthrite, d'arthrite rhumatoïde, ou de

spondylite ankylosante. Au cours de son développement et dans les premiers mois

suivant sa commercialisation, des rapports d'effets secondaires sérieux furent notés par

la communauté médicale. Entre autres, des cas d'hépatite sévère furent reliés à la prise de diclofenac.1 Ces premières observations ont mené rapidement à l'émission, le 4 décembre 2009, par la Food and Drug Administration (FDA) américaine, d'un avis de

sécurité concernant toutes les formulations de diclofenac.2

En 1995, une revue publiait les données relatives à 180 cas d'hépatotoxicité associée à la prise de diclofenac; cas rapportés à la FDA entre novembre 1988 et juin 1991.3 Dans 77% des cas (120 patients), la présentation clinique était associée à des symptômes alors que les autres cas furent détectés par des anomalies de laboratoire. Des

120 patients symptomatiques, 90 ont souffert de jaunisse et 7 d'entre eux en sont

décédés. Les signes de toxicité pouvaient être manifestes aussitôt qu'un mois après le

début d'un traitement chronique (24% des cas) pouvant ainsi laisser croire à une réaction immunitaire. Des analyses de cohortes et des programmes de surveillance post-

commercialisation ont permis d'établir précisément l'innocuité des formulations de

diclofenac.4 Les évènements cliniques requérant une hospitalisation ou les cas sévères de

toxicité hépatique s'observeraient entre 11/100 000 (1/9 480 patients observés) et

23/100 000 patients. 5•6

Il est donc bien établi par la communauté scientifique et médicale que l'exposition

systémique à du diclofenac durant des périodes aussi courtes qu'un mois est associée à des risques de toxicité hépatique. Le mécanisme sous-jacent à cette toxicité demeure cependant toujours nébuleux. Les élévations en transaminases (ALT/AST) souvent notées

lors de la prise de diclofenac ne s'observent pas de façon concomitante avec les

1 lveson TJ, Ryley NG, Kelly PM, Trowell JM, McGee JO, Chapman RW. Diclofenac associated hepatitis. J Hepatol 1990 :10 ;85-89. 2 FDA. Voltaren Gel (diclofenac sodium topical gel) 1%- Hepatic Effects Labeling Changes. Posted 12/04/2009. 3 Banks AT, Zimmerman HJ, lshak KG, Harter JG. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 1995:22;820-827. 4 Aithal GP. Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol 2011:7;139-150. 5 Laine L, Goldkind L, Curtis SP, Conn ors LG, Yangiong Z, Cannon CP. How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am J Gastroenterol 2009:104;356-362. 6 Bjërnsson ES, Bergmann OM, Bjërnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of lceland. Gastroenterology 2013:144;1419-1425.

4

symptômes et la présentation clinique des cas d'hépatotoxicité.5 Leur valeur prédictive est donc limitée. Le rôle de réactions immunitaires et de différents marqueurs

inflammatoires tel que les interleukines 1~ et 17 furent proposés récemment dans des modèles animaux.7 Il demeure cependant difficile de conclure si ces phénomènes sont la cause ou s'ils s'observent secondairement à un phénomène primaire entraînant une réaction inflammatoire. Actuellement, l'implication de métabolites toxiques du

diclofenac se liant de façon covalente à certaines protéines au sein des hépatocytes, soit en altérant la fonction de ces protéines ou en stimulant une réponse immunitaire, semble l'explication la plus probable.8

De fait, le diclofenac subit un métabolisme complexe par différentes isoenzymes de la superfamille des cytochromes P450 {CYP) avant d'être conjugué par des glucuronyltransférases et du glutathion. Les premières études de métabolisme ont suggéré que le diclofenac était principalement transformé en 4-hydroxydiclofenac par le

Diclolènac·3'.4'-oxide

l Glutalhione COOH

Cl H CH2

GS~~;Iô OH

4'-GS-3'-0H-3',4'-dihydro-diclofcnnc

+

4'-011-3'-US-3'.4'-dihydro-diclofcnnc

CYP

cv y COOH

Cl H CH2

HOO~;ô 4'-Hydroxydiclofenac

ÇOOH COOH

6~-62 ~ [Jr~~2 l a ~~~

0 Dicloli:nac

~yp

5-Hydroxydiclofen:~c

/ Diclofcnac-4,5·oxidc

! Glutathione COOH 1

Cl H CH2

O~;Ç(SG OH 4-0H-5-GS-4,5-dihydro-

dicloli:nac

COOH Cl H CH2

Diclofenac-1',4'-quinonc imine

~ Glutathionc

Diclofenac-2,5-quinoue iminc

~ Glulllthione

COOH

o:IÇlOH GS COOH

Cl H CH2

HO

( 5

CYP2C9 et en 5-hydroxydiclofenac par le CYP3A4.9 L'implication du CYP2C9 dans la

formation du 4-hydroxydiclofenac a cependant rapidement été remise en cause alors que

des études in vitro et in vivo chez l'humain n'ont pu mettre en relation différents polymorphismes associés au CYP2C9 et la pharmacocinétique du diclofenac.10•11 De plus,

la valeur de l'importance du CYP2C9 dans la prédiction d'interactions médicamenteuses

significatives n'a pu être démontréeY·13 Au niveau thérapeutique, aucune relation n'a pu

être démontrée entre l'inhibition des cyclooxygénases 1 et 2 par le diclofenac et les

polymorphismes génétiques du CYP2C9. 14 Enfin, aucune relation n'a pu être démontrée

entre l'activité du CYP2C9, ses polymorphismes génétiques et l'hépatotoxicité induite par

le diclofenac.15

Il existe par ailleurs plusieurs évidences que des voies métaboliques mineures

entraînent la formation de radicaux libres et au moins 4 dérivés iminés sont susceptibles

de provoquer des liaisons covalentes avec des protéines hépatiques. 16•17 Ainsi, tel que

mentionné précédemment, la voie majeure de métabolisme n'est probablement pas

directement impliquée dans la variabilité inter-individuelle dans la réponse au diclofenac

mais plutôt, des voies métaboliques mineures qui entraînent la formation de substances

réactives et toxiques. Par le fait même, les travaux de Bort et coll. ont permis de

démontrer l'implication de différentes isoenzymes dont le CYP2C8, CYP2Cl8, CYP2C19 et

CYP2B6 (et jusqu'à 7 isoformes) dans la formation de différents métabolites. 17

En lien avec ces observations, Daly et coll. ont déterminé les caractéristiques

génétiques de 24 patients ayant souffert d'une hépatotoxicité reliée à la prise de

diclofenac.18 Ces chercheurs ont démontré qu'un variant allélique (*2) dans le gène

9 Tang W, Stearns RA, Wang RW, Chiu S-HL, Saillie TA. Roles of hu man hepatic cytochromes P450s 2C9 and 3A4 in the metabolic activation of diclofenac. Chem res Toxicol1999:12;192-199. 10 Yasar U, Eliasson E, Forslund-Bergengren C, Tybring G, Gadd M, Sjëqvist F, Da hl ML, The role of CYP2C9 genotype in

the metabolism of diclofenac in vivo and in vitro. Eur J Clin Pharmacol 2001:57;729-735. 11 Brenner SS, Herrlinger C, Dilger K, Mürdter TE, Hofmann U, Marx C, Klotz U. Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib. Clin Pharmacokinet 2003:42;283-292. 12 Zi J, Liu D, Ma P, Huang H, Zhu J, Wei D, Yang J, Chen C, Effects of CYP2C9*3 and CYP2C9*13 on diclofenac metabolism and inhibition-based drug metabolism. Drug Metab Pharmacokinetic 2010:25;343-350. 13 Hynninen W, Olkkola KT, Lei no K, Lundgren S, Neuvonen P, Ra ne A, Valtonen M, Laine K. Effect of voriconazole on the pharmacokinetics of dlclofenac. Fundam Clin Pharmacol 2007:21;651-656. 14 Kirchheiner J, Meineke 1, Syeinbach N, Meisel C, Roots 1, BrockmÇoller J. Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphisms in humans. Br J Clin Pharmacol 2003:55;51-61. 15 Aithal GP, Day CP, Leathart JB, Daly AK. Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis. Pharmacogenetics 2000:10;511-518. 16 Grilla MP, Ma J, Teffera Y, Waldon DJ. A novel bioactivation pathway for 2-[2-(2,6-dichlorophenyl) aminophenyl]ethanoic acid (diclofenac) initiated by cytochrome P45-mediated oxidative decarboxylation. Drug Metab Disp 2008:36;1740-1744. 17 Bort R, Macé K, Boobls A, Gomez-Lechon MJ, Pfeifer A, Casteil J. Hepatic metabolism of diclofenac: role of human CYP in the miner oxidative pathways. Biochem Pharmacol1999:58;787-796. 18 Daly AK, Aithal GP, Leathart JB, Swainburry RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8 and ABCC2 genotypes. Gastroenterology 2007:132;272-281.

6

(UGT287} codant pour une glucurolyltransférase spécifique était environ 8 fois plus présent chez les patients atteints que chez les sujets contrôles (soit des patients exposés au diclofenac sans toxicité ou des sujets volontaires sains). Un deuxième variant allélique (C24T) observé dans le gène (ABCC2) codant pour le transporteur MRP2 était environ 5

fois plus présent chez les patients atteints comparativement aux contrôles. En bref, ces

résultats suggèrent qu'une diminution dans la capacité fonctionnelle à conjuguer des métabolites réactifs à l'acide glucuronique ou à les expulser de l'hépatocyte (transport inefficient) pourrait expliquer les risques plus élevés d'hépatotoxicité observée avec les formulations de diclofenac. Conséquemment, une stratégie de génotypage sélectif dans

le cadre d'un programme de médecine personnalisée pourrait permettre d'éviter ces réactions indésirables.

Le mécanisme de toxicité lié à la formation de métabolites réactifs et à la capacité d'élimination chez un sujet donné versus une réaction immunitaire perse introduit une notion importante dans l'évaluation du risque sous-jacent à l'exposition systémique de diclofenac. Le risque de toxicité doit donc être croissant 1) avec l'augmentation de la concentration de diclofenac (ou de ses métabolites toxiques) au sein de l'hépatocytel et 2) avec la durée de traitement. En ce qui a trait à la durée de traitement, la revue des 180 cas d'hépatotoxicité rapportés à la FDA démontre que les insultes tissulaires étaient apparentes chez 24% des cas à 1 mois, chez 63% des cas à 3 mois, et dans 85% des cas à 6 mois.3 Ces observations sont donc clairement en accord avec un mécanisme dose-dépendant plutôt qu'une réaction spontanée de type immunitaire·. Pour ce qui est de l'exposition directe de l'hépatocyte, nous devons considérer les caractéristiques

pharmacocinétiques des différentes formulations.

L'administration orale d'un médicament est associée à une exposition maximale des entérocytes et des hépatocytes au principe actif et aux métabolites qui en sont dérivés. De fait, pour le calcul des concentrations potentiellement toxiques, la FDA considère que le volume d'eau au sein du tractus gastro-intestnal est de 250 ml. Ainsi, la

1

""'" --ê 1 ~ i Ent~ocyl~ E ~

~ 7ii l <

2'

~ ~ !!:.

~ 3 S" ~

1

concentration minimale à laquelle des signes de toxicité sont observés dans des modèles pharmacologiques doit être supérieure à la dose orale divisée par ce volume. Pour le diclofenac (dose orale de 50 mg), cette concentration

s'établirait à 200 fJ.g/ml.

L'entérocyte en soit n'est plus

considéré comme une barrière passive

à l'entrée du médicament dans l'organisme qui ne pourra la pénétrer qu'en fonction de caractéristiques

7

physico-chimiques particulières (grande liposolubilité). Au contraire, l'entérocyte

possède une membrane active exprimant plusieurs transporteurs sélectifs d'influx et d'efflux qui contrôle l'entrée et l'expulsion de substances potentiellement toxiques. Ces

transporteurs fonctionnent de concert avec des systèmes enzymatiques dont des isoenzymes de CYP450s et des glucuronyltransférases qui sont exprimés au sein de son

réticulum endoplasmique lisse. La vascularisation des entérocytes compose de plus un mécanisme de défense important puisque le retour veineux s'effectue par les veines

mésentériques qui constituent en aval la veine porte. Ainsi, les substances ayant

pénétrées les entérocytes devront faire face, au niveau hépatique, à un deuxième système limitant leur pénétration dans la circulation systémique.

En effet, la circulation portal se termine au pourtour du lobule hépatique et

démontre des espacements (sinusoïdes) favorisant la pénétration des substances dans l'hépatocyte. Cette

organisation histologique de

même que l'organisation spatiale des veinules de la veine

porte juxtaposées au canal

hépatique mais à distance de la veine centre-lobulaire permet

une exposition maximale aux enzymes de métabolisme hépatique. Ainsi, avant

d'atteindre la circulation

systémique par la veine centre-

lobulaire qui rejoindra la veine

cave inférieure, les substances

seront exposées à une mono-couche d'hépatocytes favorisant ainsi leur métabolisme. La dose entière absorbée suite à son administration par voie orale doit passer par le foie avant d'atteindre la circulation systémique. Dans le cadre de médicaments pouvant générés des substances réactives et des radicaux libres1 on conçoit facilement que le foie devient alors un organe cible et à haut risque de toxicité.

8

Tel que mentionné précédemment, la présence de différentes isoenzymes du CYP450 peut mener à la formation de plusieurs métabolites toxiques du diclofenac. L'expression de cer-

taines isoenzymes de

conjugaison, dont

I'UGT2B7 permet-trait de limiter leur

liaison covalente

avec des protéines de l'hépatocyte. Une diminution fonction-

nelle en cette enzyme de conjugai-son augmenterait

Hepatocyte

~

cependant les risques de toxicité, tel que démontré chez des patients avec le variant allélique UGT287*2. 18 De plus, l'expression sélective du transporteur MRP2 au sein du

canal biliaire afin de favoriser l'expulsion des métabolites ou du diclofenac permet aussi de protéger l'hépatocyte. En absence d'activité fonctionnelle, tel qu'observé chez des patients avec le variant allélique C24T, les risques de toxicité hépatique seraient a ugmentés.18

Des formulations topiques de diclofenac sont disponibles sur le marché européen depuis plus de 20 ans. Plusieurs études ont permis d'établir leur efficacité en démontrant entre autre, des concentrations tissulaires supérieures à celles observées par voie orale.19•2° Ces mêmes études ont démontré un profil d'innocuité très favorable avec des fréquences d'effets secondaires, principalement d'irritation locale, très faibles. En ce qui a trait plus spécifiquement à la formulation topique de diclofenac sodique à 1% (Voltaren Emulgel), une étude longitudinale de 9 à 12 mois a permis d'établir l'innocuité de cette formulation administrée à raison de 4g sur 1 ou 2 genoux, 4 fois par jour Y Au total, 583 patients furent enrôlés dans cette étude et 294 patients complétèrent la période de traitement anticipée. Le seul effet secondaire rapporté chez plus de 1% des patients fût

une dermatite au site d'application. Des effets secondaires gastro-intestinaux, rénaux, hépatiques ou cardiovasculaires furent rapportés respectivement par 3, 1, 2 et 0 patients. Une amélioration de l'ordre de 35-40% fut aussi démontrée dans divers paramètres

d'efficacité fonctionnelle.

19 Rainsford KD, Kean WF, Ehrlich. Review of the pharmaceutical properties and dinical effects of the topical NSAID formulation, didofenac epolamine. Curr Med Res Opin 2008:24;2967-2992. 20 Banning M. Topical didofenac: dinical effectiveness and current uses in osteoarthritis of the knee and soft tissues injuries. Expert Opin Pharmacother 2008:9;2921-2929. 21 Peniston JH,. Morris SG, Alwine LK. An open-label, long-term safety and tolerability trial of diclofenac sodium 1% gel in patients with knee osteoarthritis. Physician and Sportsmed 2011:39;31-38.

9

Dans le but d'apprécier le risque d'effets secondaires systémiques, en l'occurrence

hépatique, suite à l'administration topique de diclofenac, il importe de comparer la biodisponibilité et la pharmacocinétique de différentes formulations. Dans une étude

randomisée à 3 bras d'étude, des sujets volontaires sains ont reçu 3 traitement différents de 7 jours à savoir :A) une application de 4 g de Voltaren Emulgel sur un genou 4 fois par jour (dose totale quotidienne de 16 g); b) une application de Voltaren Emulgel aux 2 genoux et aux 2 mains 4 fois par jour (dose totale quotidienne de 48 g); et, C) un comprimé

oral de 50 mg 3 fois par jour (dose totale quotidienne de 150 mg).22 Globalement, l'exposition systémique était de 5 (48 g) à 17 (16 g) fois plus faible avec les formulations topiques que pour la formulation orale. Les effets secondaires furent limités à une dermatite locale chez 4 sujets. La transposition de ces données à des valeurs de concentrations plasmatique peut être plus facilement appréciée en regardant la figure

publiée de l'étude de Brunner et coll. 23 Ainsi, on note que les concentrations plasmatiques suite à un traitement avec du Voltaren Emulgel (dose totale de 40 g: points ronds fermés) sont de l'ordre de 0,5 à 1 ng/mL : des concentrations largement inférieures à celles

10000

0 2 3 ~ 5 6 7 Time(h)

observées au niveau intestinal ou hépatique lors de l'administration

d'une formulation orale. Considérant les valeurs de concentrations

moyennes équivalentes au niveau

thérapeutique dérivées de l'étude de Kienzler, on peut aussi affirmer que

les concentrations moyennes

circulantes sont de 5 à 17 fois inférieures à celles observées après une administration oraleY

En conclusion, les données de la littérature démontrent :

1) Que l'hépatotoxicité reliée à l'exposition systémique de diclofenac est un phénomène rare s'observant chez 11/100 000 à 23/100 000 patients;

2) Qu'un monitoring des transaminases (ALT/AST) 11e permet pas d'établir le risque

temporel d'hépatotoxicité lors d'un traitement avec le diclofenac; 3) Que le mécanisme sous-jacent à l'hépatotoxicité induite par le diclofenac est fort

probablement lié à la formation de métabolites réactifs;

22 Kienzler JL, Gold M, Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel1% versus oral diclofenac sodium in healthy volunteers. J Cl in Pharmacol 2010:50;50-61. 23 Brunner M, Davies 0, Martin W, Leuratti C, Lackner E, Müller M. A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects. Br J Clin Pharmacol 2011:71;852-859.

10

4) Que l'apparition d'hépatotoxicité peut être rapide mais en lien avec la durée d'exposition totale. Conséquemment, que l'hypothèse d'une réaction immunitaire non prévisible peut être rejetée, l'augmentation des marqueurs inflammatoires étant probablement secondaire à la production de métabolites réactifs;

5) Qu'un génotypage des polymorphismes associés au CYP2C9, une enzyme ayant été reliée à la formation du métabolite majeur ne permet pas d'identifier les patients à risque;

6) Que plusieurs isoenzymes sont impliquées dans la formation de plusieurs

métabolites mineurs dont au moins 4 dérivés iminés possèdent des caractéristiques physico-chimiques propres à des substances réactives;

7) Qu'une diminution en activité fonctionnelle pour une enzyme de conjugaison

(UGT2B7) ou pour un transporteur d'efflux (MRP2; ABCC2) des métabolites toxiques serait reliée au risque accrue d'hépatotoxicité au diclofenac;

8) Que des analyses de génotypage pour UGT287 ou ABCC2 ne font pas partie de

standards de pratique actuels, ni recommandées par des organismes comme

PharmKBG; 9) Qu'une plus grande exposition (concentration élevée) du diclofenac au sein des

hépatocytes augmenterait le risque de toxicité; 10) Que la formulation de Voltaren Emulgel ne produit que de très faibles

concentrations plasmatiques et hépatiques par rapport à la forme orale. 11) Que les formulations topiques de diclofenac présentent un excellent profil

thérapeutique tant au niveau de l'efficacité que des effets secondaires

systémiques; 12) Qu'une plus faible exposition systémique malgré des concentrations tissulaires

locales supérieures permet d'observer une excellente efficacité en diminuant les

risques de toxicité systémique.

Compte-tenu de ces observations, je considère que l'inscription du diclofenac en Annexe Ill favoriserait l'accès aux patients à une médication active sans pour autant augmenter le risque de toxicité. La vente en pharmacie assure toujours une surveillance de la part du pharmacien.

11

Question 2

Quels sont les risques d'interactions médicamenteuses avec le Voltaren Emulgel?

Le diclofenac est connu pour interagir de façon significative avec 50 médicaments

selon les données internationales de la littérature.24 La très grande majorité de ces interactions peuvent s'expliquer soit par des mécanismes de toxicité rénale ou hépatique

communs entre le diclofenac et le médicament en interaction, soit par une augmentation du risque de saignements en raison d'une irritation gastrique causée par le diclofenac,

soit par une inhibition du CYP2C9 par le diclofenac au niveau hépatique entraînant une augmentation des concentrations de l'autre médicament; soit par une inhibition

importante du métabolisme du diclofenac. Aucune de ces conditions ne présente une

véritable contre-indication à l'utilisation topique de diclofenac considérant :

1) Une exposition systémique beaucoup plus faible de diclofenac à partir d'une formulation topique limitant ainsi le risque de toxicité rénale ou hépatique;

2) Une très faible prévalence d'irritation gastro-intestinale notée avec la formulation topique;

3} Une très faible possibilité d'inhibition enzymatique (CYP2C9) au niveau

hépatique compte-tenu des faibles concentrations arrivant au foie par l'artère hépatique.

4) Une étude d'interaction médicamenteuse entre le voriconazole (inhibiteur

puissant du CYP2C9) et le diclofenac administré par voie orale a démontré une

augmentation de l'exposition systémique du diclofenac de 178%. Une telle

interaction serait peu probable avec une formulation topique puisque l'exposition hépatique du diclofenac systémique s'effectuerait par l'artère

hépatique (et non la veine porte), une artère à faible débit qui expose qu'une petite partie du médicament dans l'organisme;13

5) Les études de pharmacogénétiques n'ont pu établir un lien entre les

polymorphismes du CYP2C9 et les concentrations plasmatiques de

diclofenac.11•12•14•15

Compte-tenu de ces observations, je considère que le risque d'interactions médicamenteuses avec le Voltaren Emu/ge/ est très faible justifiant ainsi son inscription à l'Annexe Ill. Tel que mentionné précédemment, la vente en pharmacie assure toujours une surveillance de la part du pharmacien.

24 http :/ /www. drugs.com/ drug-interactions/diclofenac-index. htm 1

Synthàso dea offets aecondalros diclarh pour Voltaron Emulgel entro 2008 tl septembre 2013

(

PRODUCT MONOGRAPH

VOLTAREN®EMULGEL™ JOINT PAIN

Diclofenac diethylamine Gel, 11.6 mg/g (1.16% w/w)

Non-Steroidal Anti-inflammatory Drug (NSAID) Analgesie agent for topical use

Novartis Consumer Health Canada Inc. 2233 Argentia Road, Suite 205 Mississauga, Ontario Canada L5N2X7

Submission Control No: 132535

Date of Revision: November 27,2009

Page 1 of30

Table of Contents

VOLT AREN® EMULGEL™ JOINT PAIN ............................................................................... 3

PART I: HEALTH PROFESSIONAL INFORMATION ..•..•..•..........•....•....•........................... 3 SUMMARY PRODUCT INFORMATION ....................................................................... .3 INDICATIONS AND CLINICAL USE ............................................... ............................... 3 CONTRAINDICATIONS ................................................................................................... 4 WARNINGS AND PRECAUTIONS ................................................ .................................. 4 ADVERSE REACTIONS .................................................................................................... 6 DRUG INTERACTIONS ................................................................... .. ............................. 11 DOSAGE AND ADMINISTRATION .............................................................................. 12 OVERDOSAGE ................................................................................................................ 12 ACTION AND CLINICAL PHARMACOLOGY ............................................................ 13 STORAGE AND STABILITY .......................................................................................... 15 SPECIAL HANDLING INSTRUCTIONS ...................................... .. ............................... 15 DOSAGE FORMS, COMPOSITION AND PACKAGING ............................................. 15

PART II: SCIENTIFIC INFORMATION ....•...•..•................................•............•.............•....... 16 PHARMACEUTICAL INFORMATION .......................................................................... 16 CLINICAL TRIALS ........................................................................................... ............... 17 DETAILED PHARMACOLOGY ..................................................................................... 18

Pharmacokinetics ................................................................................................... ........ 18 Percutaneous Absorption, Distribution, Metabo1ism, Excretion ............................. 18 Diclofenac in target tissues ...................................................................................... 20 Drug and substance interactions .............................................................................. 20 Pharmacokinetics in special patient populations ..................................................... 20

Pharmacodynamics ........................................................................................................ 21 Pharmacodynamies studies - anti-inflammatory activity .......... ... ............................ 21 Pharmacodynamies studies - analgesie activity ....................................................... 22

TOXICOLOGY .......................................................... .... ................................................... 23 REFERENCES ................................................................................................. ................. 26

PART III: CONSUMER INFORMATION .....••••.•.•••.....•.•..•.•........••.•..............•.•..........••••...... 28

Page 2 of30

VOLTAREN® EMULGEL™ JOINT PAIN

Diclofenac diethylamine

PART 1: HEAL TH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Dosage Form 1 Clinically Relevant Nonmedicinal Administration Strength Ingredients

Topical Gel 1 11.6 mg/g None. diclofenac For a complete listing see Dosage Forms, diethylamine Composition and Packaging section. (1.16% w/w)

INDICATIONS AND CLINICAL USE

Voltaren Emulgel Joint Pain (diclofenac diethylamine gel) is indicated for:

o Relief of aches and pain associated with recent (acute), localized joint or muscle injuries such as sprains, strains or sports injuries (e.g. sore ankles, knees, bands or shoulder). This is typically as an adjunct to other measures such as rest for the relief of discomfort associated with such injuries.

Voltaren Emulgel Joint Pain should be applied over the affected area 3 or 4 times daily and rubbed gently into the skin. The amount needed depends on the size of the painful area: 2 g to 4 g Voltaren Emulgel Joint Pain (1 g equals a strip approx. 2 cm long) is sufficient to treat an area of about 400-800 cm2• After application, the bands should be washed, unless they are the site being treated.

The dura ti on of treatment will depend on the natural course of healing, rest and also on clinicat response. The gel should not be used for more than 7 da ys for muscle and joint injuries, unless recommended by a doctor. Consumers should consult their doctor if the condition does not improve within 7 da ys, or if it gets worse.

Geriatries(> 65 years of age): The usual adult dosage may be used.

Paediatrics (< 16 years of age): Not for use in children under 16 years of age.

Page 3 of30

CONTRAINDICATIONS

o Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

o Hypersensitivity to diclofenac, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs.

o Patients with or without chronic asthma in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory agents.

o Concomitant use of other products containing diclofenac. o Concomitant use of oral non-steroidal anti-inflammatory drugs (NSAIDs).

W ARNINGS AND PRECAUTIONS

For the management of a suspected drug overdose, contact your regional Poison Control Centre.

General Voltaren Emulgel Joint Pain is for topical use only and should be applied only to intact, non-diseased skin and not to skin wounds or open injuries. lt should not be used with occlusion. It should not be allowed to come into contact with the eyes or mucous membranes, and should never be taken by mouth.

Systemic availability of diclofenac diethylamine through percutaneous absorption is low compared with plasma levels obtained following oral forms of diclofenac. Nevertheless, the possibility of systemic side effects cannot be completely excluded. Chances of this may be increased where Voltaren Emulgel Joint Pain is applied to a relatively large area of skin and/or over an extended period oftime (e.g., especially if this goes beyond the maximum duration recommended for use).

Sorne possibility of gastro-intestinal bleeding in patients with a significant history of peptic ulceration has been reported in isolated cases. Voltaren Emulgel Joint Pain should therefore be used with caution by patients under medication for active peptic ulcers in the stomach or duodenum (e.g., proton pump inhibitors or histamine H2 receptor antagonists). lfthe patient is uncertain, they should be advised to consult their doctor or pharmacist.

Like other drugs that inhibit prostaglandin synthetase activity, diclofenac and other NSAIDs can precipitate bronchospasm if administered to patients suffering from or with a previous history of branchial asthma.

Asthma bas been rarely reported in patients using topical NSAID preparations.

Local irritation, erythema, pruritus or dermatitis may occasionally occur with topical diclofenac diethylamine. Skin photosensitivity, desquamation, discoloration and bullous or vesicular

Page 4 of30

eruptions have been reported in isolated cases. Patients should be wamed against excessive exposure to sunlight in order to reduce the incidence ofphotosensitivity.

The following additional side effects have been observed with oral forms of diclofenac sodium.

Cardiovascular Isolated cases: palpitation, chest pain, hypertension.

Gastrointestinal Occasional: Epigastric pain, other gastro-intestinal disorders (e.g. nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia). Rare: Gastro-intestinal bleeding, peptic ulcer (with or without bleeding or perforation), bloody diarrhoea. In isolated cases: Lower gut disorders (e.g. non-specifie haemorrhagic colitis and exacerbations ofulcerative colitis or Crohn's proctocolitis, colonie damage and stricture formation), pancreatitis, aphthous stomatitis, glossitis, oesophageallesions, constipation.

Haematologic In isolated cases: Thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.

Hepatic/Biliary/Pancreatic Occasional: Elevation of serum aminotransferase enzymes (AL T, AST). Rare: Liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.

Immune Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of rare cases of anaphylactic/anaphylactoid systemic reactions including hypotension, and respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea. (See also "Skin").

Neurologie Occasional: Headache, dizziness, or vertigo. Rare: Drowsiness, tiredness. In isolated cases: Disturbances of sensation, paraesthesia, memory disturbance, disorientation, disturbance of vision (blurred vision, diplopia), impaired hearing. Tinnitus, insornnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions. Taste alteration disorders.

Renal In isolated cases: Acute renal failure, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.

Sexual Function/Reproduction

Page 5 of30

Isolated cases: Impotence (association with diclofenac is doubtful).

Skin Occasional: Rashes or skin eruptions. Rare: Urticaria. In isolated cases: Eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome, ( acute toxic epidermolysis ), photosensitivity reactions, erythroderma ( exfoliative dermatitis ), loss of hair, purpura including allergie purpura.

Special Populations

Pregnant Women: Since no experience has been acquired with diclofenac diethylamine gel in pregnancy, it is not recommended for use in these circumstances.

During the last trimes ter of pregnancy the use of prostaglandin synthetase inhibitors may result in premature closure of the ductus arteriosus, or in uterine inertia.

Animal data has shown an increased incidence of dystonia and delayed parturition when drug administration is continued into late pregnancy.

Nursing Women: Since no experience has been acquired with diclofenac diethylamine gel in lactation, it is not recommended for use in these circumstances.

Following oral doses of 50 mg diclofenac administered every 8 hours, diclofenac passes into breast milk in quantities so small that no undesirable effects on the infant are to be expected.

Geriatries(> 65 years of age): No specifie hazards are associated with geriatrie use of diclofenac diethylamine gel.

Paediatrics (< 16 years of age): Not for use in children under 16 years of age.

Monitoring and Laboratory Tests No monitoring parameters or laboratory tests are required to monitor response to therapy or possible adverse reactions.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The adverse event incidence in the clinical studies was very low. The benign safety profile documented in the clinical studies is confirmed in the post-marketing experience in over 200 million patients worldwide. The adverse events occurring in studies were usually either

Page 6 of30

( moderate or mild. Five serious adverse events occurred in ali the studies (ali unrelated, one fatal) and led to withdrawal, or interruption oftreatment, of the affected subjects.

In post-marketing surveillance, cutaneous or application site adverse events constitute about two thirds of ali adverse events reported. The most common type of serious systemic event is gastrointestinal bleeding; however, in more than half of these cases patients were known to be taking concomitant systemic medications that may precipitate gastrointestinal bleeding, such as NSAIDs, salicylates, corticosteroids and/or anticoagulants.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specifie conditions the adverse reaction rates observed in the clinical trials may not rejlect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The clinical data set includes data obtained in approximately 4926 patients with either the target indication of soft-tissue injuries (e.g. sprains, strains, bruises), osteoarthritis or soft-tissue rheumatism, 2728 ofwhom received Voltaren Emulgel Joint Pain, 1267 ofwhom received an active comparator, and 931 ofwhom received placebo. Patients were treated from 3-28 days as befitted the nature of the conditions under study.

Data from the safety population with the target indication investigated, who received short term exposure to Voltaren Emulgel Joint Pain in controlied trials and uncontrolled trials, confirm that a dose of2-4 g ofVoltaren Emulgel Joint Pain applied topically 3-4 times a day is safe and that the systemic adverse event profile observed for systemic NSAIDs is not seen with the topical formulation.

No subgroup analyses were perforrned. Long-term safety data from patients was not obtained in these studies as this is not relevant to a product intended for only short-term use up to 1 week. The safety ofVoltaren Emulgel Joint Pain was demonstrated in the safety population in clinical trials, which ali showed that the incidence and type of rare or serious events resembles tho se of active controls or placebo.

The adverse events (AEs) whether or not drug related reported in 33 clinical trials are summarized in Table 1 (WHO-ART coding).

Page 7 of30

Table 1 -Adverse events (A Es) Reported in Clinical Trials (WHO-ART coding) with a Frequency of ~1%

Voltaren Emulgel -Joint Pain Reference*

n= 2258 n=633 n= 1112 (100) (lOO) (lOO)

Local skin AEs 76 (3.4) 35 (5.5) 29 (2.6)

*Topical reference drugs (number of patients): felbinac ( 195), piroxicam (306), etofenamate ( 140), Mobilat containing adrenocortical extract, mucopolysaccharide, salicylic acid (113), Movelat containing mucopolysaccharide polysulphate, salicylic acid (78), ketoprofen (15), naproxen (15), benzydamine HCI (52), indomethacin (55), Dolobene containing dimethylsu1foxid heparin (39), monosalicylic acid (15-20). *Oral reference drug: ibuprofen (155)

Similar percentages of local skin reactions including mostly itching, burning, erythema, local allergy and blistering were reported after both Voltaren Emulgel Joint Pain (3.4%) and placebo (5.5%). Most of the local AEs were mild to moderate. There were no reports ofphotosensitivity, although one case report referred to exposure to the sun. Approximately 0.3% of patients were withdrawn due to local skin AEs after applying Voltaren Emulgel Joint Pain or placebo.

In conclusion, the absolu te numbers of reported adverse events were relatively small and there are no clinically significant differences in the incidence of adverse events in the Voltaren Emulgel Joint Pain, placebo and reference drug treatment groups. Most of the AEs are local, mild to moderate and reversible.

Less Common Clinical Trial Adverse Drug Reactions (

( Voltaren Emulgel Joint Pain worldwide spontaneous