PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 7 DOSAGE AND ADMINISTRATION 8 OVERDOSAGE 8 ACTION AND CLINICAL PHARMACOLOGY 9 STORAGE AND STABILITY 10 DOSAGE FORMS, COMPOSITION AND PACKAGING 10

PART II: SCIENTIFIC INFORMATION 11

PHARMACEUTICAL INFORMATION 11 CLINICAL TRIALS 12 DETAILED PHARMACOLOGY 14 TOXICOLOGY 14 REFERENCES 17

PART III: CONSUMER INFORMATION 18

Pr(r)

DIFFERIN

adapalene topical cream 0.1% adapalene topical gel 0.1%

PrDIFFERIN(r) XP adapalene topical gel 0.3%

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

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. Patients with eczema or seborrheic dermatitis

WARNINGS AND PRECAUTIONS

General

For external use only. Avoid contact with the eyes, lips, angles of the nose, mucous membranes and open wounds. Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning or pruritus are associated with the topical application of retinoids and can also be expected with the use of DIFFERIN (adapalene) topical cream or gel and with DIFFERIN XP (adapalene) topical gel. These treatment-related effects generally occur during the first two to four weeks of therapy and usually resolve as the skin undergoes adjustment with continued use. Depending on the degree of the side effects, patients can be directed to use the medication less frequently or temporarily discontinue use until the symptoms subside (see DOSAGE AND ADMINISTRATION). Patients should be advised to use non-comedogenic cosmetics. Colour cosmetics such as blushers and powders are acceptable, however, make-up cosmetics should be water based only. Cosmetics must be removed by thorough cleansing before the area is treated. As with any retinoid, exposure to excessive sunlight, including sunlamps, should be avoided while using the preparation, or a suitably effective sunscreen product and protective clothing over the treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with adapalene. As with other retinoids, use of "waxing" as a depilatory method should be avoided on skin treated with adapalene.

Carcinogenesis and Mutagenesis

See TOXICOLOGY.

Special Populations

Pregnant Women: It is recommended that topical adapalene should not be used by pregnant women. Topical adapalene should be used by women of childbearing years only after contraceptive counselling.

There have been rare reports of birth defects among babies born to women exposed to topical retinoids during pregnancy. However, there are no well controlled prospective studies of the use of topical retinoids, including adapalene, in pregnant women. A retrospective study of mothers exposed to topical tretinoin during the first trimester of pregnancy found no increase in the incidence of birth defects. Adapalene administered orally at doses of $ 25 mg/kg/day (38 times the Maximum Recommended Human Dose [MRHD] based on mg/m2 comparisons for rats or 65 times MRHD for rabbits) has been shown to be teratogenic. No teratogenic effects were seen in rats at oral doses of up to 5.0 mg/kg/day adapalene (7.6 times the MRHD). Cutaneous teratology studies in rats and rabbits at doses of 0.6 (0.03 %), 2.0 (0.1 %) and 6.0 (0.3 %) mg/kg/day (17 times the MRHD for rats or 32 times the MRHD for rabbits) exhibited no teratogenicity. At 2 mg/kg/day (0.1% adapalene gel), no adverse events were observed in rabbits and only a marginal increase in the incidence of additional lumbar ribs was observed in rats. However, at 6 mg/kg/day (0.3% adapalene gel), in addition to the recorded increase in foetal rib numbers in the rat and rabbit, there were also other skeletal anomalies in both species (see TOXICOLOGY). There are no adequate and well-controlled studies in pregnant women.

Nursing Women:

It is not known whether this drug is excreted in human milk. Animal pharmacology studies indicate that adapalene is excreted in milk at levels lower than plasma levels. Because many drugs are excreted in human milk, caution should be exercised when DIFFERIN topical cream or gel or DIFFERIN XP topical gel is administered to a nursing mother.

Pediatrics (12-16 years of age):

No specific monitoring or hazards are associated with the use of the product in pediatric patients between the ages of 12 and 16 years. Safety and effectiveness in children below the age of 12 have not been established.

Geriatrics (> 65 years of age):

Safety and effectiveness in geriatric patients age 65 and above have not been established.

DRUG INTERACTIONS

Overview

There are no known interactions with other medications which are likely to be used topically and concurrently with DIFFERIN (adapalene) topical cream or gel or with DIFFERIN XP (adapalene) topical gel. Absorption of adapalene through human skin is low, and therefore interaction with systemic medications is unlikely.

Drug-Drug Interactions

As DIFFERIN and DIFFERIN XP have the potential for local irritation, it is possible that concomitant use of abrasive cleansers, strong drying agents, or irritant products may produce additive irritant effects. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with DIFFERIN topical cream or gel or DIFFERIN XP. If these preparations have been used, it is advisable not to start therapy with DIFFERIN until the effects of such preparations have subsided. Other cutaneous anti-acne treatments (e.g., erythromycin topical solution, clindamycin phosphate topical solution 1% or benzoyl peroxide products in concentrations up to 10%) may be used in the morning when DIFFERIN topical cream or gel or DIFFERIN XP is used at night.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Tests

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

DIFFERIN (adapalene) topical cream and gel or DIFFERIN XP (adapalene) topical gel should be applied to the affected areas of the face, chest and back once a day before retiring and after washing. A small amount should be applied to provide a thin film, avoiding eyes, lips and mucous membranes. This medication should not be applied to cuts, abrasions, eczematous, or sunburned skin. Discontinue treatment if a severe local inflammatory response is experienced. Reinstitute therapy when the reaction has subsided, initially applying the preparation less frequently. Once daily application may be resumed if it is judged that the patient is able to tolerate the treatment. Clinical improvement is expected to be clearly evident after four to eight weeks of treatment, with further improvement expected with continued use. Cutaneous safety of DIFFERIN topical gel has been demonstrated over a six-month period of treatment. Cutaneous safety of DIFFERIN XP topical gel has been demonstrated over a 12-month period of treatment.

Missed Dose

Dosing should continue as per usual the following evening, and the usual amount should be applied.

OVERDOSAGE

DIFFERIN (adapalene) topical cream and gel and DIFFERIN XP (adapalene) topical gel are intended for cutaneous use only. If the medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling or discomfort may occur. The acute oral toxicity of adapalene topical gel, 0.1% in mice and rats is greater than 10 mL/kg (10 mg/kg). Inadvertent oral ingestion of adapalene may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A including teratogenesis in women of childbearing years. Therefore, in such cases, pregnancy testing should be carried out in women of childbearing years. In the event of accidental ingestion of the product, an appropriate method of gastric emptying might be considered.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Adapalene is a chemically stable, retinoid-like compound. Biochemical and pharmacological profile studies have demonstrated that adapalene is a potent modulator of cellular differentiation, keratinization and inflammatory processes all of which represent important features in the pathology of acne vulgaris. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but, unlike tretinoin, does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.

Pharmacodynamics

Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing the noninflammatory acne lesions (open and closed comedones). Adapalene inhibits the chemotactic (directional) and chemokinetic (random) responses of human polymorphonuclear leucocytes in in vitro assay models; it also inhibits the metabolism of arachidonic acid, by lipoxidation, to inflammatory mediators. This profile suggests that the cell mediated inflammatory component of acne is modified by adapalene. Studies in human patients provide clinical evidence that topical adapalene is effective in reducing the inflammatory components of acne (i.e., papules and pustules).

Pharmacokinetics

Table 2: Summary of Adapalene's Pharmacokinetic Parameters in Adult Patients with Acne vulgaris Following Application of 0.3% Gel

a

Derived from 15/16 subjects

b

Derived from 7/16 subjects

c

Derived from 14/16 subjects

Absorption: Absorption of adapalene through human skin is low. No quantifiable levels of parent substance have been found in the plasma of patients following chronic adapalene gel 0.1% application in controlled clinical trials (limit of quantification = 0.25 ng/mL). In adult patients with acne vulgaris who received daily applications of 0.3% gel for 10 days, the mean AUC(0-24h) on Day 10 was 8.94 ngAh/mL (SD: 8.99) and the mean Cmax was 0.553 ng/mL (SD: 0.466). The Cmax ranged from < 0.1 to 2 ng/mL and the maximum AUC(0-24h) value obtained was 36.1 ngAh/mL. The terminal apparent half-life ranged from 13 to 16 hours, thereby indicating that a pharmacokinetic steady-state was reached before Day 10. Distribution: Classical plasma protein binding techniques were not feasible for adapalene due to the physiochemical properties of the molecule. However, an alternative method was adopted which measures the partitioning of the drug between plasma or protein solutions and erythrocytes. When 3H-adapalene was incubated with human whole blood, 26% was bound to erythrocytes and total binding of adapalene in blood was > 99%. Adapalene bound primarily to lipoproteins and human serum albumin.

Metabolism:

Following 24-hour incubation with human hepatocytes, more than 90% of adapalene has been metabolized. Both metabolites and adapalene showed a possibility for conjugation - predominantly glucuronidation and sulfatation.

Excretion:

Excretion appears to be primarily by the biliary route. The majority of an administered dose of 0.3% gel was excreted by 144 hours post dose and no drug was detected after the 6th day following last application. Under maximized conditions, the mean total unchanged drug substance excreted in the faeces was 0.07% +- 0.06% of the total dose applied (range, 0.02% to 0.19%).

STORAGE AND STABILITY

DIFFERIN (adapalene) topical cream and gel and DIFFERIN XP (adapalene) topical gel should be stored at room temperature (15/ to 30/C). Keep from freezing. Keep container tightly closed. Keep in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

DIFFERIN (adapalene) topical cream, 0.1%

is supplied in the following sizes: 45 g laminate tube

Each gram of DIFFERIN topical cream contains adapalene 0.1% (1 mg) in a vehicle consisting of carbomer 934P, cyclomethicone, edetate disodium, glycerin, methyl gluceth-20 sesquistearate, methyl glucose sesquistearate, methylparaben, phenoxyethanol, propylparaben, squalane, trolamine, and purified water.

DIFFERIN (adapalene) topical gel, 0.1%

is supplied in the following sizes: 45 g laminate tube

Each gram of DIFFERIN topical gel contains adapalene 0.1% (1 mg) in a vehicle consisting of carbomer 940, edetate disodium, methylparaben, poloxamer 182, propylene glycol, sodium hydroxide and/or hydrochloric acid for pH adjustment, and purified water.

DIFFERIN XP (adapalene) topical gel, 0.3%

is supplied in the following sizes: 15 g laminate tube

45 g laminate tube Each gram of DIFFERIN XP topical gel contains adapalene 0.3% (3 mg) in a vehicle consisting of carbomer 940, edetate disodium, methylparaben, poloxamer 124, propylene glycol, sodium hydroxide and/or hydrochloric acid for pH adjustment, and purified water.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: adapalene Chemical Name: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid Molecular Formula and Molecular Mass: C28H28O3 ; 412.52 Structural Formula: Physicochemical properties: Adapalene is a white to off-white powder, which is soluble in tetrahydrofuran, sparingly soluble in ethanol and practically insoluble in water.

CLINICAL TRIALS

Study demographics and trial design

Table 3: Summary of patient demographics for North American Phase III active- and vehicle-controlled clinical trial in acne vulgaris

Male and female subjects, 12 years of age or older, were eligible to enroll in these controlled clinical trials. In study RD.06.SRE.18081, subjects with acne vulgaris with 20 to 50 inflammatory and 20 to 100 non-inflammatory lesions and no nodules or cysts were eligible to enroll in this study.

Table 4: Summary of patient demographics for European Phase III active-controlled clinical trial in acne vulgaris

Male and female subjects, 12 years of age or older, were eligible to enroll in this controlled clinical trial. In study RD.03.SRE.2673, subjects with acne vulgaris with 15 to 50 inflammatory and 30 to 200 non-inflammatory lesions and a maximum of two nodules / cysts were eligible to enroll in this study.

Study results

Table 5: Results of North American Study RD.06.SRE.18081 in acne vulgaris at Week 12 (Observed)

*CMH analysis

Table 6: Results of European Study RD.03.SRE.2673 in acne vulgaris at Week 12 (Observed)

Table 7: Results of North American Study 9111-CD271C-EV in acne vulgaris at Week 12 (Observed)

DETAILED PHARMACOLOGY

Adapalene is a chemically stable, retinoid-like compound. Biochemical and pharmacological profile studies have demonstrated that adapalene is a potent modulator of cellular differentiation, keratinization and inflammatory processes all of which represent important features in the pathology of acne vulgaris. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but, unlike tretinoin, does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation. Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing the noninflammatory acne lesions (open and closed comedones). Adapalene inhibits the chemotactic (directional) and chemokinetic (random) responses of human polymorphonuclear leucocytes in in vitro assay models; it also inhibits the metabolism of arachidonic acid, by lipoxidation, to inflammatory mediators. This profile suggests that the cell mediated inflammatory component of acne is modified by adapalene. Studies in human patients provide clinical evidence that topical adapalene is effective in reducing the inflammatory components of acne (i.e., papules and pustules).

TOXICOLOGY

Acute and Chronic Studies: The acute oral LD50 of adapalene in Sprague-Dawley rats and in Charles River CD1 mice was found to be greater than 5000 mg/kg. The acute LD50 of adapalene 0.3% gel or solution was found to be greater than 6 mg/kg in Sprague-Dawley rats (topical) and greater than 30 mg/kg in Iffa Credo OF1 mice (oral), respectively. No pharmacotoxic effects were observed in these studies. Systemic administration of adapalene produced a hypervitaminosis A syndrome in mice, rats and dogs. In rats, it was present after four weeks at 5 mg/kg with adapalene given orally by dietary administration. The main target organ appears to be the bone. Slight decreases in red blood cell parameters were observed in all species where adapalene was given orally. These slight changes were also observed in some topical studies in rats and rabbits, and occurred mainly with adapalene at 0.3% solution or aqueous gel. No morphological or histopathological changes were observed in bone marrow in several oral studies in rats and topical studies in rats and rabbits for periods up to six months. It is concluded that these changes were peripheral rather than central. The dose producing these minimal changes corresponds to 17 times the MRHD of adapalene 0.3% gel based on mg/m2 comparisons for rats and 32 times the MRHD for rabbits. Changes in clinical chemistry parameters (mostly decreases in protein and albumin concentrations, and increases in triglyceride concentration and liver-specific alkaline phosphatase activity) were observed in animals when adapalene was administered dermally (rats) or orally (rats and dogs). The effects were dose related, but reversible in recovery studies. Given topically in solution (rabbits) or in aqueous gel (rabbits and mice), adapalene gave slight to moderate irritation according to the concentration and the duration and frequency of treatment. Following 26 weeks of daily cutaneous application to rats at concentrations of up to 0.3% (6 mg/kg/day), adapalene gel was well tolerated. The dose related changes observed included erythema, flaking, and acanthosis at the application site, all of which were reversible over the course of an 8 week recovery period.

Carcinogenicity Studies:

Lifetime studies with adapalene have been completed in mice at topical doses of 0.6 (0.03%), 2 (0.1%) and 6 (0.3%) mg/kg/day and in rats at oral doses of 0.15, 0.5 and 1.5 mg/kg/day and demonstrated no carcinogenic effect. However, a high incidence of splenic extra- medullary haematopoiesis was observed in male mice treated with 6 mg/kg/day (0.3%) topically applied adapalene gel. Oral administration of adapalene to Sprague-Dawley rats at a dose of 1.5 mg/kg/day for two years resulted in a higher incidence in males, relative to controls, of benign phaeochromocytoma of the adrenal medulla. These neoplastic changes are considered to have no relevance to the topical use of adapalene in humans in clinical conditions.

Animal studies have shown an increased tumorigenic risk with the use of related drugs (e.g., tretinoin) when combined with exposure to the ultraviolet (UV) light in sunlight, or from other UV sources. Studies to determine whether adapalene may accelerate the tumorigenic effects of UV radiation have not been conducted. Mutagenicity Studies: In a series of in vivo and in vitro tests, adapalene did not demonstrate any mutagenic or genotoxic activity. Reproductive and Teratology Studies: Adapalene administered orally at doses of $ 25 mg/kg/day can induce major structural changes including cleft palate, cranial abnormalities and spina bifida in rat and rabbit foetuses. Similar teratogenic effects have also been reported with other retinoids. In the topical studies at the clinical concentration of 0.3% (equivalent to 6 mg/kg/day of applied adapalene, and corresponding to 17 times the MRHD for rats or 32 times the MRHD for rabbits), increases in additional foetal rib numbers were recorded in both rats and rabbits. In the rat, there were also other minimal increases in skeletal anomalies such as small additional fissure in the parietal bone and asymmetric pelvis. In the rabbit, the skeletal anomalies were small additional fissures in the inter-parietal bone, 27 pre-sacral vertebrae, incomplete ossification of the head of limb long bones, and tail anomalies. In the topical studies at the clinical concentration of 0.1% (equivalent to 2 mg/kg/day of applied adapalene), no adverse effects were observed in rabbits and only a marginal increase in the incidence of rudimentary additional lumbar ribs in rats was observed. The doses used in the topical teratology studies correspond to about 51 and 96 times the MRHD of adapalene 0.1% in the rat and rabbit respectively. No effects of adapalene (doses up to 20 mg/kg/day) were found in rats on the reproductive performance or fertility of the F0 males or females. Total litter loss was suffered by 3 out of 25 F0 female rats (12%) orally dosed at 15 mg/kg/day; these females had pale and inactive mammary tissues. There were no detectable effects on the growth, development and subsequent reproductive function of the F1 offspring.

REFERENCES

1. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol 1993; 6(suppl 1):61-69.

2. Griffiths CEM, Elder JT, Bernard BA, Rossio P, Cromie MA, Finkel LJ, Shroot B, Voorhees JJ. Comparison of CD271 (Adapalene) and all-trans retinoic acid in human skin: Dissociation of epidermal effects and CRABP-II MRNA expression. J Invest Dermatol 1993; 101:325-328.

3. Hensby CN, Cavey D, Bouclier M, Chatelus A, Algate D, Eustache J, Shroot B. The in vivo and in vitro anti-inflammatory activity of CD271, a new retinoid-like modulator of cellular differentiation. Pharmacol Skin 1989; 3:160-162.

4. Jamoulle JC, Lamaud E, Grandjean L, Shroot B, Schaefer H. Follicular penetration, distribution and migration for CD271, a new naphthoic acid derivative for topical acne treatment. Pharmacol Skin 1989; 3:198-200.

5. Verschoore M, Langner A, Wolska H, Jablonska S, Czernielewski J, Schaefer H. Efficacy and safety of CD271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol 1991; 124:368-371.

6. Verschoore M, Bouclier M, Czernielewski J, Hensby C. Topical retinoids; Their uses in dermatology. Dermatol Clin 1993; 11:107-115.

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