Differin: Indications, Dosage, Precautions, Adverse Effects
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Differin - Product Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Acne
Class: Dermatological agents
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: Adapalene, Carbomer 934P (Carbomer 940 or Carbomer 941), cyclomethicone, edetate disodium, glycerin, methyl gluceth 20 sesquistearate, methyl glucose sesquistearate, methylparaben, phenoxyethanol, propylparaben, squalane, trolamine, and purified water, propylene glycol, sodium hydroxide and/or hydrochloric acid, medium chain triglycerides, poloxamer 124 (poloxamer 182 ), polyoxyl-6-polyoxyl-32 palmitostearate, PPG-12 / SMDI copolymer, stearyl alcohol.

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
topical cream 0.1% w/w None
gel 0.1%, 0.3% w/w None
lotion 0.1% w/w None

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

DIFFERIN (adapalene) topical cream, gel and lotion, and DIFFERIN XP (adapalene) topical gel are indicated for:

  • Topical treatment of acne vulgaris in patients 12 years of age and older.

Geriatrics (> 65 Years of Age)

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

Pediatrics (< 12 Years of Age)

Safety and effectiveness in children below the age of 12 have not been established.

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, gel or lotion, 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 a moisturizer, use the medication less frequently or temporarily discontinue use until the symptoms subside (see Dosage and Administration).

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.

Avoid concomitant use of other potentially irritating topical products (abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes).

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.

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, gel or lotion, 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.

Adverse Reactions

Adverse Drug Reaction Overview

Treatment-related adverse reactions typically associated with use of DIFFERIN and DIFFERIN XP include mild to moderate application site reactions, such as skin irritation characterized by scaling, dryness, erythema, burning and stinging. DIFFERIN XP results in a slightly greater incidence of these events, as would be expected with the higher concentration of adapalene. These reactions usually occur early in the treatment, and tend to resolve after 2 to 4 weeks of therapy (see Warnings and Precautions).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect 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.

DIFFERIN (adapalene) Topical Cream or Topical Gel

In clinical trials with DIFFERIN topical gel and cream 0.1%, most of the reactions occurred within two to four weeks of initiation of therapy and were generally observed to resolve with continued use of the product or temporary adjustment of the treatment schedule. Contact allergy to topical adapalene was not reported during clinical trials. To date, all adverse effects of DIFFERIN topical cream or gel 0.1% have been reversible upon discontinuation of therapy.

DIFFERIN Topical Lotion

During two multicentre, active- and vehicle-controlled, Phase III clinical trials, patients with acne vulgaris, 12 years and older, were treated with DIFFERIN Lotion or its vehicle once daily for 12 weeks. A total of 1068 patients were exposed to DIFFERIN Lotion in these trials. In general, most of the signs and symptoms of cutaneous irritation (erythema, scaling, dryness, and/or burning/stinging) were either mild or moderate in severity, and occurred primarily during the first two weeks of treatment, and decreased thereafter. The majority of cases of local irritation were managed with moisturizers.

DIFFERIN XP (adapalene) Topical Gel

In a multi-centre, placebo- and active-controlled Phase III clinical trial, signs and symptoms of local cutaneous irritation were monitored in 258 adult acne patients who used DIFFERIN XP topical gel 0.3% once daily for 12 weeks. Of the patients who experienced cutaneous irritation (erythema, scaling, dryness, and/or burning/stinging), the majority of cases were mild to moderate in severity, occurred in the first week of treatment, and decreased thereafter.

In a one-year, open-label safety study of 551 patients with acne vulgaris who used DIFFERIN XP, the pattern of adverse events was similar to the 12-week controlled study. The percentage of subjects who experienced cutaneous irritation (scaling, erythema, dryness, and/or stinging/burning) greater than baseline was highest after one week of treatment and decreased thereafter, continuing to decrease during the one-year treatment period.

Related Adverse Drug Reactionsa From Open, and Vehicle- and Active-Controlled Studies
DIFFERIN XP
adapalene gel
0.3%
n= 1087
(%)
DIFFERIN
adapalene gel
0.1%
n=1463
(%)
DIFFERIN
adapalene
cream 0.1%
n=311
(%)
DIFFERIN
adapalene
lotion 0.1%
n=1068
(%)
Gel Vehicle
n=134
(%)
Lotion Vehicle
n=1073
(%)
Total No. (%) of
Subjects with Related1
Adverse Drug
Reaction(s)
267 (24.6%) 153 (10.5%) 16 (5.1%) 109 (10.2%) 6 (4.5%) 49 (4.6%)
Skin and Appendages 263 (24.2%) 164 (11.2%) 17 (5.5%) 109 (10.2%) 6 (4.5%) 48 (4.5%)
Skin dry 117 (10.8%) 58 (4.0%) 1 (0.3%) 79 (7.4%) 2 (1.5%) 32 (3.0%)
Erythema 27 (2.5%) 18 (1.2%) 0 (0%) 2 (0.2%) 0 (0%) 0 (0%)
Skin discomfort 70 (6.4%) 40 (2.7%) 1 (0.3%) 5 (0.5%) 0 (0%) 0 (0%)
Desquamation 28 (2.6%) 9 (0.6%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Pruritus 18 (1.7%) 13 (0.9%) 0 (0%) 5 (0.5%) 0 (0%) 5 (0.5%)
Sunburn 21 (1.9%) 13 (0.9%) 3 (1.0%) 2 (0.2%) 2 (1.5%) 1 (0.1%)
Irritant dermatitis 59 (5.4%) 33 (2.3%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Skin irritation 0 (0%) 4 (0.4%) 5 (1.6%) 8 (0.7%) 0 (0%) 7 (0.7%)

1 Related = Possibly, probably, or definitely related
a Adverse drug reactions do not include known local adverse events (local tolerability)of retinoids

The proportion of subjects with adverse events was generally higher for the DIFFERIN XP group compared to the adapalene gel 0.1% group, as was expected with the higher concentration. Almost all related adverse events were in the Skin and Appendages body system and most were mild to moderate in severity.

In controlled clinical trials for DIFFERIN Gel or Cream, 0.1%, local cutaneous irritation in acne patients was monitored. Patients commonly experienced cutaneous irritation (erythema, scaling, dryness, pruritis, and/or burning/stinging); the majority of cases were mild to moderate in severity.

In a controlled clinical trial for DIFFERIN Gel, 0.3%, local cutaneous irritation in acne patients was monitored. Patients very commonly experienced cutaneous irritation (erythema, scaling, dryness, and/or burning/stinging), the majority of cases were mild to moderate in severity, occurred early in treatment and decreased thereafter.

In controlled clinical trials for DIFFERIN Lotion, 0.1%, the incidence of local cutaneous irritation in acne patients was monitored and the data is provided in the following table:

Table 2: Incidence of Local Cutaneous Irritation - Emergent Signs and Symptoms for Adapalene Lotion in RD.06.SPR.18113 and RD.06.SPR.18114 (Combined)
Combined Studies Maximum Severity
During Treatment
(N=1057)
End of Treatment (12 Weeks)
Severity
(N=950)
Local Cutaneous Irritation (skin
irritation)
Mild Moderate Severe Mild Moderate Severe
Erythema 21.8% 8.0% 0.2% 7.9% 2.6% 0.2%
Scaling 25.3% 6.5% 0.1% 5.3% 1.1% 0
Dryness 36.1% 7.3% 0.3% 7.6% 2.0% 0
Stinging/burning 22.1% 7.0% 0.9% 4.6% 1.0% 0.4%

Less Common Clinical Trial Adverse Drug Reactions (<1%)

The following less common events have been designated as related (possibly, probably, definitely) to treatment with DIFFERIN AND DIFFERIN XP, considering all patients in the clinical trials in acne vulgaris:

Skin and Appendages:

Eczema, contact dermatitis, atopic dermatitis, skin edema, dermatitis, acne, worsening of treated disease, urticaria, skin discolouration, seborrhea, herpes simplex, vesicular rash, eyelid edema, burning/stinging, pityriasis alba, erythematous rash, skin exfoliation

Body as a Whole>Pain, facial edema

Special SensesEye pain, keratoconjunctivitis

Abnormal Haematology and Clinical ChemistryNo significant abnormal values were observed in the short term controlled studies or the long term safety study.

Post-Market Adverse Drug Reactions

The following isolated (one report each) serious, unexpected adverse events have been designated as probably/possibly related to treatment with an adapalene topical formulation: Papilloedema, hepatitis/cholectasis, convulsions, foetal disorders.

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, gel or lotion, 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, gel or lotion, or with 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, gel or lotion, 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, gel and lotion, 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, gel and lotion, 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.

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

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 3: Summary of Adapalene's Pharmacokinetic Parameters in Adult Patients with Acne vulgaris Following Application of 0.3% Gel
Cmax t2(h) AUC0-24 Clearance
Repeated dose mean 0.553 ± 0.466
ng/mLa
13 - 16b 8.94 ± 8.99
ng.hr/mLc
Within 72 hours

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 ng.h/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 ng.h/mL. The terminal apparent half-life ranged from 13 to 16 hours, thereby indicating that a pharmacokinetic steady-state was reached before Day 10.

Systemic exposure of adapalene following a topical application of adapalene lotion 0.1% was studied in one clinical study. Fourteen adult subjects with severe acne were treated with 2 g of adapalene lotion once daily for 30 days to approximately 1000 cm² of acne involved skin. Serial plasma samples were collected for 24 or 72 hours following application on days 1, 15 and 30. All plasma concentrations for 12 out of 14 patients were below the limit of quantification (LOQ=0.1 ng/mL). One patient had one sample above LOQ at day 30 and the other patient had four plasma samples above LOQ on both days 1 and 15, which ranged from 0.102 and 0.131 ng/mL. Due to the limited number of available data points, PK analysis was not undertaken.

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, gel and lotion, 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% w/wis supplied in the following sizes:
    60 g laminate tube

Each gram of DIFFERIN topical cream contains adapalene 0.1% w/w (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% w/wis supplied in the following sizes:
    60 g laminate tube

Each gram of DIFFERIN topical gel contains adapalene 0.1% w/w (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 (adapalene) topical lotion, 0.1% w/wis supplied in the following sizes:
    60 mL HDPE bottle with pump
    120 mL HDPE bottle with pump

Each gram of DIFFERIN topical lotion contains adapalene 0.1% w/w (1 mg) in a vehicle consisting of carbomer 941, disodium edetate, medium chain triglycerides, methylparaben, phenoxyethanol, poloxamer 124, polyoxyl-6-polyoxyl-32 palmitostearate, PPG-12 / SMDI copolymer, propylene glycol, propylparaben, sodium hydroxide, stearyl alcohol, and purified water.

DIFFERIN XP (adapalene) topical gel, 0.3% w/w is supplied in the following sizes:
    60 g laminate tube

Each gram of DIFFERIN XP topical gel contains adapalene 0.3% w/w (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.