New Zealand - English - Medsafe (Medicines Safety Authority)
New Zealand Datasheet
1 PRODUCT NAME
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Adapalene 1 mg/g topical cream
3 PHARMACEUTICAL FORM
DIFFERIN topical cream is a smooth white cream containing 1 mg/g adapalene.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
DIFFERIN topical cream 0.1% is indicated for the topical treatment of comedo, papular and
pustular acne (acne vulgaris) of the face, chest or back.
4.2 Dosage and method of administration
A thin film of DIFFERIN topical cream should be applied to the affected areas once a day
before bedtime and after washing avoiding the eyes lips and mucous membranes. The
affected areas should be dry before application.
Clinical improvement is expected to be evident in four to eight weeks of treatment, with
further improvement to be expected with continued use. Cutaneous safety of DIFFERIN
topical cream has been demonstrated in 311 patients for up to 12 weeks of treatment. Since
it is customary to alternate therapies in the treatment of acne vulgaris, it is recommended
that the physician assess continued treatment of the patient with DIFFERIN topical cream
after three months of use.
The safety and effectiveness of DIFFERIN products have not been studied in children below
12 years of age.
Not to be used in patients who are hypersensitive to the active substance or any of the
Women planning a pregnancy.
4.4 Special warnings and precautions for use
FOR EXTERNAL USE ONLY
DIFFERIN topical cream should not come into contact with the eyes, lips, mouth and mucous
membranes, angles of the nose or broken skin (cuts and abrasions), sunburn or eczematous
skin, nor should it be used in patients with severe acne involving large areas of the body. If
product enters the eye, wash immediately with warm water. Because of a potential for
increased irritation DIFFERIN topical cream should not be used by patients with eczema,
seborrhoeic dermatitis or severe acne involving large areas of the body.
If a reaction suggesting severe irritation occurs, discontinue use of the medication. If the
irritation is not severe, use the medication less frequently, discontinue use temporarily until
symptoms subside, or discontinue use altogether.
If patients use cosmetics, these should be non-comedogenic and non-astringent. Only oil-
free moisturisers should be used to relieve dry facial skin.
Because DIFFERIN topical cream may cause some irritation, it is possible that simultaneous
use of abrasive cleansers, astringents or strong drying agents or irritant products may cause
additive irritant effects.
Animal studies on compounds with a similar mode of action to adapalene have suggested
that these may enhance the development of skin cancers caused by UV light. Adapalene is
essentially stable to oxygen and light and is chemically non-reactive. Whilst short term
studies have shown no phototoxic to photoallergic potential of adapalene, small numbers of
reactions consistent with phototoxicity were reported in clinical studies, the safety of using
adapalene during long or repeated exposures to sunlight or UV radiation has not been
sunlamps) should be avoided during treatment with adapalene. Use of sunscreen products
and protective clothing over treated areas is recommended when exposure cannot
conglobulata) have not been studied.
parahydroxybenzoate (E216) that can cause allergic reactions (can arise after the treatment
Use in children
Safety and efficacy in children below the age of 12 years have not been studied.
Adapalene did not demonstrate mutagenic or clastogenic activity in in vitro tests with
bacterial and mammalian cells and showed no clastogenic activity in mammalian cells in vitro
and an in vitro test in mice.
Lifetime studies with adapalene have been completed in mice at topical doses of 0.6, 2 and 6
mg/kg and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg. Phaeochromocytomas were
observed in the adrenal medulla of male rats dosed at 1.5 mg/kg but not at the lower doses.
This finding was not observed in female rats or in mice. The relevance of the finding in male
rats to the use of DIFFERIN topical cream in acne vulgaris is not known.
4.5 Interaction with other medicines and other forms of interaction
There are no known interactions with other medications which might be used topically and
concurrently with DIFFERIN topical cream; however other retinoids or drugs with a similar
mode of action should not be used concurrently with adapalene. Exposure of adapalene to
other topical anti-acne drugs such as erythromycin, clindamycin phosphate or benzoyl
peroxide does not produce any mutual degradation.
interaction with systemic medication is unlikely.
DIFFERIN topical cream has potential for local irritation and it is possible that concomitant
use of peeling agents, astringents or irritant products may produce additive irritant effects.
4.6 Fertility, Pregnancy and lactation
Use in Pregnancy
Orally administered retinoids have been associated with congenital abnormalities. When
used in accordance with the prescribing information, topically administered retinoids are
generally assumed to result in low systemic exposure due to minimal dermal absorption.
However, there could be individual factors (e.g. damaged skin barrier, excessive use) that
contribute to an increased systemic exposure.
In pregnant rats and rabbits, adapalene administered orally at relatively high doses (
mg/kg leading to exposures
25 times that anticipated clinically based on AUC) was found to
induce foetal abnormalities. In addition, the incidences of various skeletal variations were
increased at lower oral doses in rats. Topical administration at doses up to 6 mg/kg, resulting
in an exposure level about 45 times greater (based on AUC) than that anticipated clinically,
naturally occurring skeletal variations were still observed following topical administration to
rats at 2mg/kg (AUC exposure about 13 times that anticipated clinically); topical no effect
levels were 0.6 and 2mg/kg respectively (AUC about 5 times that anticipated clinically).
Because of the risk of teratogenicity shown in animals, and since there are no adequately
controlled studies in pregnant women, adapalene should not be used by women who are
pregnant or who plan to become pregnant during treatment. DIFFERIN should not be used
during pregnancy. In case of unexpected pregnancy, treatment should be discontinued.
Use in lactation
It is not known whether adapalene is excreted in human milk. Therefore, the preparation
should be used with caution in nursing mothers, and only on areas away from the chest.
DIFFERIN can be used during breastfeeding. To avoid contact exposure of the infant,
application of DIFFERIN to the chest should be avoided when used during breast-feeding.
4.7 Effects on ability to drive and use machines
DIFFERIN Cream has no influence on the ability to drive and use machines.
4.8 Undesirable effects
A feeling of warmth, burning, pruritus, dryness, scaling or slight stinging may occur following
application. Local adverse events may persist despite cessation of therapy. No systemic
reactions have been attributed to the application of the cream to date. The allergic potential
of adapalene has not been established.
The incidences of cutaneous side effects reported by patients treated with Adapalene
(1mg/g) cream during clinical trials were as follows:
Common (> 1% and < 10%): :
Burning sensation at the site of application
Uncommon (> 0.1% and < 1%):
Facial and eyelid oedema
Most reactions occurred within one month of the initiation of therapy and were generally
observed to resolve with continued use of the product or temporary adjustment of the
treatment schedule. The incidence of patients withdrawing from the trials because of these
topical effects was 7/311 (2.2%).
Table: Adverse events (> 1%) reported by patients treated with Adapalene (1mg/g) cream,
Adapalene vehicle and Tretinoin cream during controlled clinical trials. These
necessarily drug related.
Body as a whole
Skin & Appendage
Post Marketing Data
DIFFERIN topical cream 0.1% and DIFFERIN topical gel 0.1% are two formulations with the
same active ingredient, adapalene. The gel formulation was first marketed in France in
September 1995. The post marketing data detailed below refer to reports collected from the
worldwide sales with the gel formulation.
Body as a Whole
Rare (> 0.01% and < 0.1%):
Lack of drug effect
Immune System Disorders
Uncommon (> 0.1% and < 1%):
Skin and Subcutaneous Tissue Disorders
Common (> 1% and < 10%):
Burning sensation at the site of application
Uncommon (> 0.1% and < 1%):
Transient worsening of acne
Exfoliative dermatitis - predominantly associated with
mechanical abrasion such as waxing
Application site burn
Dermatitis allergic (allergic contact dermatitis).
Pain of skin
Eye disorders: Eyelid irritation
*Post marketing surveillance data
These events often spontaneously resolve upon adaptation to therapy regimen.
DIFFERIN topical cream is intended for topical 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.
DIFFERIN topical cream is not to be taken orally. The oral route toxicity for DIFFERIN
Topical cream in mice is greater than 10 mL/kg. Unless the amount accidentally ingested is
small, an appropriate method of gastric emptying should be considered.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: D10A Anti-Acne Preparations for Topical Use - ATC code:
Adapalene is a chemically stable compound with retinoid-like pharmacological activity.
Biochemical and pharmacological profile studies have demonstrated that adapalene is a
potent modulator of cellular differentiation, keratinisation and inflammatory processes all of
important features in
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 normalises the differentiation of follicular
epithelial cells resulting in decreased microcomedone formation. Adapalene inhibits the
polymorphonuclear leucocytes in in vitro assay models. It also inhibits the metabolism of
arachidonic acid by lipoxidation, to inflammatory mediators.
The efficacy of DIFFERIN topical cream has been assessed in two randomised, double blind,
parallel comparison clinical trials. In the first trial, 350 subjects with acne vulgaris associated
with at least 20 facial non-inflammatory comedones and 10 inflammatory lesions were
enrolled for treatment with DIFFERIN topical cream or the cream vehicle administered once
daily. For DIFFERIN topical cream and vehicle groups respectively after twelve weeks
treatment, the mean % reductions from baseline in total lesions were 32% vs 15% (p<0.05),
in non-inflammatory lesion counts were 37% vs 15% (p<0.05) and investigator’s global
assessment scores were 1.13 vs 1.26 (p<0.05). The difference between the treatment
groups in % reduction in inflammatory lesions (15% vs 5%) was not statistically significant.
In the second
DIFFERIN topical cream or tretinoin cream 0.05% administered once daily. For DIFFERIN
topical and tretinoin treatment groups respectively after twelve weeks treatment, the mean %
reductions from baseline in total lesions were 60% vs 67% (p<0.05), in non inflammatory
lesions were 64% vs 72% (p<0.05), in inflammatory lesions were 43% vs 56% (p<0.05) and
in the investigator’s global assessment scores were 51% vs 57% (p<0.05).
5.2 Pharmacokinetic properties
In clinical trials adapalene was seldom detected in plasma, and then only in trace amounts
nanograms/mL. After administration of (
C)-adapalene to rats, rabbits and dogs, radioactivity
was distributed in several tissues, the highest levels being found in liver, spleen, adrenals
and ovaries. Metabolism in animals is maintained by O-demethylation, hydroxylation and
conjugation, and excretion is primarily by the biliary route.
In a human study performed using the gel formulation in which male volunteers followed a
course of exaggerated topical application, 30g (a full tube) was applied all over the body
each day for seven consecutive days, the resultant circulating plasma levels were below the
limit of detection (0.15 nanogram mL
). There were low quantities of the parent substance in
the faeces. In another study healthy volunteers used radiolabelled adapalene 0.1% topical
gel, four of the subjects received 14 daily topical applications of non-radiolabelled adapalene
0.1% topical gel prior to the single application of radiolabelled adapalene 0.1% topical gel.
The other four subjects received a single topical application of the radiolabelled product.
Levels of radioactivity in all plasma, urine, faeces and skin strip samples analysed were
below the limits of reliable quantification, indicating that either very little or no radioactivity
was absorbed through the skin.
A further study carried out to investigate the distribution of adapalene in the adipose tissue of
women after repeated daily application of adapalene gel for three months, found that there
was no evidence of circulating adapalene in the plasma (limit of detection 0.15 nanogram
). On day 90, adapalene levels in the adipose tissue were not quantifiable in five of the
concentration at three sites was 1.1, 1.3 and 5.5 nanogram.g
. These concentrations were
no longer evident when re-evaluated at the same sites in this subject one month after the
cessation of treatment.
5.3 Preclinical safety data
In animal studies, adapalene was well tolerated on cutaneous application for periods of up to
six months in rabbits and for up to two years in mice. The major symptom of toxicity found in
all animal species by the oral route were related to a hypervitaminosis A syndrome, and
included bone dissolution, elevated alkaline phosphatase and a slight anaemia. Large oral
doses of adapalene produced no adverse neurological, cardiovascular or respiratory effects
completed in mice at cutaneous doses of 0.6, 2 and 6 mg/kg/day and in rats at oral doses of
0.15, 0.5 and 1.5 mg/kg/day. The only significant finding was a statistically significant
increase of benign phaeochromocytomas of the adrenal medulla among male rats receiving
adapalene at 1.5 mg/kg/day. These changes are unlikely to be of relevance to the cutaneous
use of adapalene.
Adapalene produces teratogenic effects by the oral route in rats and rabbits. At cutaneous
doses up to 200-fold the therapeutic dose, producing circulating plasma levels of adapalene
at least 35 to 120 times higher than plasma levels demonstrated in therapeutic use,
adapalene increased the incidence of additional ribs in rats and rabbits, without increasing
the incidence of major malformations.
It is not known whether adapalene is secreted in animal or human milk. In animal studies,
infant rats suckled by mother with circulating levels of adapalene at least 300 times those
demonstrated in clinical use developed normally.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
sesquistearate, phenoxyethanol, cyclomethicone, sodium hydroxide, purified water
6.3 Shelf life
6.4 Special precautions for storage
Store below 25°C and out of reach of children. Avoid exposure to excessive heat. Replace
cap tightly after use.
Replace cap tightly after use.
6.5 Nature and contents of container
Collapsible aluminium tube of 5 g, 30 g or 50 g, coated internally with an epoxy-phenolic
resin and fitted with a white polypropylene screw cap.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with
7 MEDICINE SCHEDULE
Prescription Medicine except in medicines containing 1 milligram or less per milliliter or gram
and when supplied by a pharmacist in a pack containing not more than 30 grams for the
treatment of comedo, papular and pustular acne (acne vulgaris) of the face, chest or back.
Sponsor and distributor in New Zealand
58 Richard Pearse Drive
Ph (09) 918 5100
Fax (09) 918 5101
Galderma Australia Pty Ltd
Suite 4, 13B Narabang Way,
Belrose NSW 2085
9 DATE OF FIRST APPROVAL
17 December 1998
10 DATE OF REVISION OF THE TEXT
12 December 2019
SUMMARY TABLE OF CHANGES
Summary of new information
Additional adverse effects added for Anaphylactic reaction, Angioedema,