Differin

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Adapalene 0.1% w/w;  
Available from:
Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics
INN (International Name):
Adapalene 0.1% w/w
Dosage:
0.1% w/w
Pharmaceutical form:
Topical cream
Composition:
Active: Adapalene 0.1% w/w   Excipient: Carbomer Cyclomethicone Disodium edetate dihydrate Glycerol Macrogol 1000 methyl glucose sesquistearate Methyl hydroxybenzoate Phenoxyethanol Propyl hydroxybenzoate Purified water Sodium hydroxide Squalane
Units in package:
Tube, aluminium, epoxy lined, sample, 5 g
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Helsinn Chemicals SA
Therapeutic indications:
Topical treatment of comedo, papular and pustular acne (acne vulgaris) of the face, chest or back.
Product summary:
Package - Contents - Shelf Life: Tube, aluminium, epoxy lined, sample - 5 g - 3 years from date of manufacture stored at or below 25°C - Tube, aluminium, epoxy lined - 30 g - 3 years from date of manufacture stored at or below 25°C - Tube, aluminium, epoxy lined - 50 g - 3 years from date of manufacture stored at or below 25°C
Authorization number:
TT50-5275/2
Authorization date:
1997-07-31

New Zealand Datasheet

1 PRODUCT NAME

DIFFERIN

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.

4.3 Contraindications

Not to be used in patients who are hypersensitive to the active substance or any of the

excipients.

Pregnancy.

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

established

animals

humans.

Exposure

sunlight

irradiation

(including

sunlamps) should be avoided during treatment with adapalene. Use of sunscreen products

and protective clothing over treated areas is recommended when exposure cannot

avoided.

Efficacy

safety

treatment

severe

pustular

deep

cystic

acne

(acne

conglobulata) have not been studied.

DIFFERIN

Cream

contains

methyl

parahydroxybenzoate

(E218)

propyl

parahydroxybenzoate (E216) that can cause allergic reactions (can arise after the treatment

is completed).

Use in children

Safety and efficacy in children below the age of 12 years have not been studied.

Genotoxicity

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.

Carcinogenicity

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.

Absorption

adapalene

through

human

skin

(see

section

5.2)

therefore

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

(Category D)

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,

associated

with

teratogenicity.

Nevertheless,

increased

incidences

various

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.

Side Effects

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%): :

Redness

Dry skin

Burning sensation at the site of application

Scaling

Skin irritation

Erythema

Sunburn

Uncommon (> 0.1% and < 1%):

Contact dermatitis/eczema

Skin discomfort

Skin exfoliation

Acne flare

Facial and eyelid oedema

Vesiculobullous eruptions

Herpes labialis

Conjunctivitis

Pruritus

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

are not

necessarily drug related.

Adapalene cream

(n= 311)

Incidence (%)

Adapalene Vehicle

(n= 175)

Incidence (%)

Tretinoin cream

(n= 141)

Incidence (%)

Body as a whole

Flu syndrome

4.8%

3.4%

2.1%

Headache

7.4%

9.1%

Accidental injury

Pain back

Surg./Med. Procedure

1.5%

Unevaluable reaction

1.4%

Digestive

Tooth Anomaly

Tooth Disorder

1.2%

Respiratory System

Pharyngitis

2.8%

1.4%

Rhinitis

4.5%

6.0%

Sinusitis

1.7%

Skin & Appendage

Skin Dry

2.1%

Skin Irritation

1.6%

2.9%

Sunburn

2.2%

3.4%

Special Senses

Conjunctivitis

1.0%

Urogenital System

Dysmenorrhea

1.5%

4.0%

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%):

Allergic reaction

Lack of drug effect

Immune System Disorders

Uncommon (> 0.1% and < 1%):

Anaphylactic reaction

Angioedema

Skin and Subcutaneous Tissue Disorders

Common (> 1% and < 10%):

Irritation

Redness

Dry skin

Burning sensation at the site of application

Erythema

Uncommon (> 0.1% and < 1%):

Contact eczema

Contact dermatitis

Transient worsening of acne

Exfoliative dermatitis - predominantly associated with

mechanical abrasion such as waxing

Skin discomfort,

Sunburn,

Pruritus,

Skin exfoliation,

Acne

Scaling

Application site burn

Skin hypopigmentation

Skin hyperpigmentation.

Unknown*:

Dermatitis allergic (allergic contact dermatitis).

Pain of skin

Skin swelling

Eye disorders: Eyelid irritation

Eyelid erythema

Eyelid pruritus

Eyelid swollen

*Post marketing surveillance data

These events often spontaneously resolve upon adaptation to therapy regimen.

4.9 Overdose

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:

D10AD03

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

which represent

important features in

pathology

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 normalises the differentiation of follicular

epithelial cells resulting in decreased microcomedone formation. Adapalene inhibits the

chemotactic

(directional)

chemokinetic

(random)

responses

human

polymorphonuclear leucocytes in in vitro assay models. It also inhibits the metabolism of

arachidonic acid by lipoxidation, to inflammatory mediators.

Clinical Trials

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

trial,

277 subjects

with

acne vulgaris

were

enrolled for

treatment

with

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

following

chronic

topical

application

with

analytical

limit

quantification

0.25

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

volunteers

(limit

detection

nanogram

sixth

volunteer

mean

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

animals.

Adapalene

mutagenic.

Lifetime

studies

with

adapalene

have

been

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

Carbomer

934P,

PEG-20

methyl

glucose

sesquistearate,

glycerol,

squalane,

methyl

hydroxybenzoate,

propyl

hydroxybenzoate,

disodium

edetate,

methyl

glucose

sesquistearate, phenoxyethanol, cyclomethicone, sodium hydroxide, purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months.

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

local requirements.

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.

8 SPONSOR

Sponsor and distributor in New Zealand

Healthcare Logistics

58 Richard Pearse Drive

Airport Oaks

Auckland

New Zealand

Ph (09) 918 5100

Fax (09) 918 5101

For:

Galderma Australia Pty Ltd

Suite 4, 13B Narabang Way,

Belrose NSW 2085

Australia

9 DATE OF FIRST APPROVAL

17 December 1998

10 DATE OF REVISION OF THE TEXT

12 December 2019

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Additional adverse effects added for Anaphylactic reaction, Angioedema,

Scaling,

Application

site

burn,

Skin

hypopigmentation,

Skin

hyperpigmentation

Similar products

Search alerts related to this product

Share this information