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Differin
Gel
Adapalene 0.1%
Presentation
DIFFERIN™ gel is a
smooth white gel containing 1 mg/g adapalene. The gel contains
carbomer 980, propylene glycol, poloxamer, disodium edetate,
methyl hydroxybenzoate, phenoxyethanol, sodium hydroxide and
purified water.
Actions
Adapalene
is a chemically stable retinoid-like compound. Although the
exact mode of action of adapalene is unknown, evidence
suggests that adapalene normalises the differentiation of
follicular epithelial cells by binding to specific retinoic
acid receptors thereby decreasing microcomedone formation.
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 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. 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 components of acne is modified by
adapalene. Studies on Differin Gel in human patients provide
clinical evidence that adapalene is effective in reducing the
inflammatory components of acne (i.e. papules and
pustules).
Pharmacokinetics
Absorption
through the human skin is low; in clinical trials adapalene
was seldom detected in plasma, and then only in trace amounts
following chronic topical application with an analytical limit
of quantification of 0.25 nanograms/mL. After administration
of (14C)-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.Indications
DIFFERIN
gel 0.1% is proposed for the topical treatment of Grade II -
Grade III acne (acne vulgaris) where comedones, papules and
pustules predominate.
Safety and
effectiveness have not been established in severe pustular and
deep cystic nodular acne (acne conglobulata ).
Dosage and Administration
DIFFERIN
Gel should be applied to the affected areas once a day before
retiring and after washing. A thin film of gel should be
applied to the dried areas using the fingertips and avoiding
the eyes and lips (see Warnings and Precautions below).
Clinical improvement is
expected to be clearly evident after four to eight weeks of
treatment, with further improvement expected with continued
use. The cutaneous safety of Differin gel has been
demonstrated in 181 patients over six months of treatment.
Since it is customary to alternate therapies in the treatment
of acne, it is recommended that the physician assess the
improvement of the patient after three months of treatment
with Differin Gel.
In patients for whom it
is necessary to reduce the frequency of application or to
temporarily discontinue treatment , frequency of application
may be restored or therapy resumed once it is judged that the
patient can again tolerate the treatment.
If patients use
cosmetics these should be non-comedogenic and non-astringent.
Only oil-free moisturisers should be used to relieve dry
facial skin.
The safety and
effectiveness of Differin gel has not been studied in neonates
and young children.
Contraindications
Hypersensitivity to any ingredient of the
product.
Warnings and Precautions
If severe irritation
occurs, patients should be directed to use the medication less
frequently, to temporarily discontinue use or to discontinue
use altogether.
DIFFERIN™ gel is for
external use only and should not come into contact with the
eyes, mouth, angles of the nose or mucous membranes. If
product enters the eye, wash with warm water.The product
should not be applied to broken skin (cuts or abrasions) or to
eczematous or psoriatic skin.
Because of a potential
for increased irritation DIFFERIN™ gel should not be used by
patients with eczema or seborrhoeic dermatitis.
Adapalene is
essentially stable to oxygen and light and is chemically
non-reactive. 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. 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 in animals
or humans. Exposure to excessive sunlight or UV irradiation
(including sunlamps) should be avoided during treatment with
adapalene.
Use in pregnancy
There are
no adequate or well controlled reproduction studies in
pregnant women. Because of the potential risk of adverse
effects on foetal development at high systemic exposure
levels, it is prudent to avoid use of this drug during
pregnancy unless clearly needed.
In rats and rabbits,
adapalene administered orally at relatively high doses (25
mg/kg or greater) was found to induce foetal abnormalities. In
addition the incidences of various skeletal variations were
increased at lower oral dose in rats. Topical administration
at doses up to 6 mg/kg resulted in exposure levels lower than
those associated with teratogenicity following oral
administration. Nevertheless, increased incidences of various
naturally occurring skeletal variations were still observed
following topical administration to rats 2mg/kg and to rabbits
at 6 mg/kg; topical no effect levels were 0.6 and 2 mg/kg
respectively. Adapalene is not mutagenic. Large oral doses of
adapalene produced no adverse neurological, cardiovascular or
respiratory effects in animals.
Use in lactation
It is not
known whether this drug is excreted in human milk. Differin
gel should be avoided in lactating women.
Adverse Effects
In clinical
trials of efficacy and safety with Differin Gel the total
incidence of adverse reactions related to treatment was 4.2%
(28 reports from 661 participants). The most frequent adverse
reactions reported were erythema (0.9%), dry skin (0.9%), skin
irritation (0.6%), burning and stinging (0.6%) and acne flare
(0.5%). Other adverse experiences which were attributed to
treatment or were possibly related to treatment but occurred
less frequently (in less than 0.5% of patients) were pruritis
and one case of sunburn. None of the reactions was severe and
most occurred within one month of the initiation of therapy
and were observed to resolve with continued use of the product
or temporary adjustment of the treatment schedule.
The major side effect
of Differin Gel is skin irritation which is reversible when
treatment is discontinued or reduced in frequency. A feeling
of burning, pruritis, dryness, scaling or stinging may occur
following application.
Interactions
There are no known
interactions with other medications which might be used
topically and concurrently with DIFFERIN ™ topical gel;
however other retinoids or drugs with a similar mode of action
should not be used concurrently with adapalene.
Absorption of adapalene
through human skin is low (see Pharmacokinetic properties) and
therefore interaction with systemic medication is
unlikely.
DIFFERIN™ topical gel
has potential for local irritation and it is possible that
concomitant use of peeling agents, astringents or irritant
products may produce additive irritant effects. However
cutaneous antiacne treatments e.g. erythromycin, clindamycin
phosphate (1% as the base) solutions or benzoyl peroxide water
based gels up to 10% may be used in the morning when Differin
gel is used at night since no mutual degradation or cumulative
irritation occurs with these products.
Overdosage
Differin gel is
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 dose of
Differin gel required to produce toxic effects in mice and
rats is greater than 10mL.kg-1. Nevertheless unless the amount
accidentally ingested is small, an appropriate method of
gastric emptying should be considered.
Pharmaceutical Precautions
Store below 25°C. Keep
out of reach of children. Do not freeze.
Package Quantities
Product is packaged in
a low density polyethylene tube containing 30g of gel and
fitted with a white polypropylene screw cap.
Further Information
Nil.
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