Symptoms and signs
Oral ingestion of a 30g tube of topical isotretinoin would result in less exposure than achieved with the recommended dosage of oral isotretinoin. Consequently, the theoretical occurrence of symptoms of overdosage (e.g. hypervitaminosis A) is highly unlikely.
The gel formulation contains more than 95% ethanol. Systemic absorption of this should be considered in the event of oral ingestion.
Treatment
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
a) For the product as packaged for sale
3 years
b) After first opening the container
Two months
Not applicable.
Butylated Hydroxytoluene
Hydroxypropylcellulose
Ethanol
The frequency of adverse reactions listed below is defined using the following convention: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Skin and subcutaneous tissue disorders
| Very common: | Application site erythema, skin exfoliation, skin pain, application site pruritus, skin irritation, skin tenderness, skin burning sensation, application site stinging, dry skin |
Post-marketing data:
The following adverse drug reactions are based on post-marketing reports. Since these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency, however in reality the following reactions are rarely seen.
Skin and subcutaneous tissue disorders
| Not known: | Skin hyperpigmentation, skin hypopigmentation, photosensitivity reaction |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Carcinogenesis/Mutagenesis
In a carcinogenicity study in Fischer 344 rats given oral isotretinoin up to 32 mg/kg/day, there was an increased incidence of phaeochromocytomas relative to controls in both sexes at 32 mg/kg/day and in males at 8 mg/kg/day. Given the high rate of spontaneous rate of occurrence of phaeochromoyctoma in Fischer 344 rats, the relevance of this tumour to humans is uncertain.
Studies in hairless mice suggest that concurrent dermal exposure to isotretinoin at dose levels up to 500 mg/kg may enhance the tumorigenic potential of UV irradiation. The significance of these studies to humans is not clear.
The mutagenic potential of isotretinoin was evaluated in the Ames assay with and without S9 metabolic activation and in the Chinese hamster lung cell for chromosome aberrations, both of which were negative.
Reproductive Toxicology
Fertility
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dose levels of isotretinoin up to 32 mg/kg/day.
In dogs, testicular atrophy was noted after approximately 30 weeks at isotretinoin dose levels of 20 or 60 mg/kg/day. However, in studies of men receiving oral isotretinoin, no significant effects have been seen on semen parameters.
Pregnancy
Reproduction studies conducted in rabbits using isotretinoin gel applied topically at up to 60 times the human dose have revealed no harm to the foetus.
Topical application of high doses of tretinoin (an isomer of isotretinoin) induces maternal toxicity, which limits the maximum dose to a level potentially below that associated with embryofoetal alterations by other routes of administration.
In one study, topical doses of a 0.1% ethanol solution, given to Wistar rats through gestational days (GDs) 6 to 16, were not tolerated at 10 mg/kg/day, causing severe local and systemic maternal toxicity. Offspring of dams receiving 5 mg/kg weighed significantly less than those of controls. Maternal toxicity (reduced weight gain and food consumption) was also evident at doses of 2.5 mg/kg/day or more. A significant increase in the occurrence of supernumerary ribs was observed at this dose, a result thought to be nonspecific or maternally mediated.
Topical administration of tretinoin at a dose of 10.5 mg/kg/day for 3 days to intact skin of hamsters on GDs 7, 8, and 9 resulted in erythema and/or epidermal hyperplasia at the site of application, but did not cause a significant teratogenic response.
Topical administration of 5 g 0.05% tretinoin ointment (corresponding to a dose of ~ 10 mg/kg) to the shaved backs of pregnant rats on GD 12 resulted in some retinoid-specific patterns of anomalies (humerus short 9%, radius bent 6%, ribs wavy 80%). This dose was ~100 fold that expected in humans.
Pharmacotherapeutic group: retinoids for topical use in acne, isotretinoin.
ATC Code: D10A D04
Mechanism of action
Isotretinoin is structurally and pharmacologically related to vitamin A which regulates epithelial cell growth and differentiation. It is thought that topically applied isotretinoin acts in a comparable way to its stereoisomer, tretinoin, and:
- stimulates mitosis in the epidermis
- reduces intercelluar cohesion in the stratum corneum
- contests the hyperkeratosis characteristic of acne vulgaris
- aids desquamation, preventing the formation of lesions
- mediates an increased production of less cohesive epidermal sebaceous cells, which appears to promote the initial expulsion of comedones and their subsequent prevention.
Isotretinoin has topical anti-inflammatory actions. Topically applied isotretinoin inhibits leukotriene-B4-induced migration of polymorphonuclear leukocytes, which accounts for topical isotretinoin's anti-inflammatory action. A significant inhibition was produced by topically applied isotretinoin but only a weak inhibition by topical tretinoin. This may account for the reduced rebound effect seen with topical isotretinoin when compared with topical tretinoin.
Pharmacodynamic effects
The pharmacological action of isotretinoin remains to be fully elucidated.
Isotretinoin binds to the 3 retinoic acid receptors (RAR) alpha, beta and gamma with less affinity and is unable to bind to retinoid X receptors (RXR) and the retinoic acid cellular receptor (CRABP).
There are studies which show similar activity to systemic actions when administered topically. Inhibition of sebum production by topical isotretinoin has been demonstrated in the ears and flank organs of the Syrian hamster. Application of isotretinoin to the ear for 15 days led to a 50% reduction in sebaceous gland size, and application to the flank organ resulted in a 40% reduction. Topical application of isotretinoin has also been shown to have an effect on the epidermal differentiation of rhino mouse skin. Reduction in the size of the utriculi or superficial cysts leading to normal looking follicles was a predominant feature of isotretinoin treatment and has been used to quantify the antikeratinising effects of isotretinoin.
Absorption
Following isotretinoin 0.05% gel application to acne patients at a daily dose of 20g (equivalent to 10 mg of isotretinoin) to the face, chest and back for 30 days, plasma concentrations of isotretinoin and tretinoin were not measurable (< 20 ng/mL)
Distribution
Systemic (oral) isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism
In vivo studies in humans showed that the three major metabolites identified in human plasma following systemic (oral) administration of isotretinoin were 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). In vitro studies indicated that all of these metabolites had retinoid activity.
In vitro studies indicate that the major enzymes responsible for isotretinoin metabolism are cytochrome P450 isoenzymes 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates and excreted in urine and faeces.
Elimination
Following systemic (oral) administration of an 80 mg dose of 14C-isotretinoin, radioactivity in the blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately eliminated in the faeces and urine in similar amounts (total of 65% to 83%).
03rd April 2014
GlaxoSmithKline UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
Trading as Stiefel
Stockley Park West
Uxbridge
Middlesex
UB11 1BT
Store below 25°C. Keep the tube tightly closed when not in use. Contents are flammable. Keep away from fire, flame or heat. Do not leave Isotrex gel in direct sunlight.
Aluminium tube of 5g, 15g, 25g, 30g, 50g, 60g fitted with a screw cap.
Not all pack sizes may be marketed.
PL 19494/0063
There are no special instructions for use or handling of Isotrex Gel.
20/12/2005
