Isotrexin Gel

For excipients, see 6.1.

Gel

A pale yellow soft gel.

Isotrexin is indicated for the topical treatment of moderate acne.

Adults

Apply Isotrexin sparingly over the entire affected area once or twice daily, preferably after cleaning the skin.

Patients should be advised that, in some cases, six to eight weeks of treatment may be required before the full therapeutic effect is observed.

Patients should wash their hands after application of Isotrexin Gel.

The patient should be advised to avoid over-saturation with Isotrexin to the extent that excess medication could run into their eyes, and angles of the nose or other areas where treatment is not intended. Patients should be advised that if Isotrexin is applied excessively, no more rapid or better results would be obtained and marked redness, peeling or discomfort may occur. Should this occur accidentally or through over enthusiastic use application should be discontinued for a few days.

Use in Children

Not established for prepubescent children, in whom acne vulgaris rarely presents.

Use in the Elderly

No specific recommendations as acne vulgaris does not present in the elderly.

Isotrexin should not be used in patients with known hypersensitivity to any of the ingredients.

Isotrexin should not be used in patients with acute eczema, rosacea and perioral dermatitis.

Istorexin is contraindicated in pregnancy, in women intending to conceive and in lactation (see section 4.6).

Contact with the mouth, eyes and mucous membranes and with abraded or eczematous skin should be avoided. The excipient butylated hydroxytoluene may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes. Application to sensitive areas of skin, such as the neck, should be made with caution. As Isotrexin may cause increased sensitivity to sunlight, deliberate or prolonged exposure to sunlight or sunlamps should be avoided or minimised. In case of “sunburn” reaction the treatment should be temporarily interrupted.

When exposure to sunlight cannot be avoided use of sunscreen products providing adequate UVB and UVA protection and protective clothing over treated areas is recommended. Following prolonged use of a peeling agent it is advisable to “rest” a patient's skin until the effects of the peeling subside before starting to use Isotrexin. When Isotrexin and peeling agents are alternated, irritancy or dermatitis may result and the frequency of application may have to be reduced.

Concomitant topical antibiotics, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol and/or astringents, should be used with caution as a cumulative irritant effect may occur. Particular caution should be exercised when using preparations containing a peeling agent (for example benzoyl peroxide).

The safety of Isotrexin for use in human pregnancy has not been established (see section 5.3).

Isotretinoin has been associated with teratogenicity in humans when administered systemically. Isotrexin is contraindicated in pregnant women and those intending to conceive. Treatment should be discontinued for one cycle prior to intended conception.

Use during lactation

Percutaneous absorption of isotretinoin from Isotrexin is negligible. However, as it is not known if isotretinoin is excreted into maternal milk, Isotrexin must not be used during lactation.

None

Isotrexin may cause stinging, burning or irritation; erythema and peeling at the site of application may occur. These local effects usually subside with continued treatment. If undue irritation occurs, treatment should be interrupted temporarily and resumed once the reaction subsides. If irritation persists, treatment should be discontinued. Reactions will usually resolve on discontinuation of therapy.

Heightened susceptibility to either sunlight or other sources of UVB light has been reported (See 4.4).

Long-term use of erythromycin-containing preparations may rarely trigger gram-negative folliculitis. In this case the product should be withdrawn and therapy continued with an antibiotic-free monopreparation.

Acute overdosage of Isotrexin has not been reported to date. The isotretinoin and erythromycin components are not expected to cause problems on ingestion of the topical gel.

Excessive application of Isotrexin does not improve the results of treatment and may induce marked irritation e.g. erythema, peeling, pruritis etc.

ATC Code: D10A X30

Isotretinoin is structurally and pharmacologically related to vitamin A, which regulates epithelial cell growth and differentiation. The pharmacological action of isotretinoin has not been fully determined. When used systemically, it suppresses sebaceous gland activity and reduces sebum production; it also affects comedogenesis, inhibits follicular keratinisation, suppresses Propionibacterium acnes and reduces inflammation. It is thought that topically applied isotretinoin stimulates mitosis in the epidermis and reduces intercellular cohesion in the stratum corneum; contests the hyperkeratosis characteristics of acne vulgaris and aids desquamation, preventing the formation of lesions. It is also thought that it mediates an increased production of less cohesive epidermal sebaceous cells. This appears to promote the initial expulsion and subsequent prevention of comedones.

Studies in animal models have shown similar activity when isotretinoin is applied 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.

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.

Erythromycin is a macrolide antibiotic which acts by interfering with bacterial protein synthesis by reversibly binding to ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. In the treatment of acne, it is effective through reduction in the population of Propionibacterium acnes, and through prevention of release of inflammatory mediators by the bacteria. Resistance of P. acnes to topical erythromycin can occur, but evidence exists that the combination of erythromycin and isotretinoin in Isotrexin is effective against erythromycin-resistant strains of P. acnes.

Isotrexin is effective in treating both inflammatory and non-inflammatory lesions. The isotretinoin component treats the comedonal phase of the disease. The erythromycin component is effective in the treatment of moderate inflammatory acne vulgaris.

Percutaneous absorption of isotretinoin and erythromycin from Isotrexin is negligible. In a maximised study of the topical absorption of the two components from Isotrexin in patients suffering from widespread acne, isotretinoin levels were shown to be only slightly raised from baseline levels (isotretinoin is normally present in plasma). Levels remained below 5 ng/ml, and were not increased in the presence of erythromycin when compared to topical isotretinoin alone. The levels of erythromycin were not detectable.

Under conditions of normal use in patients with acne, percutaneous absorption of the active components was negligible.

Isotretinoin and erythromycin, the active ingredients in Isotrexin are well-established pharmacopoeial substances which are regularly used in the topical and systemic treatment of acne vulgaris. Preclinical safety studies have not been conducted on Isotrexin, as an extensive range of toxicological studies has been conducted on isotretinoin and erythromycin as well as their respective topical formulations. A human patch test for irritation has shown the combination to be comparable to the application of either component alone, with an acceptably low potential for irritation.

Isotretinoin has been associated with teratogenicity in humans when administered systemically. However, reproduction studies conducted in rabbits using topical isotretinoin applied at up to 10 times the human therapeutic dose have revealed no harm to the foetus.

Hydroxypropylcellulose

Butylated Hydroxytoluene (BHT)

Anhydrous Ethanol

Not applicable

18 months

Do not store above 25°C.

Internally lacquered membrane-sealed aluminium tubes fitted with a polyethylene screw-cap, packed into a carton. Pack sizes: 6, 25, 30, 40 and 50 grammes.

Not all pack sizes may be marketed.

See section 4.2.

GlaxoSmithKline UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as Stiefel

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

PL 19494/0068

26^th March 2007

15 December 2010