Summary of Product Characteristics

Transcription

1 Summary of Product Characteristics 1 NAME OF THE MEDICINAL PRODUCT Isotrexin 2% % w/w Gel 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Erythromycin Isotretinoin 2.00% w/w 0.05% w/w Excipients: Contains Butylated Hydroxytoluene E % w/w. For a full list of excipients, see section PHARMACEUTICAL FORM Gel Pale yellow soft gel with an odour of ethanol. 4 CLINICAL PARTICULARS 4.1 Therapeutic Indications ISOTREXIN is indicated for the topical treatment of mild to moderate acne vulgaris and is effective in treating both inflammatory and non-inflammatory lesions. 4.2 Posology and method of administration Adults Apply ISOTREXIN sparingly over the entire affected area once or twice daily. Patients should wash their hands after application of the gel. Patients should be advised that, in some cases, six to eight weeks of treatment may be required before the full therapeutic effect is observed. 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 will be obtained and marked redness, peeling or discomfort may occur. If this occurs accidentally, or through over enthusiastic use, application should be discontinued for a few days. Use in Paediatric Patients The safety and efficacy of ISOTREXIN has not been established in prepubescent children.. Use in the Elderly There are no specific recommendations for ISOTREXIN use in the elderly. Acne vulgaris is not common in this age group. Renal impairment In view of the low systemic exposure to isotretinoin and erythromycin following topical application, renal impairment is not expected to result in systemic exposure of clinical concern, see Section 5.2, Pharmacokinetics. Date Printed 20/11/2012 CRN page number: 1

2 Hepatic impairment In view of the low systemic exposure to isotretinoin and erythromycin following topical application, hepatic impairment is not expected to result in systemic exposure of clinical concern, see Section 5.2, Pharmacokinetics. 4.3 Contraindications Known hypersensitivity to isotretinoin, erythromycin or to any of the excipients. Pregnancy, women intending to conceive and lactation, see Section 4.6. Although tretinoin, an isomer of isotretinoin, has not been shown to initiate or promote carcinogenesis in humans, tretinoin applied topically to albino hairless mice had resulted in a dose-related acceleration in ultraviolet-b radiation induced cutaneous tumours. The opposite effect was observed in another study of low, non-irritating concentrations of tretinoin. The significance of these findings as related to man is unknown. In view of the condition being treated, Isotrexin is contraindicated in patients with a personal or family history of skin cancer. 4.4 Special warnings and precautions for use Contact with the mouth, eyes and mucous membranes and with abraded or eczematous skin should be avoided. Care should be taken not to let the medication accumulate in skin fold areas and in the angles of the nose. 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. Use with caution in patients with concomitant rosacea or perioral dermatitis, due to the irritant nature of isotretinoin. As ISOTREXIN may cause increased sensitivity to sunlight, deliberate or prolonged exposure to sunlight or sunlamps should be avoided or minimised. When exposure to strong sunlight cannot be avoided a sunscreen product and protective clothing should be used. Patients with sunburn should not use ISOTREXIN due to the possibility of increased sensitivity to sunlight. Concomitant topical medication should be used with caution during therapy with ISOTREXIN because of the potential for cumulative irritant effects (also see section 4.5). As with other broad spectrum antibiotics, pseudomembranous colitis has been reported rarely with erythromycin. Although this is unlikely to occur with topically applied erythromycin, if prolonged or significant diarrhoea occurs or the patient suffers from abdominal cramps, treatment should be discontinued immediately and the patient investigated further, as the symptoms may indicate antibiotic-associated colitis. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant application of oxidising agents, such as benzoyl peroxide, should be avoided, since they may reduce the efficacy topical isotretinoin. If combination therapy is required, they should be applied at different times of the day, e.g. one in the morning and the other in the evening. If irritancy or dermatitis results, the frequency of application may have to be reduced. 4.6 Fertility, pregnancy and lactation Fertility Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of sperm and does not jeopardise the formation and development of the embryo on the part of the men taking isotretinoin Pregnancy There are no or limited data on the use of ISOTREX in pregnant women. Isotretinoin has been associated with teratogenicity in humans when administered systemically. Date Printed 20/11/2012 CRN page number: 2

3 Reproduction studies conducted in rabbits using topical isotretinoin applied at up to 60 times the human therapeutic dose have revealed no harm to the foetus. There have been a reports of birth defects among babies born to women exposed to topical tretinoin during pregnancy, but causality has not been proven. The teratogenic blood level of isotretinoin is not clear In view of the condition for which ISOTREXIN is used and the known association of systemically administered isotretinoin with human foetal abnormalities, ISOTREXIN is contraindicated in pregnant women or those who may become pregnant during treatment. Use during lactation Percutaneous absorption of isotretinoin and erythromycin from ISOTREXIN is negligible. However, as it is not known if isotretinoin is excreted in human milk, ISOTREXIN should not be used during lactation. 4.7 Effects on ability to drive and use machines None. 4.8 Undesirable effects ISOTREXIN may cause: Immune System Disorders Allergic reaction Gastrointestinal disorders Diarrhoea Skin and subcutaneous tissue disorders Stinging, burning sensation, pruritus or skin irritation; erythema, dry skin, skin exfoliation; skin thinning, skin hyperpigmentation, skin hypopigmentation and photosensitivity reaction. 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. 4.9 Overdose Acute overdosage of ISOTREXIN has not been reported to date. Accidental ingestion of isotretinoin resulting in overdosage of isotretinoin could be expected to induce symptoms of hypervitaminosis A. These include severe headaches, nausea or vomiting, drowsiness, irritability and pruritus. Erythromycin is not expected to cause problems on ingestion of ISOTREXIN. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. Date Printed 20/11/2012 CRN page number: 3

4 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Retinoids for topical use in acne, isotretinoin, combinations ATC code: D10AD54 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 characteristic 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. The isotretinoin component of ISOTREXIN is very useful in treating the comedonal phase of the disease, while the erythromycin component is effective in the treatment of mild to moderate inflammatory acne vulgaris. Since most cases of acne consist of a combination of comedonal and inflammatory disease, combination topical therapy involving erythromycin and isotretinoin represents a logical approach to treatment. 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. 5.2 Pharmacokinetic properties Percutaneous absorption of isotretinoin and erythromycin for ISOTREXIN is negligible.in a maximised study of the topical absorption of the two components from ISOTREXIN,30g of gel were applied to the face, chest and back of patients for 30 days, Isotretinoin levels were shown to be only slightly raised from baseline levels (isotretinoin is normally present in plasma). Levels remained below 5ng/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. Date Printed 20/11/2012 CRN page number: 4

5 5.3 Preclinical safety data 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. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Hydroxypropylcellulose Butylated Hydroxytoluene Ethanol 6.2 Incompatibilities Not applicable. 6.3 Shelf life 18 months. 6.4 Special precautions for storage Store below 25ºC. 6.5 Nature and contents of container Internally lacquered membrane-sealed aluminium tubes fitted with a plastic screw-cap, packed into a carton. Pack sizes: 6, 25, 30, 40, and 50 grammes. Not all pack sizes may be marketed in Ireland. 6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product No special requirements. 7 MARKETING AUTHORISATION HOLDER GlaxoSmithKline (Ireland) Ltd Stonemasons Way Rathfarnham Dublin 16 Ireland Trading as Stiefel 8 MARKETING AUTHORISATION NUMBER PA 1077/123/001 Date Printed 20/11/2012 CRN page number: 5

6 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 October 1998 Date of last renewal: 02 October DATE OF REVISION OF THE TEXT January 2012 Date Printed 20/11/2012 CRN page number: 6