Isotrexin (+isotretinoin)

Isotrexin Gel

Also contains butylated hydroxytoluene (E321).

Gel

A pale yellow soft gel.

Isotrexin is indicated for the topical treatment of moderate acne.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Isotrexin is for topical use only.

Adults and Adolescents (aged 12 years and above)

Apply Isotrexin in a thin film over the entire affected area once or twice daily, preferably after cleaning the skin gently with a mild cleanser and drying fully. Avoid close proximity to eyes, lips, and other mucous membranes.

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 efficacy and safety of Isotrexin has not been studied beyond 12 weeks in acne vulgaris clinical trials. The prescriber should evaluate the benefit of continuing treatment beyond 12 weeks of uninterrupted use, taking account of an increased risk of antimicrobial resistance.

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 patients may use a moisturiser as needed and should reduce frequency of application or application should be discontinued for a few days. The normal frequency of application should be resumed once the irritation subsides. Treatment should be discontinued if the irritation persists. Efficacy has not been established for less than once daily dosing frequencies.

Due to the flammable nature of Isotrexin, patients should avoid smoking or being near an open flame during application and immediately after use.

Paediatric population

The safety and efficacy of Isotrexin have not been established in children less than 12 years of age, therefore Isotrexin is not recommended for use in this population.

Elderly patients

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

Renal impairment

No dosage adjustment is necessary. As there is low systemic absorption of Isotrexin following topical application, renal impairment is not expected to result in systemic exposure of clinical significance.

Hepatic impairment

No dosage adjustment is necessary. As there is low systemic absorption of Isotrexin following topical application, hepatic impairment is not expected to result in systemic exposure of clinical significance.

Isotrexin is contraindicated in pregnancy, in women intending to conceive and in lactation.

Irritancy

Contact with the mouth, eyes, lips, mucous membranes and areas with abraded skin should be avoided. In case of accidental contact, rinse well with water. Care should be taken not to let the medicine accumulate in skin folds.

The excipient butylated hydroxytoluene may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Due to the irritant nature of Isotrexin, caution should be used when applying to sensitive areas of skin, such as the neck, abraded or eczematous skin, or when treating patients with inflammatory skin conditions that may coexist with acne e.g. rosacea or perioral dermatitis. Isotrexin should also be used with caution in patients who have had a problem tolerating this or similar retinoid products in the past.

Due to the potential for severe irritation, application to eczematous skin should be avoided.

Isotrexin should be used with caution in patients with a history of photoallergy.

Concomitant topical acne therapy should be used with caution because a cumulative irritant effect may occur. If irritancy or dermatitis occurs, reduce frequency of application or temporarily interrupt treatment and resume once the irritation subsides. Treatment should be discontinued if the irritation persists.

In patients whose skin has been subjected to procedures such as depilation, chemical hair treatments, chemical peels, dermabrasion, or laser resurfacing the skin should be allowed to recover before application is considered.

Cosmetics that have a strong drying effect, including products with high concentrations of alcohol and/or astringents, or that have a potential irritating effect should be used with caution as a cumulative irritant effect may occur.

Resistance to erythromycin

The treatment of acne with topical antibiotics is associated with the development of antimicrobial resistance in Propionibacterium acnes as well as other bacteria (e.g. Staphylococcus aureus, Streptococcus pyogenes). The use of erythromycin may result in developing resistance in these organisms.

If there is evidence of the development of clinical antimicrobial resistance during treatment (e.g. poor response or worsening of the condition), treatment with Isotrexin should be discontinued.

Cross-resistance

Cross-resistance with other antibiotics of the macrolide group and with clindamycin may occur. The use of antibiotic agents may be associated with the overgrowth of antibiotic-resistant organisms. If this occurs, discontinue use.

Pseudomembranous colitis

Isotrexin should be used with caution in patients with or with a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis (including pseudomembranous colitis).

Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. Although this is less likely to occur with topically applied erythromycin, if prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further.

Sensitivity to sunlight and environmental exposure

As Isotrexin may cause increased sensitivity to sunlight, deliberate or prolonged exposure to sunlight or sunlamps should be avoided or minimised. 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. Due to the potential for photosensitivity, resulting in greater risk for sunburn, Isotrexin should be used with caution in patients with a personal or family history of skin cancer.

If a patient has sunburn, this should be resolved before using Isotrexin.

Weather extremes, such as wind or cold, may be more irritating to patients using Isotrexin.

No formal drug-drug interaction studies have been conducted with Isotrexin.

Clindamycin and erythromycin have been shown to be antagonistic in vitro. No clinical data is available.

Concomitant application of oxidising agents, such as benzoyl peroxide, should be avoided since they may reduce the efficacy of topical isotretinoin. If combination therapy is required, the products should be applied at different times of the day (e.g. one in the morning and the other in the evening).

Pregnancy

The safety of Isotrexin for use in human pregnancy has not been established.

Isotrexin is contraindicated during pregnancy and in women of childbearing potential unless an effective method of contraception is used during treatment. Treatment should be discontinued for one cycle prior to intended conception.

There are limited data available from the use of topical isotretinoin in pregnant women. However, studies totalling 1535 women exposed to topical tretinoin (an isomer of isotretinoin) in early pregnancy did not provide evidence of an increased risk of congenital abnormalities, including retinoic acid embryopathy or major structural defects.

In the clinical setting however, use of topical tretinoin in early pregnancy has been temporally associated with retinoic acid specific embryopathy. There are also a few reports of the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these reports in terms of risk to the foetus is uncertain, since no causal association has been established from these cases and these effects have not been reproduced.

Orally administered retinoids have been associated with congenital abnormalities. When used in accordance with the prescribing information, there is negligible systemic absorption from topically administered isotretinoin. However, risk cannot be excluded since there may be other factors that contribute to an increased systemic exposure.

No specific contraceptive precautions are necessary for men using Isotrexin.

Breastfeeding

Isotrexin has not been studied during breastfeeding.

Percutaneous absorption of erythromycin from Isotrexin is negligible. However, it is not known whether erythromycin is excreted into maternal milk after topical application. Erythromycin is excreted into maternal milk following oral and parenteral administration.

Percutaneous absorption of isotretinoin from Isotrexin is negligible. However, as it is not known if isotretinoin is excreted into maternal milk, a risk to the newborn/infant cannot be excluded.

A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Isotrexin therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Fertility

There are no data on the effect of Isotrexin (or the single actives) on fertility in humans, but isotretinoin in oral therapeutic dosages does not affect the number, motility, and morphology of sperm.

Isotrexin has no or negligible influence on the ability to drive and use machines.

Adverse drug reactions (ADRs) are summarised below for Isotrexin and include any additional ADRs that have been reported for the single active ingredients, topical erythromycin or isotretinoin. ADRs are listed below by MedDRA system organ class and by frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1,000 and <1/100), rare (>1/10,000 and <1/1,000) very rare (<1/10,000), not known (cannot be estimated from available data).

¹Based 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, systemic reactions are rarely seen. ²Reported from tolerability assessments during 12 week clinical study. ³Reported from clinical studies conducted with topical erythromycin and topical isotretinoin.

Local tolerability

Local Tolerance Assessments from Clinical Study at Baseline, Weeks 4, 8 and End of Treatment (Week 12)

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

Symptoms and signs

Acute overdosage of Isotrexin has not been reported to date.

Oral ingestion of a tube of Isotrexin would result in less exposure than achieved with the recommended dosage of oral isotretinoin. Consequently, the theoretical occurrence of symptoms of isotretinoin overdosage (e.g. hypervitaminosis A) is highly unlikely.

In the event of accidental ingestion, gastrointestinal adverse reactions similar to those following orally administered erythromycin may be seen (e.g. nausea, vomiting, diarrhoea).

The gel formulation contains a significant quantity of ethanol. Systemic absorption of this should be considered in the event of oral ingestion.

Treatment

Appropriate symptomatic measures should be taken to provide relief from skin irritation due to excessive application.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

Pharmacotherapeutic group: Retinoids for topical use in acne, isotretinoin combinations, ATC Code: D10AD54

Mechanism of action

Isotretinoin

Isotretinoin is structurally and pharmacologically related to vitamin A, which regulates epithelial cell growth and differentiation. 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 acts in a comparable way to its stereoisomer, tretinoin, and:

- stimulates mitosis in the epidermis

- reduces intercellular cohesion in the stratum corneum

- contests the hyperkeratosis characteristics 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 and subsequent prevention of comedones.

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

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.

Depending on the organism and dose administered, erythromycin exhibits either bacteriostatic or bactericidal activity.

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 Propionibacterium 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 Propionibacterium acnes.

Resistance and cross-resistance

Cross-resistance can develop as a result of point mutations in the genes encoding the 23S ribosomal RNA. As a result of these point mutations, most strains of Propionibacterium acnes that are resistant to erythromycin may be cross-resistant to clindamycin.

The prevalence of acquired resistance may vary geographically and with time for selected organisms. Local information on resistance is desirable.

Pharmacodynamic effects

Isotretinoin

The pharmacological action of isotretinoin has not been fully determined.

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.

Erythromycin

The exact mechanism by which erythromycin reduces lesions of acne vulgaris is not fully known. However, the effect appears to be due in part to the antibacterial activity and anti-inflammatory effects of erythromycin.

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.

Clinical studies

The safety and efficacy of Isotrexin (applied twice daily) were evaluated in a 12-week, double-blind, randomised, placebo-controlled, parallel group study in 161 patients aged 16-32 years, with mild to moderate acne vulgaris. Isotrexin was compared with an erythromycin 2% gel, isotretinoin 0.05% gel and a placebo gel.

Efficacy was assessed by comparison between the groups of the total number of lesions, total number of inflammatory lesions, total number of non-inflammatory lesions, acne severity grade, global change scores (investigator assessment) and the patient's self-rating assessment of their condition. A summary of the main findings are presented in the table below.

Changes from Baseline to Week 12 in Lesion Counts and Acne Severity Grade

All statistical tests were 2-tailed and performed at the 5% level of significance (p=0.05).

Analysis of variance was used to compare the 4 treatment groups for changes of week 4, 8 and 12 from baseline.

Isotrexin gave the greatest improvement for all acne assessments at week 12. Isotrexin significantly (p<0.05) reduced the mean total lesions (inflammatory and non-inflammatory) when compared with placebo.

Absorption

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.

Distribution

There is no evidence that the active components are absorbed to any extent after being applied to the skin.

Isotretinoin

Systemic (oral) isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Erythromycin

Systemic (oral) erythromycin is about 65% bound to plasma proteins, primarily to alpha 1 acid glycoprotein (approximately 55%).

Metabolism

Isotretinoin

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.

Erythromycin

No data exist relating to the metabolism, if any, of erythromycin on the skin.

After systemic (oral) administration, erythromycin is inactivated in the liver by demethylation of the d-desosamine group, a reaction catalyzed by cytochrome P450 IIA.

Elimination

Isotretinoin

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%).

Erythromycin

If very small quantities of erythromycin are absorbed, it will be oxidised and excreted in bile or in urine, respectively.

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.

Carcinogenesis/Mutagenesis

Isotretinoin

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.

Erythromycin

Carcinogenicity studies in mice and rats with dietary administration of erythromycin stearate did not show evidence of tumorigenicity.

Erythromycin stearate was not mutagenic in a bacterial mutagenicity assay (Salmonella typhimurium) in the presence and absence of metabolic activation, and was not genotoxic in a chromosome aberration assay and a sister chromatid exchange assay in Chinese Hamster Ovary cells, in the presence and absence of metabolic activation. A small increase in mutation frequency of questionable biological relevance was observed in the mouse L5178Y lymphoma cell assay in the absence of metabolic activation.

Reproductive Toxicology

Fertility

Isotretinoin

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.

Erythromycin

There are no data on the effect of topical erythromycin on fertility.

Pregnancy

Isotretinoin

Isotretinoin has been associated with teratogenicity in humans when administered systemically. However, reproduction studies conducted in rabbits using topical isotretinoin gel applied at 10 - 60 times the human therapeutic 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.

Erythromycin

There are no data on the effect of topical erythromycin on embryo-fetal development.

Hydroxypropylcellulose

Butylated Hydroxytoluene (BHT)

Anhydrous Ethanol

Not applicable

Do not store above 25°C.

Internally lacquered membrane-sealed aluminium tubes fitted with a polyethylene screw-cap, packed into a carton. Pack sizes: 5, 6, 15, 25, 30, 40 and 50 grammes.

Not all pack sizes may be marketed.

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

09^th December 2013