PANRETIN Gel Ref.[6133] Active ingredients: Alitretinoin

Retinoids as a class have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of Panretin gel in the clinical studies. However, patients must be cautioned to minimise exposure of treated areas to sunlight or other ultraviolet (UV) light. (see section 5.3).

It is recommended that daily dietary intake of vitamin A should not exceed the Recommended Dietary Intake value.

Alitretinoin may cause harm to the foetus. Women of child-bearing potential must use a reliable form of contraception during treatment with Panretin gel (see section 4.6) and until one month after cessation of treatment.

The use of other topical products on Panretin treated KS lesions should be avoided. Mineral oil may be used between Panretin applications in order to help prevent excessive dryness or itching. However, mineral oil should not be applied for at least two hours before or after the application of Panretin.

It is not recommended for patients to apply Panretin gel concurrently with products that contain N,N-diethyl-m-toluamide (DEET), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.

The range and frequency of detection of quantifiable plasma 9-cis-retinoic acid concentrations in patients with KS applying the medicinal product to up to 64 lesions were comparable to respective values in untreated patients. Therefore, there is a low potential for interactions with systemic medicinal products.

There was no clinical evidence in the vehicle-controlled studies of interactions with systemic antiretroviral agents, including protease inhibitors; macrolide antibiotics and azole antifungals. While no data are available, it is possible that co-administration of medicinal products which induce CYP isozymes may reduce circulating levels of alitretinoin, with a possible negative effect on the efficacy of Panretin gel.

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during, and up to one month after cessation of treatment.

Men using Panretin should take precautions to ensure that their female partners do not become pregnant.

Pregnancy

Orally administered retinoids have been associated with congenital abnormalities. When used in accordance with the prescribing information topically administered retinoids are generally assumed to result in low systemic exposure due to minimal dermal absorption. However there could be individual factors (e.g. damaged skin barrier, excessive use) that contribute to an increased systemic exposure.

In rabbits, alitretinoin was shown to be teratogenic at a dose which resulted in plasma concentrations about 60 times the highest observed plasma concentration in male patients with KS following topical application of the gel. However, it is not currently certain to what extent topical treatment with Panretin gel would increase 9-cis-retinoic acid plasma concentrations, in women with KS above naturally occurring levels; therefore, Panretin is contraindicated (see section 4.3) in pregnancy, or in women planning a pregnancy. If the product is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued.

Breast-feeding

It is not known whether this medicinal product is excreted in human milk. Based on the plasma concentrations observed in patients, milk concentrations of 9-cis-retinoic acid probably pose a low risk for the infant. However, because of the potential for undesirable effects from Panretin gel in infants being breast-fed, mothers must discontinue breast-feeding prior to using the medicinal product and not initiate breast-feeding while using the medicinal product.

Care should be taken not to bring the neonate into skin contact with areas to which Panretin has been recently applied. It is recommended that HIV-infected mothers do not breast-feed their children to exclude the risk of transmission of the virus.

Fertility

No specific studies on fertility have been conducted in men or women. However, alitretinoin is teratogenic so both men and women should take adequate precautions to avoid female partners becoming pregnant.

Panretin gel is for cutaneous use and is unlikely to have an effect on the ability to drive and use machines.

Adverse events associated with the use of Panretin gel in AIDS-related KS occurred almost exclusively at the site of application. The dermal toxicity typically begins as erythema; with continued application of Panretin gel erythema may increase and oedema may develop. Dermal toxicity may become treatment-limiting, with intense erythema, oedema, and vesiculation. When applying Panretin gel, 69.1% of patients experienced adverse drug reactions at the application site.

Table 3 shows the following application-site drug-related adverse reactions were reported during clinical studies in patients with KS. The frequency of adverse events are classified as very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to <1/100). Adverse events include verbatim terms in parentheses.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3. Adverse reactions reported in patients in clinical trials:

Blood and lymphatic system disorders

Uncommon: Lymphadenopathy

Nervous system disorders

Common: Paraesthesia (stinging, tingling)

Vascular disorders

Common: Haemorrhage (bleeding at or around lesions), Oedema (oedema, swelling, inflammation), Peripheral oedema

Uncommon: Phlebitis, Vascular disorder

Skin and subcutaneous tissue disorder

Very common: Skin disorder (cracking, scab, crusting, excoriation, drainage, oozing), Rash (erythema, redness, scaling, irritation, dermatitis), Pruritus (itching, pruritus)

Common: Skin ulcer, Serous drainage, Exfoliative dermatitis (flaking, peeling, desquamation, exfoliation), Skin discoloration (brown discoloration, surrounding hyperpigmentation, paler), Dry skin

Uncommon: Cellulitis, Vesiculobullous rash, Maculopapular rash, Allergic reaction

General disorders and administration site conditions

Very common: Pain (burning, pain, soreness)

Uncommon: Infection, including bacterial infection

The safety of Panretin gel has been assessed in clinical studies of more than 469 patients with AIDS-related KS, 439 of whom were treated with an alitretinoin concentration of 0.1%.

The incidence of drug-related skin disorder, skin ulcer, pain and rash appeared to be greater in patients applying Panretin gel four times daily than in those applying it less frequently. However, the incidence of other equally common drug-related adverse events such as pruritus, oedema, exfoliative dermatitis and dry skin did not appear to increase as a function of the frequency of application.

The incidence of mild/moderate rash (all events regardless of causality) was less in patients treated for less than 16 weeks than in those treated for 16 weeks or more (mild, 33% v 63%; moderate, 29% v 43%). The incidence of severe skin rash was independent of the duration of treatment (10% in both cases).

Local dermal toxicity associated with Panretin gel therapy generally resolved with treatment adjustment or discontinuation (see section 4.2).

Only two serious adverse reactions were reported (sepsis and cellulitis in the same patient).

The adverse events seen with Panretin gel are similar to those seen with other topical retinoids. It is unlikely that the undesirable systemic side effects associated with oral retinoids will be observed with the use of Panretin gel because the range and frequency of quantifiable 9-cis-retinoic acid plasma levels concentrations after application of the medicinal product were comparable to the range and frequency of quantifiable plasma concentrations of circulating, naturally occurring 9-cis-retinoic acid in untreated individuals.

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 national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. The use of other topical products on treated KS lesions should be avoided. Panretin gel should not be used concurrently with products containing DEET.