Panretin

Alitretinoin is a retinoid, related to vitamin A. Alitretinoin affects the growth and development of skin cells.

Alitretinoin topical (for the skin) is used to treat skin lesions caused by AIDS-related Kaposi's sarcoma.

Alitretinoin topical may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use this medicine if you are allergic to alitretinoin, isotretinoin, or tretinoin (Retin-A).

Before you use alitretinoin topical, tell your doctor about all your medical conditions and allergies. Also make sure your doctor knows if you are pregnant or breast-feeding.

FDA pregnancy category D. Do not use alitretinoin topical if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether alitretinoin topical passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not use this medication on anyone under 18 years old without medical advice.

There has been no experience with acute overdose of Panretin® gel in humans. Systemic toxicity following acute overdosage with topical application of Panretin® gel is unlikely because of limited systemic plasma levels observed with normal therapeutic doses. There is no specific antidote for overdosage.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

It is not likely that other drugs you take orally or inject will have an effect on topically applied alitretinoin. But many drugs can interact with each other. Tell each of your health care providers about all medicines you use, including prescription and over-the-counter medicines, vitamins, and herbal products.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Panretin (alitretinoin (topical)), please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Panretin. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Panretin.

Review Date: October 4, 2017

Mechanism of Action

Alitretinoin (9-cis-retinoic acid) is a naturally-occurring endogenous retinoid that binds to and activates all known intracellular retinoid receptor subtypes (RARα, RARβ, RARγ, RXRα, RXRβ and RXRγ). Once activated these receptors function as transcription factors that regulate the expression of genes that control the process of cellular differentiation and proliferation in both normal and neoplastic cells. Alitretinoin inhibits the growth of Kaposi’s sarcoma (KS) cells in vitro.

Pharmacokinetics

No studies have examined plasma 9-cis-retinoic acid concentrations before and after treatment with Panretin® gel. There is, however, indirect evidence that absorption is not extensive. Plasma concentrations of 9-cis-retinoic acid were evaluated during clinical studies in patients with cutaneous lesions of AIDS-related KS after repeated multiple-daily dose application of Panretin® gel for up to 60 weeks. The range of 9-cis-retinoic acid plasma concentrations in these patients was similar to the range of circulating, naturally-occurring 9-cis-retinoic acid plasma concentrations in untreated healthy volunteers.

Although there are no detectable plasma concentrations of 9-cis-retinoic acid metabolites after topical application of Panretin® gel, in vitro studies indicate that the drug is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP 2C9, 3A4, 1A1, and 1A2 enzymes. In vivo, 4-oxo-9-cis-retinoic acid is the major circulating metabolite following oral administration of 9-cis-retinoic acid.

No formal pharmacokinetic drug interaction studies between Panretin® gel and antiretroviral agents have been conducted.

Clinical Studies

Panretin® gel is not a systemic therapy; it therefore cannot treat visceral Kaposi’s sarcoma (KS) nor prevent the development of new KS lesions where it has not been applied. Visceral KS disease was not monitored in these trials, and the appearance of new KS lesions was not considered part of the response assessment in clinical trials.

Panretin® gel was evaluated in two multicenter, prospective, randomized, double-blind, vehicle-controlled studies in patients with cutaneous lesions of AIDS-related KS. In both studies the primary efficacy endpoint was the patients’ cutaneous KS tumor response rate through 12 weeks of study drug treatment which was assessed by evaluating from 3 to 8 KS index lesions according to the modified AIDS Clinical Trials Group (ACTG) response criteria as applied to topical therapy (i.e., evaluation of height and area reductions of the index lesions only; progressive disease in non-index lesions and new lesions were not considered progressive disease; progressive disease was scored only in the treated index lesions). A global evaluation by physicians was also carried out. It considered all of the patient’s treated lesions (index and other) compared to baseline. In this evaluation, patients with at least a 50% improvement in the KS lesions were considered responders. In addition, photographs of lesions in patients considered responders by the modified ACTG criteria were examined by the FDA for a cosmetically beneficial response, defined as at least a 50% improvement in appearance compared to baseline, considering both the KS lesions and dermal toxicity at the lesion site, in at least 50% of the index lesions and maintained for at least 3 weeks. Patients were also asked about their satisfaction with the treatment.

In Study 1, a total of 268 patients were entered from centers in the U.S. and Canada. Patients were treated topically three to four times a day with either Panretin® gel or a matching vehicle gel for a minimum of 12 weeks, followed by an open-label phase in patients who had not yet progressed on Panretin® gel. Responses during the double-blind phase are shown in Table 1. Responses to Panretin® gel were seen in both previously untreated patients and in patients with prior systemic and/or topical KS treatment. A total of 72 patients responded to Panretin® gel during the randomized or crossover portions of the study. At a median duration of monitoring of 16 weeks, only 15% of the 72 patients had relapsed. Panretin® gel would not be expected to affect development of new lesions in untreated areas and these were seen in about 50% of patients, at similar rates in treated and untreated patients, responders and non-responders. The patients’ assessment of their overall satisfaction with the drug effect on all treated lesions significantly favored Panretin® gel.

Study 2 was an international study with a planned enrollment of 270 patients. Patients were treated topically twice a day with Panretin® gel or a matching vehicle for 12 weeks. The study was stopped early because of positive interim results in the initial 82 patient data set. Results of the study are shown in Table 1. Responses to Panretin® gel were seen both in previously untreated patients and in patients with prior systemic and/or topical KS treatment.

In the clinical trials, responses were seen as early as two (2) weeks; most patients, however, required four (4) to eight (8) weeks of treatment, and some patients did not experience significant improvement until 14 or more weeks of treatment. The cumulative percentage of patients who achieved a response was less than 1% at 2 weeks, 10% at 4 weeks, and 28% at 8 weeks.

In both studies, responses occurred in patients with a wide range of baseline CD4+ lymphocyte counts, including patients with CD4+ lymphocyte counts less than 50 cells/mm3. Nearly all patients received concomitant combination antiretroviral therapy.

Photographs of patients revealed a substantial erythematous and edematous response in some cases, leading to a cosmetically mixed outcome even in apparent responders. Nonetheless, in Study 1 it appeared that a cosmetically satisfactory result occurred at about the same rate as the Physician’s Global response rate and in both studies such a response was more frequent than in the vehicle control.

Panretin® gel is indicated for topical treatment of Kaposi’s sarcoma. Patients with cutaneous T-cell lymphoma were less tolerant of topical Panretin® gel; five of seven patients had 6 episodes of treatment-limiting toxicitiesgrade 3 dermal irritationwith Panretin® gel (0.01% or 0.05%).

Information for Patients

Please see accompanying “Patient’s Instructions for Use”

Photosensitivity

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. Nonetheless, because in vitro data indicate that 9-cis-retinoic acid may have a weak photosensitizing effect, patients should be advised to minimize exposure of treated areas to sunlight and sunlamps during the use of Panretin® gel.

Drug Interactions

Patients who are applying Panretin® gel should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.

Although there was no clinical evidence in the vehicle-controlled studies of drug interactions with systemic antiretroviral agents, including protease inhibitors, macrolide antibiotics, and azole antifungals, the effect of Panretin® gel on the steady-state concentrations of these drugs is not known. No drug interaction data are available on concomitant administration of Panretin® gel and systemic anti-KS agents.

Drug/Laboratory Test Interactions

No interference with laboratory tests has been observed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to assess the carcinogenic potential of 9-cis-retinoic acid have not been conducted. 9-cis-Retinoic acid was not mutagenic in vitro (bacterial assays, Chinese hamster ovary cell HGPRT mutation assay) and was not clastogenic in vitro (chromosome aberration test in human lymphocytes) nor in vivo (mouse micronucleus test).

Pregnancy Category D

(see “Warnings” section)

Nursing Mothers

It is not known whether alitretinoin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions from Panretin® gel in nursing infants, mothers should discontinue nursing prior to using the drug.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Inadequate information is available to assess safety and efficacy in patients age 65 years or older.

The safety of Panretin® gel has been assessed in clinical studies of 385 patients with AIDS-related KS. Adverse events associated with the use of Panretin® gel in patients with AIDS-related KS occurred almost exclusively at the site of application. The dermal toxicity begins as erythema; with continued application of Panretin® gel, erythema may increase and edema may develop. Dermal toxicity may become treatment-limiting, with intense erythema, edema, and vesiculation. Usually, however, adverse events are mild to moderate in severity; they led to withdrawal from the study in only 7% of the patients. Severe local (application site) skin adverse events occurred in about 10% of patients in the U.S. study (versus 0% in the vehicle control). Table 2 lists the adverse events that occurred at the application site with an incidence of at least 5% during the double-blind phase in the Panretin® gel-treated group and in the vehicle control group in either of the two controlled studies. Adverse events were reported at other sites but generally were similar in the two groups.

Panretin® gel should initially be applied two (2) times a day to cutaneous KS lesions. The application frequency can be gradually increased to three (3) or four (4) times a day according to individual lesion tolerance. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside.

Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry for three to five minutes before covering with clothing. Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. In addition, do not apply the gel on or near mucosal surfaces of the body.

A response of KS lesions may be seen as soon as two weeks after initiation of therapy but most patients require longer application. With continued application, further benefit may be attained. Some patients have required over 14 weeks to respond. In clinical trials, Panretin® gel was applied for up to 96 weeks. Panretin® gel should be continued as long as the patient is deriving benefit.

Occlusive dressings should not be used with Panretin® gel.