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  • CLASSES

    Topical Antineoplastic Retinoids

    DEA CLASS

    Rx

    DESCRIPTION

    Topical retinoid
    Used for the treatment of cutaneous lesions in patients with AIDS-related Kaposi sarcoma
    Avoid prolonged exposure to sunlight or ultraviolet light

    COMMON BRAND NAMES

    Panretin

    HOW SUPPLIED

    Panretin Topical Gel: 0.1%

    DOSAGE & INDICATIONS

    For the treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma.
    NOTE: Alitretinoin has been designated an orphan drug by the FDA for this indication.
    Topical dosage
    Adults

    Apply topically to lesions twice daily; gradually increase the application frequency to 3 to 4 times daily based on individual lesion tolerance. If skin toxicity develops at the lesion site, reduce the application frequency or temporarily discontinue treatment for a few days until the symptoms lessen. Typically, a response will occur between 2 to 14 weeks after starting therapy. Continue alitretinoin gel for as long as the patient responds to therapy; patients received topical alitretinoin for up to 96 weeks in clinical trials. Patients with AIDS-related Kaposi sarcoma who received alitretinoin gel for the treatment of cutaneous lesions were evaluated using the modified AIDS Clinical Trials Group (ACTG) criteria for topical therapy in 2 randomized, double-blind, vehicle-controlled trials. The response rate at 12 weeks was significantly higher (35% vs. 16%; p = 0.0012) in patients who received alitretinoin gel (n = 134) compared with vehicle only gel (n = 134) in one trial. All responses were partial responses (PR) except for 1% of alitretinoin-treated patients who achieved a complete response. The 12-week response rate was also higher (36% vs. 7%) in patients who received alitretinoin gel (n = 36) compared with vehicle only gel (n = 46) in another trial. All responses were a PR.

    MAXIMUM DOSAGE

    Adults

    4 applications topically per lesion/day.

    Elderly

    4 applications topically per lesion/day.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Topical Administration

    Apply a generous coating of alitretinoin gel topically to lesions using a clean finger; avoid applying to health skin around lesions.
    Do NOT apply gel on or near mucosal surfaces of the body such as eyes, nostrils, mouth, lips, vagina, tip of the penis, rectum, or anus.
    Space applications apart as evenly as possible throughout the day.
    Some gel should be visible on the surface of the lesion; it is not necessary to rub the gel into the lesion.
    Allow the gel to dry (for about 3 to 5 minutes) before covering a treated area with loose clothing; do not cover with any other material, occlusive dressing, or bandage.
    After applying the gel, wipe fingers with a disposable tissue and wash your hands using soap and water; use a mild soap when bathing or showering.
    Do not shower, bathe, or swim until at least 3 hours after application; do not apply until at least 20 minutes after showering or bathing.
    Mineral oil may be applied 2 hours after and no sooner than 2 hours before alitretinoin gel applications to prevent dryness and itching.
    Avoid the use of other topical products on the lesions, including N,N-diethyl-m-toluamide (DEET)-containing products.

    STORAGE

    Panretin:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Sunlight (UV) exposure

    Due to the risk of photosensitivity, patients should avoid prolonged sunlight (UV) exposure and using tanning lamps during therapy with alitretinoin gel.

    Occlusive dressing

    Cover the treated area with loose clothing after the alitretinoin gel dries; do not cover with any other material, occlusive dressing, or bandage.

    Pregnancy

    Alitretinoin may cause fetal harm when administered during pregnancy, based on data from animal studies. Females of reproductive potential should avoid becoming pregnant during alitretinoin therapy. Pregnant women or women who become pregnant while receiving alitretinoin should be apprised of the potential hazard to the fetus. It is not known if topical alitretinoin gel can modulate endogenous 9-cis-retinoic acid levels in a pregnant woman or if systemic exposure is increased by application to ulcerated lesions or by duration of treatment. Embryo-fetal toxicity including an increased incidence of fused sternebrae and limb and craniofacial defects was observed in pregnant rabbits who received oral alitretinoin doses (0.5 mg/kg/day) that resulted in AUC values approximately 5-times the estimated daily human topical dose on a mg/m2 basis (assumes complete systemic absorption of 9-cis-retinoic acid after 1 month of use in a 60 kg human). Limb and craniofacial defects were also observed in the offspring of mice who received a single oral dose of 50 mg/kg on day eleven of gestation (about 127-times the estimated daily human topical dose). Early resorptions and post-implantation loss were also reported when oral 9-cis-retinoic acid was given during organogenesis to rabbits and rats at doses 15- and 25-times the estimated daily human topical dose.

    Breast-feeding

    It is not known if alitretinoin or its metabolites are secreted in human milk. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding prior to alitretinoin gel therapy.

    ADVERSE REACTIONS

    Severe

    exfoliative dermatitis / Delayed / 3.0-9.0

    Moderate

    edema / Delayed / 3.0-8.0
    erythema / Early / Incidence not known

    Mild

    rash / Early / 25.0-77.0
    paresthesias / Delayed / 3.0-22.0
    pruritus / Rapid / 8.0-11.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Alitretinoin products.

    PREGNANCY AND LACTATION

    Pregnancy

    Alitretinoin may cause fetal harm when administered during pregnancy, based on data from animal studies. Females of reproductive potential should avoid becoming pregnant during alitretinoin therapy. Pregnant women or women who become pregnant while receiving alitretinoin should be apprised of the potential hazard to the fetus. It is not known if topical alitretinoin gel can modulate endogenous 9-cis-retinoic acid levels in a pregnant woman or if systemic exposure is increased by application to ulcerated lesions or by duration of treatment. Embryo-fetal toxicity including an increased incidence of fused sternebrae and limb and craniofacial defects was observed in pregnant rabbits who received oral alitretinoin doses (0.5 mg/kg/day) that resulted in AUC values approximately 5-times the estimated daily human topical dose on a mg/m2 basis (assumes complete systemic absorption of 9-cis-retinoic acid after 1 month of use in a 60 kg human). Limb and craniofacial defects were also observed in the offspring of mice who received a single oral dose of 50 mg/kg on day eleven of gestation (about 127-times the estimated daily human topical dose). Early resorptions and post-implantation loss were also reported when oral 9-cis-retinoic acid was given during organogenesis to rabbits and rats at doses 15- and 25-times the estimated daily human topical dose.

    It is not known if alitretinoin or its metabolites are secreted in human milk. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding prior to alitretinoin gel therapy.

    MECHANISM OF ACTION

    Alitretinoin (9-cis-retinoic acid) is an endogenous retinoid that binds to and activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) on the cell nucleus causing keratinocyte differentiation and blocking neo-angiogenesis and proliferation of Kaposi sarcoma cells in vitro. Alitretinoin also exhibits anti-inflammatory and immunomodulatory effects by reducing sources of TNF-alpha (e.g., macrophages and activated dendritic cells) and decreasing the production of pro-inflammatory cytokines (e.g., IL-4, IL-1 beta, and IL-12p40).

    PHARMACOKINETICS

    Alitretinoin (9-cis-retinoic acid) is administered topically. It is metabolized to 4-hydroxy-9-cisretinoic acid and 4-oxo-9-cis-retinoic acid by CYP2C9, CYP3A4, CYP1A1, and CYP1A2 in vitro.

    Topical Route

    Systemic absorption is not extensive and there are no detectable plasma concentrations of 9-cis-retinoic acid metabolites after topical application of alitretinoin gel. In clinical trials, plasma concentrations of 9-cis-retinoic acid in patients with cutaneous lesions from AIDS-related Kaposi sarcoma who receved multiple-daily doses of alitretinoin gel for up to 60 weeks were similar to concentrations of circulating, naturally-occurring 9-cis-retinoic acid plasma concentrations in untreated healthy volunteers.