Alitretinoin

12.1 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.

1 INDICATIONS AND USAGE 1.1 Kaposi’s Sarcoma PANRETIN GEL is indicated for topical treatment of cutaneous lesions in adults with AIDS related Kaposi’s sarcoma (KS). Limitations of Use: PANRETIN GEL is not indicated when systemic anti-KS therapy is required (including more than 10 new KS lesions in the prior month, symptomatic lymphedema, symptomatic pulmonary KS, or symptomatic visceral involvement) [see Clinical Studies ( 14.1 )] . PANRETIN GEL is a retinoid indicated for the topical treatment of cutaneous lesions in adults with AIDS-related Kaposi’s sarcoma (KS). Limitations of Use : PANRETIN GEL is not indicated when systemic anti-Kaposi’s sarcoma therapy is required.

2 DOSAGE AND ADMINISTRATION PANRETIN GEL is for topical use only. Do not use occlusive dressings with PANRETIN GEL. Apply PANRETIN GEL twice daily to coat the entire cutaneous Kaposi sarcoma lesions. Gradually increase the application frequency up to four (4) times a day as tolerated. Continue PANRETIN GEL as long as patient is deriving benefit. Reduce application frequency for application site toxicity. Interrupt treatment for severe irritation; may resume at a reduced application frequency once symptoms improve. Avoid application of gel to normal skin and do not apply on or near mucosal surfaces. Wash hands after application unless gel is applied to Kaposi sarcoma lesions on the hands. Allow gel to dry for three to five minutes before covering with clothing. • Apply to the affected lesions twice daily; increase to 4 times daily as tolerated. ( 2 ) • For topical use only. ( 2 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Photosensitivity [see Warnings and Precautions ( 5.2 )] Most common adverse reactions (> 5%) at the application site are rash, pain, paresthesia, pruritis, exfoliative dermatitis, edema, and skin disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Advanz Pharma (US) Corp. at 1-877-370-1142 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PANRETIN GEL was assessed in two multicenter, prospective, randomized, double-blind, vehicle-controlled trials (Trial 1 and Trial 2) in patients with cutaneous lesions of AIDS-related KS [see Clinical Studies ( 14.1 )] . In a pooled analysis of both trials, the most common adverse reactions in ≥ 5% of patients were rash, pain, paresthesia, pruritis, exfoliative dermatitis, edema, and skin disorder. In Trial 1, severe local skin adverse reactions (erythema and edema with or without vesiculation) occurred in 10% of patients during the first 12 weeks of treatment (versus 0% in the vehicle control). Adverse reactions led to withdrawal from the study in 7% of patients. In Trial 2, severe local skin adverse reactions (erythema and edema with or without vesiculation) occurred in 6% of patients during the first 12 weeks of treatment (versus 0% in the vehicle control) and 1 patient withdrew due to severe skin irritation. Table 1 lists the most common application site adverse reactions that occurred in a least 5% of patients during the double-blind phase who received PANRETIN GEL in either of the two controlled studies. TABLE 1: Adverse Reactions at Application Site in Trial 1 and 2 in ≥ 5% of Patients Treated with PANRETIN GEL A dverse Event Term Trial 1 Trial 2 PANRETIN GEL N=134 % Vehicle Gel N=134 % PANRETIN GEL N=36 % Vehicle Gel N=46 % Rash 1 77 11 25 4 Pain 2 34 7 0 4 Pruritus 3 11 4 8 4 Exfoliative dermatitis 4 9 2 3 0 Skin disorder 5 8 1 0 0 Edema 6 8 3 3 0 Parethesia 7 3 0 22 7 Includes Investigator terms: 1 Erythema, scaling, irritation, redness, rash, dermatitis 2 Burning, pain 3 Itching, pruritus 4 Flaking, peeling, desquamation, exfoliation 5 Excoriation, cracking, scab, crusting, drainage, eschar, fissure or oozing 6 Edema, swelling, inflammation 7 Stinging, tingling