TOLAK

Tolak (fluorouracil) Cream, 4% contains 40 mg of fluorouracil per gram of white cream for topical application. It is a nucleoside metabolic inhibitor. Chemically, fluorouracil is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. The molecular formula of 5-fluorouracil is C 4 H 3 FN 2 O 2 , and its molecular weight is 130.1. Its structural formula is: Tolak Cream contains the following inactive ingredients: arlacel-165, butylated hydroxytoluene, cetyl alcohol, anhydrous citric acid, glycerin, isopropyl myristate, methyl gluceth-10, methylparaben, propylparaben, purified water, peanut oil, sodium hydroxide, stearic acid, and stearyl alcohol. Tolak Cream formulation has an alkaline pH at 8.3 to 9.2. Chemical Structure

Tolak (fluorouracil) Cream is indicated for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp. Tolak (fluorouracil) Cream, 4%, is a nucleoside metabolic inhibitor indicated for the topical treatment of actinic keratosis lesions of the face, ears, and scalp ( 1 ).

Prior to application of Tolak Cream, wash, rinse, and dry the treatment areas. Apply Tolak Cream once daily in an amount sufficient to cover the lesions of the face, ears, and/or scalp with a thin film, using the fingertips to gently massage the medication uniformly into the skin. Apply Tolak Cream for a period of 4 weeks as tolerated. Thoroughly wash hands following Tolak Cream application. Tolak Cream is for topical use only. Do not apply to eyes, nose, mouth or mucous membranes. Not for ophthalmic, oral or intravaginal use. Apply Tolak Cream after washing, rinsing, and drying the treatment area(s) ( 2 ). Apply Tolak Cream once daily in an amount sufficient to cover the lesions of the face, ears, and/or scalp with a thin film, using the fingertips to gently massage the medication uniformly into the skin ( 2 ). Tolak Cream should be applied for a period of 4 weeks as tolerated ( 2 ). Wash hands thoroughly following Tolak Cream application ( 2 ). Tolak Cream is for topical use only. Do not apply to eyes, nose, mouth or mucous membranes ( 2 ). Not for ophthalmic, oral, or intravaginal use ( 2 ).

Tolak Cream is contraindicated: During pregnancy [see Warnings and Precautions (5.5 , 8.1) ] In patients with dihydropyrimidine dehydrogenase (DPD) deficiency [see Warnings and Precautions (5.6) ] Pregnancy ( 4.1 , 8.1 ). Dihydropyrimidine dehydrogenase (DPD) deficiency ( 4.2 ). 4.1 Pregnancy Tolak Cream may cause fetal harm when administered during pregnancy and is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus. 4.2 Dihydropyrimidine Dehydrogenase Deficiency Tolak Cream is contraindicated in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

The following serious adverse reactions are discussed in more detail in other sections of the labeling: Application Site Adverse Reactions [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Ophthalmic Adverse Reactions [see Warnings and Precautions (5.3) ] Photosensitivity [see Warnings and Precautions (5.4) ] Embryofetal toxicity [see Warnings and Precautions (5.5) ] Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency [see Warnings and Precautions (5.6) ] The most common (incidence > 68%) adverse reactions occur at the application site and include erythema, scaling/dryness, crusting, pruritus, stinging/burning, edema, and erosions. Erythema is observed in 99% of patients with actinic keratosis treated with Tolak Cream ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hill Dermaceuticals at 1-800-344-5707 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 data described below reflect exposure to Tolak Cream in 397 subjects with actinic keratosis in vehicle-controlled trials. The population ranged in age from 33 to 94 years, was 80% male, and almost all were Caucasian. Most subjects were treated with Tolak Cream once daily for 4 weeks. Throughout the 4-week treatment and the 4-week post-treatment periods, the trials specifically monitored for adverse reactions related to tolerability, including erythema, scaling/dryness, edema, crusting, erosions, stinging/burning, and pruritus. The number and percentage of subjects with each of these monitored adverse reactions at one or more post-baseline visit(s) during the clinical trials are shown in Table 1. Table 1: Incidence of Application Site Adverse Reactions Occurring with 4 Weeks of Tolak Cream Treatment in Clinical Trials 1 and 2 Tolak Cream N=397 n (%) Vehicle N=120 n (%) Mild, Moderate or Severe Severe Only Mild, Moderate or Severe Severe Only Erythema 394 (99%) 174 (44%) 102 (85%) 0 (0%) Scaling/ Dryness 377 (95%) 94 (24%) 99 (83%) 0 (0%) Crusting 346 (87%) 87 (22%) 46 (38%) 0 (0%) Pruritus 337 (85%) 65 (16%) 46 (38%) 1 (1%) Stinging/ Burning 346 (87%) 101 (25%) 42 (35%) 0 (0%) Edema 275 (69%) 30 (8%) 11 (9%) 0 (0%) Erosions 271 (68%) 44 (11%) 14 (12%) 0 (0%) In these clinical trials, the intensity of the adverse reactions in subjects using Tolak Cream generally increased over the 4-week treatment period, usually reaching maximal levels at 4 weeks of treatment and then diminishing to baseline levels within 4 weeks after cessation of treatment. In Trials 1 and 2, 11% of Tolak Cream-treated and 3% of vehicle-treated subjects discontinued treatment because of adverse reactions. Of these subjects, the majority had adverse reactions at the application site. Eye swelling, leading to discontinuation, occurred in one subject with Tolak Cream use . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topical fluorouracil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : leukocytosis, pancytopenia, thrombocytopenia, eosinophilia, neutrophil toxic granulation Eye disorders : corneal disorder, conjunctival disorder, eye irritation, conjunctivitis, lacrimation Gastrointestinal disorders : stomatitis General Disorders and Administration Site Conditions : medicinal taste Infections and Infestations : herpes simplex Neoplasms : chronic lymphocytic leukemia, non-melanoma skin cancer Nervous system disorders : insomnia, irritability Psychiatric disorders : emotional distress Skin and subcutaneous tissue disorders : blistering, allergic contact dermatitis, photosensitivity, pain, scarring, skin irritation, rash, ulceration, hyperpigmentation, alopecia, bullous pemphigoid, ichthyosis, suppuration, swelling, soreness, telangiectasia, tenderness, urticaria

Subjects using systemic steroids, immunosuppressants, and immunomodulators were generally excluded from the clinical studies of Tolak Cream, as were subjects who used retinoids, topical steroids, glycolic acid products, alpha-hydroxy products, and chemical peeling products in the treatment areas. No clinical trials were designed to specifically evaluate drug interactions.

16.2 Storage and Handling Store at 25°C (77°F), with excursion permitted from 15°C to 30°C (59°F - 86°F) [See USP Controlled Room Temperature]. Do not freeze.