Tolak Cream

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.

Application Site Adverse Reactions

Application site reactions (erythema, scaling/dryness, edema, crusting, erosions, stinging/burning, and pruritus) were observed in almost all patients during treatment of actinic keratosis on the face, ears, and/or scalp with topical fluorouracil [see Adverse Reactions (6.1)]. In the clinical trials of Tolak Cream, application site irritation returned to baseline (pre-treatment) levels within 4 weeks after discontinuing treatment.

Do not apply Tolak Cream directly into eyes, nose, mouth, or other mucous membranes because irritation, local inflammation and ulceration can occur.

Hypersensitivity Reactions

Allergic contact dermatitis (delayed type hypersensitivity reaction) has been noted for topical fluorouracil drugs. While application site reactions are observed in almost all patients during treatment of actinic keratosis with topical fluorouracil [see Adverse Reactions (6.2)], delayed type hypersensitivity should be suspected in the event of severe pruritus or eczema at the application site or at a distant site. Although the potential for a delayed hypersensitivity reaction to fluorouracil exists, patch testing to confirm hypersensitivity may be inconclusive.

Tolak Cream contains peanut oil. If signs of hypersensitivity occur, patients should discontinue Tolak Cream immediately and contact their healthcare provider.

Ophthalmic Adverse Reactions

Corneal and conjunctival disorders have occurred with topical fluorouracil use [see Adverse Reactions (6.2)]. Avoid application to the periocular area. To avoid transfer of the drug into the eyes and to the periocular area during and after application, patients should wash hands well after applying Tolak Cream. If accidental exposure occurs, the patient should flush eye(s) with large amounts of water and seek medical care as soon as possible.

Photosensitivity

Topical fluorouracil is associated with photosensitivity reactions including severe sunburn. Minimize exposure to ultraviolet rays including sunlight, sun lamps, and tanning beds during and immediately following treatment with Tolak Cream because the intensity of the photosensitivity reaction may be increased.

Embryofetal Toxicity

Cases of miscarriage and birth defects (including cleft lip and cleft palate) have been reported when pregnant women were exposed to a topical or parenteral fluorouracil product. In addition, ventricular septal defect and cases of miscarriage occurred when pregnant women applied a topical fluorouracil product to mucous membranes (Tolak Cream is not indicated for use on the mucous membrane). Furthermore, fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA), inhibits the formation of ribonucleic acid (RNA), and provokes unbalanced growth and death of cells. Therefore, Tolak Cream is contraindicated in pregnancy.

Advise females of reproductive potential to use effective contraception during Tolak use and for one month after the last dose of Tolak Cream.

Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency

Life-threatening systemic toxicity has been reported with the topical use of fluorouracil in a patient with DPD deficiency. Symptoms included severe abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, inflammation of the esophagus, stomach and small bowel.

A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency may result in increased availability of fluorouracil to the anabolic pathway, which may lead to increased interference with DNA and RNA synthesis and increased cytotoxic activity and potential toxicities [see Clinical Pharmacology (12.1)]. Therefore, Tolak Cream is contraindicated in patients with DPD deficiency.

Patients should discontinue Tolak Cream if symptoms of fluorouracil's systemic toxicity develop.

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 C4H3FN2O2, 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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Important Administration Instructions

Advise patients of the following:

• Tolak Cream is for external use only.
• Do not apply to eyes, nose, mouth or mucous membranes.
• Avoid inadvertent transfer of Tolak Cream to other body areas, or to another person.
• Keep out of the reach of children.

Instruct patients to do the following:

• Apply after washing, rinsing, and drying the treatment area.
• Wash hands thoroughly after application.

Hypersensitivity Reactions

• Inform patients that Tolak Cream contains peanut oil and that hypersensitivity reactions may occur with its use.
• Inform patients to discontinue Tolak Cream immediately and seek medical attention if signs of severe hypersensitivity occur [see Warnings and Precautions (5.2)].

Ophthalmic Adverse Reactions

• Inform patients that ophthalmic adverse reactions can occur with Tolak Cream use.
• Advise patients that Tolak Cream is not for ophthalmic use.
• Advise patients to avoid application around the eyes.
• If accidental exposure occurs, advise patients to flush eye(s) with large amounts of water and seek medical care [see Warnings and Precautions (5.3)].

Increased Sensitivity to UV Light

• Inform patients that topical fluorouracil is associated with photosensitivity reactions including severe sunburn.
• Advise patients to minimize exposure to sun, sun lamps, and tanning beds while using Tolak Cream.
• Advise patients that sunscreens may be applied after Tolak Cream application [see Warnings and Precautions (5.4)].

Embryofetal Toxicity

• Inform females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during and for one month after the last dose of Tolak Cream and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5)].

Systemic Toxicity in Patients with DPD deficiency

• Advise patient to stop using Tolak immediately and contact physician if abdominal (stomach) pain, bloody diarrhea, vomiting, fever, and/or chills occur with Tolak Cream use.
• Inform patient that these symptoms could be manifestations of a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) [see Warnings and Precautions (5.6)].

Distributed by:
Pierre Fabre Pharmaceuticals, Inc.
Parsippany, NJ 07054 USA