warnings and cautions
5 WARNINGS AND PRECAUTIONS Application site adverse reactions are likely to occur during and for 4 weeks after treatment of actinic keratosis with Tolak Cream ( 5.1 ). Hypersensitivity reactions may occur with Tolak Cream ( 5.2 ). Avoid treatment in the periocular area. Eye disorders, including corneal reactions have occurred with topical fluorouracil use. Avoid accidental transfer of the drug into eyes and to the periocular area. If accidental exposure occurs, seek medical care ( 5.3 ). Increased sensitivity to ultraviolet light may occur during and immediately after treatment with Tolak Cream ( 5.4 ). Fluorouracil may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception ( 5.5 ). Increased fluorouracil exposures may occur in DPD deficiency. Discontinue Tolak Cream if symptoms of fluorouracil's systemic toxicity develop ( 5.6 ). 5.1 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. 5.2 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. 5.3 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. 5.4 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. 5.5 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 . 5.6 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.