Fluorouracil Cream, 0.5%

Description

DESCRIPTION Fluorouracil cream, 0.5%, contains fluorouracil for topical dermatologic use. Chemically, fluorouracil is 5-fluoro-2,4(1H, 3H)-pyrimidinedione. The molecular formula is C 4 H 3 FN 2 O 2 . Fluorouracil has a molecular weight of 130.08. Fluorouracil cream contains 0.5% fluorouracil, with 0.35% being incorporated into a patented porous microsphere (Microsponge ® ) composed of methyl methacrylate/glycol dimethacrylate crosspolymer and dimethicone. The cream formulation contains the following other inactive ingredients: Carbomer Homopolymer Type C, glycerin, methyl gluceth-20, methylparaben, octyl hydroxy stearate, polyethylene glycol 400, polysorbate 80, propylene glycol, propylparaben, purified water, sorbitan monooleate, stearic acid, and trolamine. chemical-structure

What Is Fluorouracil Cream, 0.5% Used For?

INDICATIONS AND USAGE Fluorouracil cream, 0.5% is indicated for the topical treatment of multiple actinic or solar keratoses of the face and anterior scalp.

Dosage and Administration

DOSAGE AND ADMINISTRATION Fluorouracil cream, 0.5% should be applied once a day to the skin where actinic keratosis lesions appear, using enough to cover the entire area with a thin film. Fluorouracil cream, 0.5% should not be applied near the eyes, nostrils, or mouth. Fluorouracil cream, 0.5% should be applied 10 minutes after thoroughly washing, rinsing, and drying the entire area. Fluorouracil cream, 0.5% may be applied using the fingertips. Immediately after application, the hands should be thoroughly washed. Fluorouracil cream, 0.5% should be applied up to 4 weeks as tolerated. Continued treatment up to 4 weeks results in greater lesion reduction. Local irritation is not markedly increased by extending treatment from 2 to 4 weeks, and is generally resolved within 2 weeks of cessation of treatment.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS The following were adverse events considered to be drug related and occurring with a frequency of 1% with fluorouracil cream, 0.5%: application site reaction (94.6%), and eye irritation (5.4%). The signs and symptoms of facial irritation (i.e., application site reaction) are presented below. Summary of Facial Irritation Signs and Symptoms - Pooled Phase 3 Studies Clinical Sign or Symptom Active 1 Week N=85 Active 2 Week N=87 Active 4 Week N=85 ALL Active Treatments N=257 Vehicle Treatments N=127 n (%) n (%) n (%) n (%) n (%) Erythema 76 (89.4) 82 (94.3) 82 (96.5) 240 (93.4) 76 (59.8) Dryness 59 (69.4) 76 (87.4) 79 (92.9) 214 (83.3) 60 (47.2) Burning 51 (60.0) 70 (80.5) 71 (83.5) 192 (74.7) 28 (22.0) Erosion 21 (24.7) 38 (43.7) 54 (63.5) 113 (44.0) 17 (13.4) Pain 26 (30.6) 34 (39.1) 52 (61.2) 112 (43.6) 7 (5.5) Edema 12 (14.1) 28 (32.2) 51 (60.0) 91 (35.4) 6 (4.7) During clinical trials, irritation generally began on Day 4 and persisted for the remainder of treatment. Severity of facial irritation at the last treatment visit was slightly below baseline for the vehicle group, mild to moderate for the 1-week active treatment group, and moderate for the 2- and 4-week active treatment groups. Mean severity declined rapidly for each active group after completion of treatment and was below baseline for each group at the Week 2 post-treatment follow-up visit. Thirty-one patients (12% of those treated with fluorouracil cream, 0.5% in the Phase 3 clinical studies) discontinued study treatment early due to facial irritation. Except for three patients, discontinuation of treatment occurred on or after Day 11 of treatment. Eye irritation adverse events, described as mild to moderate in intensity, were characterized as burning, watering, sensitivity, stinging, and itching. These adverse events occurred across all treatment arms in one of the two Phase 3 studies. Summary of All Adverse Events Reported in ≥ 1% of Patients in the Combined Active Treatment and Vehicle Groups – Pooled Phase 3 Studies 9721 and 9722 Combined Adverse Event Active 1 Week N=85 Active 2 Week N=87 Active 4 Week N=85 ALL Active Treatments N=257 Vehicle Treatments N=127 n (%) n (%) n (%) n (%) n (%) BODY AS A WHOLE Headache Allergy Infection Upper Respiratory 7 (8.2) 3 (3.5) 4 (4.7) 0 0 6 (6.9) 2 (2.3) 0 2 (2.3) 0 12 (14.1) 3 (3.5) 2 (2.4) 1 (1.2) 0 25 (9.7) 8 (3.1) 6 (2.3) 3 (1.2) 0 15 (11.8) 3 (2.4) 3 (2.4) 2 (1.6) 2 (1.6) MUSCULOSKELETAL Muscle Soreness 1 (1.2) 0 1 (1.1) 0 1 (1.2) 0 3 (1.2) 0 5 (3.9) 2 (1.6) RESPIRATORY Sinusitis 5 (5.9) 4 (4.7) 0 0 1 (1.2) 0 6 (2.3) 4 (1.6) 6 (4.7) 2 (1.6) SKIN & APPENDAGES Application site Reaction Irritation Skin 78 (91.8) 78 (91.8) 1 (1.2) 83 (95.4) 83 (95.4) 0 82 (96.5) 82 (96.5) 2 (2.4) 243 (94.6) 243 (94.6) 3 (1.2) 85 (66.9) 83 (65.4) 0 SPECIAL SENSES Eye Irritation 6 (7.1) 5 (5.9) 4 (4.6) 3 (3.4) 6 (7.1) 6 (7.1) 16 (6.2) 14 (5.4) 6 (4.7) 3 (2.4) Adverse Experiences Reported by Body System: In the Phase 3 studies, no serious adverse event was considered related to study drug. A total of five patients, three in the active treatment groups and two in the vehicle group, experienced at least one serious adverse event. Three patients died as a result of adverse event(s) considered unrelated to study drug (stomach cancer, myocardial infarction, and cardiac failure). Post-treatment clinical laboratory tests other than pregnancy tests were not performed during the Phase 3 clinical studies. Clinical laboratory tests were performed during conduct of a Phase 2 study of 104 patients and 21 patients in a Phase 1 study. No abnormal serum chemistry, hematology, or urinalysis results in these studies were considered clinically significant. To report SUSPECTED ADVERSE EVENTS, contact Dr. Reddy’s Laboratories Inc, at 1-888-375-3784 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Contraindications

CONTRAINDICATIONS Fluorouracil may cause fetal harm when administered to a pregnant woman. Fluorouracil is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. No adequate and well-controlled studies have been conducted in pregnant women with either topical or parenteral forms of fluorouracil. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when fluorouracil was applied to mucous membrane areas. Multiple birth defects have been reported in the fetus of a patient treated with intravenous fluorouracil. Animal reproduction studies have not been conducted with fluorouracil cream, 0.5%. Fluorouracil, the active ingredient, has been shown to be teratogenic in mice, rats, and hamsters when administered parenterally at doses greater than or equal to 10, 15, and 33 mg/kg/day, respectively, [4X, 11X and 20X, respectively, the Maximum Recommended Human Dose (MRHD) based on body surface area (BSA)]. Fluorouracil was administered during the period of organogenesis for each species. Embryolethal effects occurred in monkeys at parenteral doses greater than 40 mg/kg/day (65X the MRHD based on BSA) administered during the period of organogenesis. Fluorouracil cream, 0.5% should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities. Fluorouracil cream, 0.5% is contraindicated in patients with known hypersensitivity to any of its components.

Pregnancy and Breastfeeding

Pregnancy See CONTRAINDICATIONS.

Nursing Women It is not known whether fluorouracil is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fluorouracil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Overdosage

OVERDOSE Ordinarily, topical overdosage will not cause acute problems. If Fluorouracil cream, 0.5% is accidentally ingested, induce emesis and gastric lavage. Administer symptomatic and supportive care as needed. If contact is made with the eye, flush with copious amounts of water.

How Supplied

HOW SUPPLIED Fluorouracil Cream, 0.5%, is a white to off-white cream, supplied as follows: NDC 75907-169-11: 30 g tube Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].