Fluorouracil

INDICATIONS AND USAGE Fluorouracil 5% Topical Cream is recommended for the topical treatment of multiple actinic or solar keratoses. In the 5% strength, it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Safety and efficacy in other indications have not been established. The diagnosis should be established prior to treatment, since this method has not been proven effective in other types of basal cell carcinomas. With isolated, easily accessible basal cell carcinomas, surgery is preferred since success with such lesions is almost 100%. The success rate with Fluorouracil 5% Topical Cream is approximately 93%, based on 113 lesions in 54 patients. Twenty-five lesions treated with the solution produced 1 failure and 88 lesions treated with the cream produced 7 failures.

DOSAGE AND ADMINISTRATION When Fluorouracil 5% Topical Cream is applied to a lesion, a response occurs with the following sequence: erythema, usually followed by vesiculation, desquamation, erosion, and re-epithelialization. Fluorouracil 5% Topical Cream should be applied preferably with a nonmetal applicator or suitable glove. If Fluorouracil 5% Topical Cream is applied with the fingers, the hands should be washed immediately afterward. Actinic or Solar Keratosis Apply cream or solution twice daily in an amount sufficient to cover the lesions. Medication should be continued until the inflammatory response reaches the erosion stage, at which time use of the drug should be terminated. The usual duration of therapy is from 2 to 4 weeks. Complete healing of the lesions may not be evident for 1 to 2 months following cessation of Fluorouracil 5% Topical Cream therapy. Superficial Basal Cell Carcinomas Only the 5% strength is recommended. Apply cream or solution twice daily in an amount sufficient to cover the lesions. Treatment should be continued for at least 3 to 6 weeks. Therapy may be required for as long as 10 to 12 weeks before the lesions are obliterated. As in any neoplastic condition, the patient should be followed for a reasonable period of time to determine if a cure has been obtained.

CONTRAINDICATIONS Fluorouracil 5% Topical Cream may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women with either the topical or the parenteral forms of fluorouracil. One birth defect (cleft lip and palate) has been reported in the newborn of a patient using Fluorouracil 5% Topical Cream as recommended. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when Fluorouracil 5% Topical Cream was applied to mucous membrane areas. Multiple birth defects have been reported in a fetus of a patient treated with intravenous fluorouracil. Animal reproduction studies have not been conducted with Fluorouracil 5% Topical Cream. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats, and hamsters when given at doses equivalent to the usual human intravenous dose; however, the amount of fluorouracil absorbed systemically after topical administration to actinic keratoses is minimal (see CLINICAL PHARMACOLOGY ). Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on Day 10 or 12 of gestation. Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between Days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg/kg given to hamsters between Days 8 and 11 of gestation were teratogenic and/or embryotoxic (i.e., resulted in increased resorptions or embryolethality). In monkeys, divided doses of 40 mg/kg given between Days 20 and 24 of gestation were not teratogenic. Doses higher than 40 mg/kg resulted in abortion. Fluorouracil 5% Topical Cream 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 5% Topical Cream is contraindicated in women who are or may become pregnant during therapy. 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. Fluorouracil 5% Topical Cream is also contraindicated in patients with known hypersensitivity to any of its components.

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.

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

OVERDOSAGE There have been no reports of overdosage with Fluorouracil 5% Topical Cream. The oral LD 50 for the 5% topical cream was 234 mg/kg in rats and 39 mg/kg in dogs. These doses represented 11.7 and 1.95 mg/kg of fluorouracil, respectively. Studies with a 5% topical solution yielded an oral LD 50 of 214 mg/kg in rats and 28.5 mg/kg in dogs, corresponding to 10.7 and 1.43 mg/kg of fluorouracil, respectively. The topical application of the 5% cream to rats yielded an LD 50 of greater than 500 mg/kg.

HOW SUPPLIED Fluorouracil Cream, USP 5% is available in 40 g tubes containing 5% fluorouracil (NDC 21922-049-17) in a vanishing cream base consisting of methylparaben, polysorbate 60, propylene glycol, propylparaben, purified water, stearyl alcohol, and white petrolatum. Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202, Durham, NC 27713 USA Revised: 01/2025