Fluorouracil Cream, 0.5%

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 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.

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.