profound dpd enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil. applications to mucous membranes should be avoided due to the possibility of local inflammation and ulceration.

ment. 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 7 (8.2) 6 (6.9) 12 (14.1) 25 (9.7) 15 (11.8) headache 3 (3.5) 2 (2.3) 3 (3.5) 8 (3.1) 3 (2.4) common cold 4 (4.7) 0 2 (2.4) 6 (2.3) 3 (2.4) allergy 0 2 (2.3) 1 (1.2) 3 (1.2) 2 (1.6) infection upper 0 0 0 0 2 (1.6) respiratory musculoskeletal 1 (1.2) 1 (1.1) 1 (1.2) 3 (1.2) 5 (3.9) muscle soreness 0 0 0 0 2 (1.6) respiratory 5 (5.9) 0 1 (1.2) 6 (2.3) 6 (4.7) sinusitis 4 (4.7) 0 0 4 (1.6) 2 (1.6) skin & appendages 78 (91.8) 83 (95.4) 82 (96.5) 243 (94.6) 85 (66.9) application site 78 (91.8) 83 (95.4) 82 (96.5) 243 (94.6) 83 (65.4) reaction irritation skin 1 (1.2) 0 2 (2.4) 3 (1.2) 0 special senses 6 (7.1) 4 (4.6) 6 (7.1) 16 (6.2) 6 (4.7) eye irritation 5 (5.9) 3 (3.4) 6 (7.1) 14 (5.4) 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 reactions, contact mylan at 1-877-446-3679 (1-877-4-info-rx) or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

0 treated with efudex ® 5% cream. patients were treated for a maximum of 28 days with fluorouracil cream, 0.5%, 1 g once daily in the morning; or efudex ® 5% cream, 1 g twice daily, in the morning and evening. steady-state plasma concentrations and the amounts of fluorouracil in urine resulting from the topical application of either product were measured. three patients who received fluorouracil cream, 0.5% and nine patients who received efudex ® 5% cream had measurable plasma fluorouracil levels; however, only one patient receiving fluorouracil cream, 0.5% and six patients receiving efudex ® 5% cream had a sufficient number of data points to calculate mean pharmacokinetic parameters. plasma pharmacokinetic summary pk parameter fluorouracil cream, 0.5% n=1 efudex ® (mean ± sd) n=6 c max 0.77 ng/ml 11.49 ± 8.24 ng/ml t max 1.00 hr 1.03 ± 0.028 hr auc (0–24) 2.80 ng∙hr/ml 22.39 ± 7.89 ng∙hr/ml five of 10 patients receiving fluorouracil cream, 0.5% and nine of 10 patients receiving efudex ® 5% cream had measurable urine fluorouracil levels. urine pharmacokinetic summary pk parameter fluorouracil cream, 0.5% (mean ± sd) (range) n=10 efudex ® (mean ± sd) (range) n=10 cum ae cumulative urinary excretion 2.74 ± 5.22 mcg 119.83 ± 94.80 mcg (min-max) (0-15.02) (0-329.87) max excretion rate 0.19 ± 0.52 mcg/hr 40.27 ± 47.14 mcg/hr (min-max) (0-1.67) (0-164.5) both fluorouracil cream, 0.5% and efudex ® 5% cream demonstrated low measurable plasma concentrations for fluorouracil when administered under steady-state conditions. cumulative urinary excretion of fluorouracil was low for fluorouracil cream, 0.5% and for efudex ® , corresponding to 0.055% and 0.24% of the applied doses, respectively. clinical trials under the experimental conditions of the topical safety studies, fluorouracil cream 0.5% was not observed to cause contact sensitization. however, approximately 95% of subjects in the active arms of the phase 3 clinical studies experienced facial irritation. irritation is likely and sensitization is unlikely based on the results of the topical safety and phase 3 studies. two phase 3 identically designed, multicenter, vehicle-controlled, double-blind studies were conducted to evaluate the clinical safety and efficacy of fluorouracil cream, 0.5%. patients with five or more actinic keratoses (aks) on the face or anterior bald scalp were randomly allocated to active or vehicle treatment in a 2:1 ratio. patients were randomly allocated to treatment durations of 1, 2, or 4 weeks in a 1:1:1 ratio. they applied the study cream once daily to the entire face/anterior bald scalp. each patient's clinical response was evaluated 4 weeks after the patient's last scheduled application of study cream. no additional post-treatment follow-up efficacy or safety assessments were performed beyond 4 weeks after the last scheduled application. the following graphs show the percentage of patients in whom 100% of treated lesions cleared, and the percentage of patients in whom 75% or more of treated lesions cleared. treatment with fluorouracil cream, 0.5% for 1, 2, or 4 weeks is compared to treatment with vehicle cream. outcomes from 1, 2, and 4 weeks of treatment with vehicle cream are pooled because duration of treatment with vehicle had no substantive effect on clearance. results from the two phase 3 studies are shown separately. although all treatment regimens of fluorouracil cream, 0.5% studied demonstrated efficacy over vehicle for the treatment of actinic keratosis, continuing treatment up to 4 weeks as tolerated results in further lesion reduction and clearing. clinical efficacy and safety in the treatment of aks on the ears and other sun-exposed areas were not evaluated in the studies. percentage of subjects with 100% clearance percentage of subjects with 75% clearance

ream, 0.5% n=1 efudex ® (mean ± sd) n=6 c max 0.77 ng/ml 11.49 ± 8.24 ng/ml t max 1.00 hr 1.03 ± 0.028 hr auc (0–24) 2.80 ng∙hr/ml 22.39 ± 7.89 ng∙hr/ml five of 10 patients receiving fluorouracil cream, 0.5% and nine of 10 patients receiving efudex ® 5% cream had measurable urine fluorouracil levels. urine pharmacokinetic summary pk parameter fluorouracil cream, 0.5% (mean ± sd) (range) n=10 efudex ® (mean ± sd) (range) n=10 cum ae cumulative urinary excretion 2.74 ± 5.22 mcg 119.83 ± 94.80 mcg (min-max) (0-15.02) (0-329.87) max excretion rate 0.19 ± 0.52 mcg/hr 40.27 ± 47.14 mcg/hr (min-max) (0-1.67) (0-164.5) both fluorouracil cream, 0.5% and efudex ® 5% cream demonstrated low measurable plasma concentrations for fluorouracil when administered under steady-state conditions. cumulative urinary excretion of fluorouracil was low for fluorouracil cream, 0.5% and for efudex ® , corresponding to 0.055% and 0.24% of the applied doses, respectively.

positive in in vivo micronucleus assays in rats and mice following intraperitoneal administration. some patients receiving cumulative doses of 0.24 to 1.0 g of fluorouracil parenterally have shown an increase in numerical and structural chromosome aberrations in peripheral blood lymphocytes. fluorouracil has been shown to impair fertility after parenteral administration in rats. fluorouracil administered at intraperitoneal doses of 125 and 250 mg/kg has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats. in mice, single-dose intravenous and intraperitoneal injections of fluorouracil have been reported to kill differentiated spermatogonia and spermatocytes at a dose of 500 mg/kg and produce abnormalities in spermatids at 50 mg/kg.

sightly during and after therapy. 9. if you develop abdominal pain, bloody diarrhea, vomiting, fever, or chills while on fluorouracil cream, 0.5% therapy, stop the medication and contact your physician and/or pharmacist. 10. report any side effects to the physician and/or pharmacist.

cil, can cause serious side effects in patients who are dpd enzyme deficient. if you have dpd enzyme deficiency and use medications containing fluorouracil, you may develop serious side effects such as stomach pain, bloody diarrhea, vomiting, fever, or chills. • if you are allergic to the ingredients in fluorouracil cream, 0.5%. ask your doctor or pharmacist about the inactive ingredients. • if you are under 18 years of age. fluorouracil cream, 0.5% should not be used in children. tell your doctor if you are able to become pregnant. your doctor may advise you about birth control to avoid pregnancy. how should i use fluorouracil cream, 0.5%? use fluorouracil cream, 0.5% once a day as instructed by your doctor. use it only on your skin. you should use fluorouracil cream, 0.5% for up to 4 weeks. 1. clean the area where you will apply fluorouracil cream, 0.5%. rinse well and dry the area with a towel and wait 10 minutes before applying fluorouracil cream, 0.5%. 2. put fluorouracil cream, 0.5% on your face as directed by your physician, using your fingertips. use enough to cover the affected skin. 3. avoid contact with your eyes, nostrils, and mouth. 4. wash your hands as soon as you finish putting fluorouracil cream, 0.5% on your skin. 5. a moisturizer/sunscreen may be applied 2 hours after fluorouracil cream, 0.5% has been applied. do not use any other skin products, including creams, lotions, medications, or cosmetics - unless instructed by your doctor. what should i avoid while using fluorouracil cream, 0.5%? avoid sunlight or other ultraviolet light (such as tanning booths) as much as possible while using fluorouracil cream, 0.5%. sunlight may increase your side effects. when exposed to sunlight, wear a hat and use sunscreen. do not cover the treated skin with a dressing. do not breast feed or become pregnant while using fluorouracil cream, 0.5%. if you do become pregnant, stop using fluorouracil cream, 0.5% and tell your doctor right away. what are the possible side effects of fluorouracil cream, 0.5%? most patients using fluorouracil cream, 0.5% get skin reactions where the medicine is used. these reactions include redness, dryness, burning, pain, erosion (loss of the upper layer of skin), and swelling. irritation may continue for 2 or more weeks after treatment is over. the treated area may become unsightly during therapy. some patients get eye irritation. eye irritation might consist of burning, sensitivity, itching, stinging, and watering. if you are concerned about side effects, talk to your doctor. a few patients have reported side effects such as stomach pain, diarrhea, vomiting, fever, or chills, possibly due to the lack of a specific enzyme, dpd, in their body. if you experience any of these symptoms, discontinue therapy immediately, and contact your doctor. storage information keep this medicine at room temperature 68° to 77° f (20° to 25°c). throw away unused medicine. keep this medicine out of reach of children. general advice about prescription medicines medicines are sometimes prescribed for conditions that are not described in patient information leaflets. do not use fluorouracil cream, 0.5% for a condition for which it was not prescribed. this medicine is for your use only. never give it to other people. it may harm them even if their skin problem appears to be the same as yours. do not use fluorouracil cream, 0.5% after the expiration date on the tube. manufactured for: mylan pharmaceuticals inc. morgantown, wv 26505 u.s.a. manufactured by: valeant pharmaceuticals international, inc. laval, quebec h7l 4a8, canada u.s. patent number 6,670,335 revised: 1/2019 val:pl:fluorcr:r2