Fluorouracil Cream

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 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.

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.

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. Fluorouracil Structural Formula

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.

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.

WARNINGS The potential for a delayed hypersensitivity reaction to fluorouracil exists. Patch testing to prove hypersensitivity may be inconclusive. Patients should discontinue therapy with fluorouracil cream, 0.5% if symptoms of DPD enzyme deficiency develop. Rarely, unexpected systemic toxicity (e.g., stomatitis, diarrhea, neutropenia, neurotoxicity) associated with parenteral administration of fluorouracil has been attributed to deficiency of dihydropyrimidine dehydrogenase "DPD" activity. One case of life-threatening systemic toxicity has been reported with the topical use of 5% fluorouracil in a patient with a complete absence of DPD enzyme activity. 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. Although this case was observed with 5% fluorouracil cream, it is unknown whether patients with 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.

OVERDOSAGE 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.

CLINICAL PHARMACOLOGY There is evidence that the metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner, fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA). Since DNA and RNA are essential for cell division and growth, the effect of fluorouracil may be to create a thymine deficiency that provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells that grow more rapidly and take up fluorouracil at a more rapid rate. The contribution to efficacy or safety of individual components of the vehicle has not been established. Pharmacokinetics A multiple-dose, randomized, open-label, parallel study was performed in 21 patients with actinic keratoses. Twenty patients had pharmacokinetic samples collected: 10 patients treated with fluorouracil cream, 0.5% and 10 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

Pharmacokinetics A multiple-dose, randomized, open-label, parallel study was performed in 21 patients with actinic keratoses. Twenty patients had pharmacokinetic samples collected: 10 patients treated with fluorouracil cream, 0.5% and 10 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.

20190115

5

Fluorouracil Cream fluorouracil FLUOROURACIL FLUOROURACIL METHYL METHACRYLATE/GLYCOL DIMETHACRYLATE CROSSPOLYMER DIMETHICONE CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) GLYCERIN METHYL GLUCETH-20 METHYLPARABEN ETHYLHEXYL HYDROXYSTEARATE POLYETHYLENE GLYCOL 400 POLYSORBATE 80 PROPYLENE GLYCOL PROPYLPARABEN SORBITAN MONOOLEATE STEARIC ACID TROLAMINE

Carcinogenesis, Mutagenesis, and Impairment of Fertility Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with fluorouracil. Studies with the active ingredient of fluorouracil cream, 0.5%, fluorouracil, have shown positive effects in in vitro and in vivo tests for mutagenicity and on impairment of fertility in in vivo animal studies. Fluorouracil produced morphological transformation of cells in in vitro cell transformation assays. Morphological transformation was also produced in an in vitro assay by a metabolite of fluorouracil, and the transformed cells produced malignant tumors when injected into immunosuppressed syngeneic mice. Fluorouracil has been shown to exert mutagenic activity in yeast cells, Bacillus subtilis , and Drosophila assays. In addition, fluorouracil has produced chromosome damage at concentrations of 1.0 and 2.0 mcg/mL in an in vitro hamster fibroblast assay, was positive in a microwell mouse lymphoma assay, and was 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.

NDA020985

Fluorouracil Cream

fluorouracil

0378-8078

HUMAN PRESCRIPTION DRUG

TOPICAL

Laboratory Tests To rule out the presence of a frank neoplasm, a biopsy may be considered for those areas failing to respond to treatment or recurring after treatment.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 0.5% NDC 0378-8078-49 Rx only Fluorouracil Cream 0.5% FOR TOPICAL USE ONLY Net Wt. 30 g Each gram 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. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Usual Dosage: APPLY ONCE A DAY. For complete product information, see package insert. For topical use only. Not for ophthalmic, oral, or intravaginal use. Keep out of reach of children. Keep tightly closed. U.S. Patent Number 6,670,335 Microsponge is a registered trademark of Amcol International Corporation. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A Manufactured by: Valeant Pharmaceuticals International, Inc. Laval, Quebec H7L 4A8, Canada Product of Canada Mylan.com VAL:8078:49:1C:R2 9645401 Fluorouracil Cream 0.5% Carton Label

Information for Patients Patients using fluorouracil cream, 0.5% should receive the following information and instructions: 1. This medication is to be used as directed. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. It is for topical use only. 4. Avoid contact with the eyes, eyelids, nostrils, and mouth. 5. Cleanse affected area and wait 10 minutes before applying fluorouracil cream, 0.5%. 6. Wash hands immediately after applying fluorouracil cream, 0.5%. 7. Avoid prolonged exposure to sunlight or other forms of ultraviolet irradiation during treatment, as the intensity of the reaction may be increased. 8. 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 at the application site may persist for two or more weeks after therapy is discontinued. Treated areas may be unsightly 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.

Geriatric Use No significant differences in safety and efficacy measures were demonstrated in patients age 65 and older compared to all other patients.

Nursing Mothers 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.

Pediatric Use Actinic keratosis is not a condition seen within the pediatric population, except in association with rare genetic diseases. Fluorouracil cream, 0.5% should not be used in children. The safety and effectiveness of fluorouracil cream, 0.5% have not been established in patients less than 18 years old.

Pregnancy See CONTRAINDICATIONS

HOW SUPPLIED NDC 0378-8078-49 30 g tube Store at 20° to 25° C (68° to 77° F) [see USP Controlled Room Temperature]. Keep out of reach of children. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured by: Valeant Pharmaceuticals International, Inc. Laval, Quebec H7L 4A8, Canada Microsponge is a registered trademark of Amcol International Corporation. Efudex is a registered trademark of Valeant Pharmaceuticals North America LLC. All other trademarks are the trademarks or the registered trademarks of their respective owners. U.S. Patent Number 6,670,335 Revised: 1/2019 VAL:FLUORCR:R2

General There is a possibility of increased absorption through ulcerated or inflamed skin.

PRECAUTIONS General There is a possibility of increased absorption through ulcerated or inflamed skin. Information for Patients Patients using fluorouracil cream, 0.5% should receive the following information and instructions: 1. This medication is to be used as directed. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. It is for topical use only. 4. Avoid contact with the eyes, eyelids, nostrils, and mouth. 5. Cleanse affected area and wait 10 minutes before applying fluorouracil cream, 0.5%. 6. Wash hands immediately after applying fluorouracil cream, 0.5%. 7. Avoid prolonged exposure to sunlight or other forms of ultraviolet irradiation during treatment, as the intensity of the reaction may be increased. 8. 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 at the application site may persist for two or more weeks after therapy is discontinued. Treated areas may be unsightly 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. Laboratory Tests To rule out the presence of a frank neoplasm, a biopsy may be considered for those areas failing to respond to treatment or recurring after treatment. Carcinogenesis, Mutagenesis, and Impairment of Fertility Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with fluorouracil. Studies with the active ingredient of fluorouracil cream, 0.5%, fluorouracil, have shown positive effects in in vitro and in vivo tests for mutagenicity and on impairment of fertility in in vivo animal studies. Fluorouracil produced morphological transformation of cells in in vitro cell transformation assays. Morphological transformation was also produced in an in vitro assay by a metabolite of fluorouracil, and the transformed cells produced malignant tumors when injected into immunosuppressed syngeneic mice. Fluorouracil has been shown to exert mutagenic activity in yeast cells, Bacillus subtilis , and Drosophila assays. In addition, fluorouracil has produced chromosome damage at concentrations of 1.0 and 2.0 mcg/mL in an in vitro hamster fibroblast assay, was positive in a microwell mouse lymphoma assay, and was 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. Pediatric Use Actinic keratosis is not a condition seen within the pediatric population, except in association with rare genetic diseases. Fluorouracil cream, 0.5% should not be used in children. The safety and effectiveness of fluorouracil cream, 0.5% have not been established in patients less than 18 years old. Geriatric Use No significant differences in safety and efficacy measures were demonstrated in patients age 65 and older compared to all other patients. Pregnancy See CONTRAINDICATIONS Nursing Mothers 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.