Prescription Drugs

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 which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells which grow more rapidly and which take up fluorouracil at a more rapid rate. Following intravenous injection, fluorouracil distributes into tumors, intestinal mucosa, bone marrow, liver and other tissues throughout the body. In spite of its limited lipid solubility, fluorouracil diffuses readily across the blood-brain barrier and distributes into cerebrospinal fluid and brain issue. Seven to twenty percent of the parent drug is excreted unchanged in the urine in six hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. The catabolic metabolism of fluorouracil results in degradation products (e.g.,CO2, urea and α-fluoro-β-alanine) which are inactive. The inactive metabolites are excreted in the urine over the next 3 to 4 hours. When fluorouracil is labeled in the six carbon position, thus preventing the 14C metabolism to CO2, approximately 90% of the total radioactivity is excreted in the urine. When fluorouracil is labeled in the two carbon position approximately 90% of the total radioactivity is excreted in expired CO2. Ninety percent of the dose is accounted for during the first 24 hours following intravenous administration. Following intravenous administration of fluorouracil, the mean half-life of elimination from plasma is approximately 16 minutes, with a range of 8 to 20 minutes, and is dose dependent. No intact drug can be detected in the plasma 3 hours after an intravenous injection.

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 which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells which grow more rapidly and take up fluorouracil at a more rapid rate. The catabolic metabolism of fluorouracil results in degradation products (e.g., CO2, urea, α-fluoro-β-alanine) which are inactive. Systemic absorption studies of topically applied fluorouracil have been performed on patients with actinic keratoses using tracer amounts of 14C-labeled fluorouracil added to a 5% preparation. All patients had been receiving nonlabeled fluorouracil until the peak of the inflammatory reaction occurred (2 to 3 weeks), ensuring that the time of maximum absorption was used for measurement. One gram of (2 to 3 weeks), ensuring that the time of maximum absorption was used for measurement. One gram of labeled preparation was applied to the entire face and neck and left in place for 12 hours. Urine samples were collected. At the end of 3 days, the total recovery ranged between 0.48% and 0.94% with an average of 0.76%, indicating that approximately 5.98% of the topical dose was absorbed systemically.If applied twice daily, this would indicate systemic absorption of topical fluorouracil to be in the range of 5 to 6 mg per daily dose of 100 mg. In an additional study, negligible amounts of labeled material were found in plasma, urine and expired CO after 3 days of treatment with topically applied Clabeled fluorouracil.

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 Carac (fluorouracil) and 10 treated with Efudex®‡‡ 5% Cream. Patients were treated for a maximum of 28 days with Carac (fluorouracil) , 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 Carac (fluorouracil) and nine patients who received Efudex® 5% Cream had measurable plasma fluorouracil levels; however, only one patient receiving Carac (fluorouracil) and six patients receiving Efudex® 5%Cream had a sufficient number of data points to calculate mean pharmacokinetic parameters. Plasma Pharmacokinetic Summary PK Parameter Carac n=1 Efudex (Mean ± SD) n=6 Cmax 0.77 ng/mL 11.49 ± 8.24 ng/ml Tmax 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 Carac (fluorouracil) and nine of 10 patients receiving Efudex® 5% Cream had measurable urine fluorouracil levels. Urine Pharmacokinetic Summary PK Parameter Carac (fluorouracil) (Mean ± SD) (Range) n=10 Efudex (Mean ± SD) (Range) n=10 Cum Ae† (min-max) 2.74 ± 5.22 mcg (0-15.02) 119.83 ± 94.80 mcg (0-329.87) Max excretion rate (min-max) 0.19 ± 0.52 mcg/hr (0-1.67) 40.27 ± 47.14 mcg/hr (0-164.5) † Cumulative urinary excretion Both Carac (fluorouracil) 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 Carac (fluorouracil) 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, Carac (fluorouracil) 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, multi-center, vehicle-controlled, double-blind studies were conducted to evaluate the clinical safety and efficacy of Carac (fluorouracil) . Patients with 5 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 Carac (fluorouracil) cream 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 Carac (fluorouracil) 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. Percentage of Subjects with 100% Clearance Percentage of Subjects with at Least 75% Clearance Clinical efficacy and safety in the treatment of AKs on the ears and other sun-exposed areas were not evaluated in the studies.

FLUOROURACIL fluorouracil Injection USP WARNING It is recommended that Fluorouracil Injection, USP be given only by or under the supervision of a qualified physician who is experienced in cancer chemotherapy and who is well versed in the use of potent antimetabolites. Because of the possibility of severe toxic reactions, it is recommended that patients be hospitalized at least during the initial course of therapy. These instructions should be thoroughly reviewed before administration of Fluorouracil Injection, USP. DESCRIPTION Fluorouracil Injection, USP an antineoplastic antimetabolite, is a sterile, nonpyrogenic injectable solution for intravenous administration. Each mL contains 50 mg fluorouracil in water for injection USP, pH is adjusted to approximately 9.2 with sodium hydroxide. Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. It is a white to practically white crystalline powder which is sparingly soluble in water. The molecular weight of fluorouracil is 130.08 and the structural formula is: Molecular formula: C4H3FN2O2 Molecular weight:130.08

Find Lowest Prices on EFUDEX® (fluorouracil) Topical Solutions And Cream FOR TOPICAL USE ONLY - NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. DESCRIPTION Efudex Solutions and Cream are topical preparations containing the fluorinated pyrimidine 5- fluorouracil, an antineoplastic antimetabolite. Efudex Solution consists of 2% or 5% fluorouracil on a weight/weight basis, compounded with propylene glycol, tris (hydroxymethyl) aminomethane, hydroxypropyl cellulose, parabens (methyl and propyl) and disodium edetate. Efudex Cream contains 5% fluorouracil in a vanishing cream base consisting of white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, parabens (methyl and propyl), and purified water. Chemically, fluorouracil is a 5-fluoro-2,4(1H,3H)-pyrimidinedione. It is a white to practically white, crystalline powder which is sparingly soluble in water and slightly soluble in alcohol. One gram of fluorouracil is soluble in 100 mL of propylene glycol. The molecular weight of 5-fluorouracil is 130.08 and the structural formula is:

Find Lowest Prices on Carac® Cream, 0.5% (fluorouracil) Cream FOR TOPICAL DERMATOLOGICAL USE ONLY (NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE) DESCRIPTION Carac® (fluorouracil cream) Cream, 0.5% , contains fluorouracil for topical dermatologic use. Chemically, fluorouracil is 5-fluoro-2,4(1H, 3H)-pyrimidinedione. The molecular formula is C4H3FN2O2. Fluorouracil has a molecular weight of 130.08. Carac Cream contains 0.5% fluorouracil, with 0.35% being incorporated into a patented porous microsphere (Microsponge®)↑ composed of methyl methacrylate / glycol dimethacrylate cross polymer and dimethicone. The cream formulation contains the following other inactive ingredients: carbomer 940, dimethicone, glycerin, methyl gluceth-20, methyl methacrylate / glycol dimethacrylate crosspolymer, methylparaben, octyl hydroxy stearate, polyethylene glycol 400, polysorbate 80, propylene glycol, propylparaben, purified water, sorbitan monooleate, stearic acid, and trolamine.

INDICATIONS Fluorouracil Injection, USP is effective in the palliative management of carcinoma of the colon, rectum, breast, stomach and pancreas. DOSAGE AND ADMINISTRATION General Instructions Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation. No dilution is required. All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention. It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil Injection, USP. Dosage Twelve mg/kg are given intravenously once daily for four successive days. The daily dose should not exceed 800 mg. If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs. No therapy is given on the 5th, 7th, 9th or 11th days. Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent. (See WARNINGS and PRECAUTIONS.) Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS) should receive 6 mg/kg/day for three days. If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs. No therapy is given on the 4th, 6th or 8th days. The daily dose should not exceed 400 mg. A sequence of injections on either schedule constitutes a "course of therapy." Maintenance Therapy In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules: Repeat dosage of first course every 30 days after the last day of the previous course of treatment. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose. Do not exceed 1 g per week. The patient's reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly. Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months. Handling And Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Although the fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected. If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using. HOW SUPPLIED For intravenous use. Fluorouracil Injection, USP is available as follows: SINGLE DOSE VIALS NDC Fluorouracil Injection, USP Volume 16729-276-03 50 mg/mL 500 mg/10 mL vial 16729-276-05 50 mg/mL 1 g/20 mL vial 10 mL vials are packaged 10 vials per shelf pack with NDC 16729-276-68. 20 mL vials are packaged 10 vials per shelf pack with NDC 16729-276-67. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light. Retain in carton until time of use. Also available in two pharmacy bulk vials as follows: PHARMACY BULK PACKAGES NDC Fluorouracil Injection, USP Volume 16729-276-11 50 mg/mL 2.5 g/50 mL vial 16729-276-38 50 mg/mL 5 g/100 mL vial REFERENCES 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC, U.S. Government Printing Office (NIH Publication No. 83-2621). 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, Mar 15, 1985; 253:1590–1592. 3. National Study Commission on Cytotoxic Exposure: Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Director of Pharmacy Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902. 4. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Aust. Apr 30, 1983; 1:426–428. 5. Jones RB, Frank R, Mass T: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. Sept–Oct 1983; 33:258–263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. Am J Hosp Pharm. Jan 1985; 42:131–137. 7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm. 1986; 43:1193–1204. Manufactured By: Intas Pharmaceuticals Limited, Plot No.: 457, 458, Village - Matoda, Bavla Road, Ta.- Sanand, Dist. – Ahmedabad – 382 210. India. Revised: March 2014

INDICATIONS Efudex 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 Efudex Cream and Solution 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 Efudex is applied to a lesion, a response occurs with the following sequence: erythema, usually followed by vesiculation, desquamation, erosion and reepithelialization. Efudex should be applied preferably with a nonmetal applicator or suitable glove. If Efudex 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 Efudex 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. HOW SUPPLIED Efudex Solution is available in 10-mL drop dispensers containing either 2% (NDC 0187-3202-10) or 5% (NDC 0187-3203-10) fluorouracil and 25-mL drop dispensers containing either 2% (NDC 0187- 3202-02) or 5% (NDC 0187-3203-02) fluorouracil on a weight/weight basis compounded with propylene glycol, tris (hydroxymethyl) aminomethane, hydroxypropyl cellulose, parabens (methyl and propyl) and disodium edetate. Efudex Cream is available in 40 g tubes containing 5% fluorouracil (NDC 0187-3204-47) in a vanishing cream base consisting of white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, parabens (methyl and propyl), and purified water. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Manufactured for: Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 USA. by: Valeant Pharmaceuticals International Inc., Laval, QC H7L 4A8, Canada. Revised: 2016

INDICATIONS Carac (fluorouracil) is indicated for the topical treatment of multiple actinic or solar keratoses of the face and anterior scalp. DOSAGE AND ADMINISTRATION Carac (fluorouracil) cream 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. Carac (fluorouracil) cream should not be applied near the eyes, nostrils or mouth. Carac (fluorouracil) cream should be applied ten minutes after thoroughly washing, rinsing, and drying the entire area. Carac (fluorouracil) cream may be applied using the fingertips. Immediately after application, the hands should be thoroughly washed. Carac (fluorouracil) 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. HOW SUPPLIED Cream - 30 gram tube NDC 0066-7150-30 Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP]. Prescribing Information as of 2006. Keep out of the reach of children. Dermik Laboratories, a business of sanofi-aventis U.S. LLC, Bridgewater, NJ 08807. FDA rev date: 12/16/2003

PATIENT INFORMATION Patients should be informed of expected toxic effects, particularly oral manifestations. Patients should be alerted to the possibility of alopecia as a result of therapy and should be informed that it is usually a transient effect.

PATIENT INFORMATION Patients should be forewarned that the reaction in the treated areas may be unsightly during therapy and, usually, for several weeks following cessation of therapy. Patients should be instructed to avoid exposure to ultraviolet rays during and immediately following treatment with Efudex because the intensity of the reaction may be increased. If Efudex is applied with the fingers, the hands should be washed immediately afterward. Efudex should not be applied on the eyelids or directly into the eyes, nose or mouth because irritation may occur.

PATIENT INFORMATION Carac® Cream, 0.5% (fluorouracil) (fluorouracil cream) Read this leaflet carefully before you start to use your medicine. Read the information you get every time you get more medicine. There may be new information about the drug. This leaflet does not take the place of talks with your doctor. If you have any questions or are not sure about something, ask your doctor or pharmacist. What is Carac (fluorouracil) ? Carac (fluorouracil) (Care ack) is a cream used by adults to treat skin conditions on the face and front part of the scalp called solar keratosis or actinic keratosis. Who should not use Carac (fluorouracil) ? Do not use Carac (fluorouracil) if you are pregnant or might become pregnant. Carac (fluorouracil) may harm your unborn child. if you are nursing a baby. We do not know if Carac (fluorouracil) can pass to the baby through the milk. If you have dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. The active ingredient in Carac, fluorouracil, 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 Carac (fluorouracil) . Ask your doctor or pharmacist about the inactive ingredients. If under 18 years of age. Carac (fluorouracil) 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 Carac (fluorouracil) ? Use Carac (fluorouracil) once a day as instructed by your doctor. Use it only on your skin. You should use Carac (fluorouracil) for up to 4 weeks. Clean the area where you will apply Carac (fluorouracil) . Rinse well and dry the area with a towel and wait 10 minutes before applying Carac (fluorouracil) . Put Carac (fluorouracil) on your face as directed by your physician, using your fingertips. Use enough to cover the affected skin. Avoid contact with your eyes, nostrils, and mouth. Wash your hands as soon as you finish putting the Carac (fluorouracil) on your skin. A moisturizer/sunscreen may be applied 2 hours after Carac (fluorouracil) 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 Carac (fluorouracil) ? Avoid sunlight or other ultraviolet light (such as tanning booths) as much as possible while using Carac (fluorouracil) . 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 Carac (fluorouracil) . If you do become pregnant, stop using Carac (fluorouracil) and tell your doctor right away. What are the possible side effects of Carac (fluorouracil) ? Most patients using Carac (fluorouracil) 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 two 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 (68-77°F/ 20-25°C). Throw away unused medicine. Keep this medicine out of the 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 it 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 Carac (fluorouracil) after the expiration date on the tube. Prescribing Information as of November 2006.

OVERDOSE The possibility of overdosage with fluorouracil is unlikely in view of the mode of administration. Nevertheless, the anticipated manifestations would be nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). No specific antidotal therapy exists. Patients who have been exposed to an overdose of fluorouracil should be monitored hematologically for at least four weeks. Should abnormalities appear, appropriate therapy should be utilized. The acute intravenous toxicity of fluorouracil is as follows: Species LD50 (mg/kg ±S.E.) Mouse 340 ± 17 Rat 165 ± 26 Rabbit 27 ± 5.1 Dog 31.5 ± 3.8 CONTRAINDICATIONS Fluorouracil Injection, USP therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function, those with potentially serious infections or those with a known hypersensitivity to Fluorouracil Injection, USP.

OVERDOSE There have been no reports of overdosage with Efudex. The oral LD50 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 LD50 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 LD50 of greater than 500 mg/kg. CONTRAINDICATIONS Efudex 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 Efudex as recommended. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when Efudex 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 Efudex. 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. Efudex 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. Efudex 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. Efudex is also contraindicated in patients with known hypersensitivity to any of its components.

OVERDOSE Ordinarily, topical overdosage will not cause acute problems. If Carac (fluorouracil) 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. 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 Carac. 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. Carac (fluorouracil) should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD). DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities. Carac (fluorouracil) is contraindicated in patients with known hypersensitivity to any of its components.

SIDE EFFECTS Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea, anorexia, nausea and emesis are commonly seen during therapy. Leukopenia usually follows every course of adequate therapy with fluorouracil. The lowest white blood cell counts are commonly observed between the 9th and 14th days after the first course of treatment, although uncommonly the maximal depression may be delayed for as long as 20 days. By the 30th day the count has usually returned to the normal range. Alopecia and dermatitis may be seen in a substantial number of cases. The dermatitis most often seen is a pruritic maculopapular rash usually appearing on the extremities and less frequently on the trunk. It is generally reversible and usually responsive to symptomatic treatment. Other adverse reactions are: Hematologic: pancytopenia, thrombocytopenia, agranulocytosis, anemia. Cardiovascular: myocardial ischemia, angina. Gastrointestinal: gastrointestinal ulceration and bleeding. Allergic Reactions: anaphylaxis and generalized allergic reactions. Neurologic: acute cerebellar syndrome (which may persist following discontinuance of treatment), nystagmus, headache. Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased pigmentation of the skin; vein pigmentation; palmar-plantar erythrodysesthesia syndrome, as manifested by tingling of the hands and feet followed by pain, erythema and swelling. Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia. Psychiatric: disorientation, confusion, euphoria. Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails). DRUG INTERACTIONS Leucovorin calcium may enhance the toxicity of fluorouracil. Also see WARNINGS.

SIDE EFFECTS The most frequent adverse reactions to Efudex occur locally and are often related to an extension of the pharmacological activity of the drug. These include burning, crusting, allergic contact dermatitis, pruritus, scarring, rash, soreness, and ulceration. Ulcerations, other local reactions, cases of miscarriage and a birth defect (ventricular septal defect) have been reported when Efudex was applied to mucous membrane areas. Leukocytosis is the most frequent hematological side effect. Although a causal relationship is remote, other adverse reactions which have been reported infrequently are: Central Nervous System: Emotional upset, insomnia, irritability. Gastrointestinal: Medicinal taste, stomatitis. Hematological: Eosinophilia, thrombocytopenia, toxic granulation. Integumentary: Alopecia, blistering, bullous pemphigoid, discomfort, ichthyosis, scaling, suppuration, swelling, telangiectasia, tenderness, urticaria, skin rash. Special Senses: Conjunctival reaction, corneal reaction, lacrimation, nasal irritation. Miscellaneous: Herpes simplex. To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 and/or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS No information provided.

SIDE EFFECTS The following were adverse events considered to be drug-related and occurring with a frequency of ≥ 1% with Carac (fluorouracil) : application site reaction (94.6%), and eye irritation (5.4%). The signs and symptoms of facial irritation (application site reaction) are presented below. Summary of Facial Irritation Signs and Symptoms - Pooled Phase 3 Studies Clinical Sign or Symptom Active One Week Active Two Week Active Four Week ALL Active Treatments Vehicle Treatments N=85 N=87 N=85 N=257 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 Carac (fluorouracil) 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 One Week Active Two Week Active Four Week ALL Active Treatments Vehicle Treatments N=85 N=87 N=85 N=257 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 Respiratory 0 0 0 0 2 (1.6) 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. DRUG INTERACTIONS No information provided.

WARNINGS (see BOX WARNING) THE DAILY DOSE OF FLUOROURACIL INJECTION, USP IS NOT TO EXCEED 800 MG. IT IS RECOMMENDED THAT PATIENTS BE HOSPITALIZED DURING THEIR FIRST COURSE OF TREATMENT. Fluorouracil Injection, USP should be used with extreme caution in poor risk patients with a history of high-dose pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal function. Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase activity. A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with worse morbidity. Absence of this catabolic enzyme appears to result in prolonged clearance of 5-fluorouracil. Pregnancy Teratogenic Effects Pregnancy Category D Fluorouracil may cause fetal harm when administered to a pregnant woman. Fluorouracil has been shown to be teratogenic in laboratory animals. 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 given to hamsters between days 8 and 11 of gestation were teratogenic. Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails. The dosages which were teratogenic in animals are 1 to 3 times the maximum recommended human therapeutic dose. In monkeys, divided doses of 40 mg/kg given between days 20 and 24 of gestation were not teratogenic. There are no adequate and well-controlled studies with fluorouracil in pregnant women. While there is no evidence of teratogenicity in humans due to fluorouracil, it should be kept in mind that other drugs which inhibit DNA synthesis (e.g., methotrexate and aminopterin) have been reported to be teratogenic in humans. Women of childbearing potential should be advised to avoid becoming pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be told of the potential hazard to the fetus. Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Combination Therapy Any form of therapy which adds to the stress of the patient, interferes with nutrition or depresses bone marrow function will increase the toxicity of fluorouracil. PRECAUTIONS General Fluorouracil is a highly toxic drug with a narrow margin of safety. Therefore, patients should be carefully supervised, since therapeutic response is unlikely to occur without some evidence of toxicity. Severe hematological toxicity, gastrointestinal hemorrhage and even death may result from the use of fluorouracil despite meticulous selection of patients and careful adjustment of dosage. Although severe toxicity is more likely in poor risk patients, fatalities may be encountered occasionally even in patients in relatively good condition. Therapy is to be discontinued promptly whenever one of the following signs of toxicity appears: Stomatitis or esophagopharyngitis, at the first visible sign. Leukopenia (WBC under 3500) or a rapidly falling white blood count. Vomiting, intractable. Diarrhea, frequent bowel movements or watery stools. Gastrointestinal ulceration and bleeding. Thrombocytopenia (platelets under 100,000). Hemorrhage from any site. The administration of 5-fluorouracil has been associated with the occurrence of palmar-plantar erythrodysesthesia syndrome, also known as hand-foot syndrome. This syndrome has been characterized as a tingling sensation of hands and feet which may progress over the next few days to pain when holding objects or walking. The palms and soles became symmetrically swollen and erythematous with tenderness of the distal phalanges, possibly accompanied by desquamation. Interruption of therapy is followed by gradual resolution over 5 to 7 days. Although pyridoxine has been reported to ameliorate the palmar-plantar erythrodysesthesia syndrome, its safety and effectiveness has not been established. Laboratory Tests White blood counts with differential are recommended before each dose. Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of fluorouracil have not been conducted. However, there was no evidence of carcinogenicity in small groups of rats given fluorouracil orally at doses of 0.01, 0.3, 1 or 3 mg per rat 5 days per week for 52 weeks, followed by a six-month observation period. Also, in other studies, 33 mg/kg of fluorouracil was administered intravenously to male rats once a week for 52 weeks followed by observation for the remainder of their lifetimes with no evidence of carcinogenicity. Female mice were given 1 mg of fluorouracil intravenously once a week for 16 weeks with no effect on the incidence of lung adenomas. On the basis of the available data, no evaluation can be made of the carcinogenic risk of fluorouracil to humans. Mutagenesis Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by fluorouracil, but the relationship between oncogenicity and mutagenicity is not clear. Fluorouracil has been shown to be mutagenic to several strains of Salmonella typhimurium, including TA 1535, TA 1537 and TA 1538, and to Saccharomyces cerevisiae, although no evidence of mutagenicity was found with Salmonella typhimurium strains TA 92, TA 98 and TA 100. In addition, a positive effect was observed in the micronucleus test on bone marrow cells of the mouse, and fluorouracil at very high concentrations produced chromosomal breaks in hamster fibroblasts in vitro. Impairment Of Fertility Fluorouracil has not been adequately studied in animals to permit an evaluation of its effects on fertility and general reproductive performance. However, doses of 125 or 250 mg/kg, administered intraperitoneally, have been shown to induce chromosomal aberrations and changes in chromosomal organization of spermatogonia in rats. Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. However, in studies with a strain of mouse which is sensitive to the induction of sperm head abnormalities after exposure to a range of chemical mutagens and carcinogens, fluorouracil did not produce any abnormalities at oral doses of up to 80 mg/kg/day. In female rats, fluorouracil, administered intraperitoneally at weekly doses of 25 or 50 mg/kg for 3 weeks during the pre-ovulatory phases of oogenesis, significantly reduced the incidence of fertile matings, delayed the development of pre- and post-implantation embryos, increased the incidence of pre-implantation lethality and induced chromosomal anomalies in these embryos. In a limited study in rabbits, a single 25 mg/kg dose of fluorouracil or 5 daily doses of 5 mg/kg had no effect on ovulation, appeared not to affect implantation and had only a limited effect in producing zygote destruction. Compounds such as fluorouracil, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on gametogenesis. Pregnancy Pregnancy Category D. See WARNINGS. Nonteratogenic Effects Fluorouracil has not been studied in animals for its effects on peri- and postnatal development. However, fluorouracil has been shown to cross the placenta and enter into fetal circulation in the rat. Administration of fluorouracil has resulted in increased resorptions and embryolethality in rats. In monkeys, maternal doses higher than 40 mg/kg resulted in abortion of all embryos exposed to fluorouracil. Compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development. Nursing Mothers It is not known whether fluorouracil is excreted in human milk. Because fluorouracil inhibits DNA, RNA and protein synthesis, mothers should not nurse while receiving this drug. Pediatric Use Safety and effectiveness in children have not been established.

WARNINGS Application to mucous membranes should be avoided due to the possibility of local inflammation and ulceration. Additionally, cases of miscarriage and a birth defect (ventricular septal defect) have been reported when Efudex was applied to mucous membrane areas during pregnancy. Occlusion of the skin with resultant hydration has been shown to increase percutaneous penetration of several topical preparations. If any occlusive dressing is used in treatment of basal cell carcinoma, there may be an increase in the severity of inflammatory reactions in the adjacent normal skin. A porous gauze dressing may be applied for cosmetic reasons without increase in reaction. Exposure to ultraviolet rays should be minimized during and immediately following treatment with Efudex because the intensity of the reaction may be increased. Patients should discontinue therapy with Efudex if symptoms of DPD enzyme deficiency develop (see CONTRAINDICATIONS). Rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported with intravenous administration of fluorouracil in patients with DPD enzyme deficiency. One case of life-threatening systemic toxicity has been reported with the topical use of Efudex in a patient with DPD enzyme deficiency. 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. PRECAUTIONS General There is a possibility of increased absorption through ulcerated or inflamed skin. Laboratory Tests Solar keratoses which do not respond should be biopsied to confirm the diagnosis. Follow-up biopsies should be performed as indicated in the management of superficial basal cell carcinoma. Carcinogenesis, Mutagenesis, 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 Efudex, 5-fluorouracil, have shown positive effects in in vitro tests for mutagenicity and on impairment of fertility. 5-Fluorouracil was positive in three in vitro cell neoplastic transformation assays. In the C3H/10T½ clone 8 mouse embryo cell system, the resulting morphologically transformed cells formed tumors when inoculated into immunosuppressed syngeneic mice. While no evidence for mutagenic activity was observed in the Ames test (3 studies), fluorouracil has been shown to be mutagenic in the survival count rec-assay with Bacillus subtilis and in the Drosophila wing-hair spot test. Fluorouracil produced petite mutations in Saccharomyces cerevisiae and was positive in the micronucleus test (bone marrow cells of male mice). Fluorouracil was clastogenic in vitro (i.e., chromatid gaps, breaks and exchanges) in Chinese hamster fibroblasts at concentrations of 1.0 and 2.0 mcg/mL and has been shown to increase sister chromatid exchange in vitro in human lymphocytes. In addition, 5-fluorouracil has been reported to produce an increase in numerical and structural chromosome aberrations in peripheral lymphocytes of patients treated with this product. Doses of 125 to 250 mg/kg, administered intraperitoneally, have been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats. Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. However, in studies with a strain of mouse which is sensitive to the induction of sperm head abnormalities after exposure to a range of chemical mutagens and carcinogens, fluorouracil was inactive at oral doses of 5 to 80 mg/kg/day. In female rats, fluorouracil administered intraperitoneally at doses of 25 and 50 mg/kg during the preovulatory phase of oogenesis significantly reduced the incidence of fertile matings, delayed the development of preimplantation and postimplantation embryos, increased the incidence of preimplantation lethality and induced chromosomal anomalies in these embryos. Single dose intravenous and intraperitoneal injections of 5-fluorouracil have been reported to kill differentiated spermatogonia and spermatocytes (at 500 mg/kg) and to produce abnormalities in spermatids (at 50 mg/kg) in mice. Pregnancy See CONTRAINDICATIONS. Nursing Mothers It is not known whether Efudex is excreted in human milk. Because there is some systemic absorption of fluorouracil after topical administration (see CLINICAL PHARMACOLOGY), because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue use of the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established.

WARNINGS The potential for a delayed hypersensitivity reaction to fluorouracil exists. Patch testing to prove hypersensitivity may be inconclusive. Patients should discontinue therapy with Carac (fluorouracil) if symptoms of DPD enzyme deficiency develop. Rarely, unexpected, systemic toxicity (e.g. stomatitis, diarrhea, neutropenia, and 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. PRECAUTIONS General There is a possibility of increased absorption through ulcerated or inflamed skin. Information for the Patient Patients using Carac (fluorouracil) should receive the following information and instructions: This medication is to be used as directed. This medication should not be used for any disorder other than that for which it was prescribed. It is for external use only. Avoid contact with the eyes, eyelids, nostrils, and mouth. Cleanse affected area and wait 10 minutes before applying Carac (fluorouracil) . Wash hands immediately after applying Carac (fluorouracil) . Avoid prolonged exposure to sunlight or other forms of ultraviolet irradiation during treatment, as the intensity of the reaction may be increased. Most patients using Carac (fluorouracil) 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. If you develop abdominal pain, bloody diarrhea, vomiting, fever, or chills while on Carac (fluorouracil) therapy, stop the medication and contact your physician and/or pharmacist. 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 Carac, 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 vitroassay 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. Carac (fluorouracil) should not be used in children. The safety and effectiveness of Carac (fluorouracil) 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 Teratogenic Effects: Pregnancy Category X: 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.