TOLAK

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Application Site Adverse Reactions [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Ophthalmic Adverse Reactions [see Warnings and Precautions (5.3) ] Photosensitivity [see Warnings and Precautions (5.4) ] Embryofetal toxicity [see Warnings and Precautions (5.5) ] Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency [see Warnings and Precautions (5.6) ] The most common (incidence > 68%) adverse reactions occur at the application site and include erythema, scaling/dryness, crusting, pruritus, stinging/burning, edema, and erosions. Erythema is observed in 99% of patients with actinic keratosis treated with Tolak Cream ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hill Dermaceuticals at 1-800-344-5707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Tolak Cream in 397 subjects with actinic keratosis in vehicle-controlled trials. The population ranged in age from 33 to 94 years, was 80% male, and almost all were Caucasian. Most subjects were treated with Tolak Cream once daily for 4 weeks. Throughout the 4-week treatment and the 4-week post-treatment periods, the trials specifically monitored for adverse reactions related to tolerability, including erythema, scaling/dryness, edema, crusting, erosions, stinging/burning, and pruritus. The number and percentage of subjects with each of these monitored adverse reactions at one or more post-baseline visit(s) during the clinical trials are shown in Table 1. Table 1: Incidence of Application Site Adverse Reactions Occurring with 4 Weeks of Tolak Cream Treatment in Clinical Trials 1 and 2 Tolak Cream N=397 n (%) Vehicle N=120 n (%) Mild, Moderate or Severe Severe Only Mild, Moderate or Severe Severe Only Erythema 394 (99%) 174 (44%) 102 (85%) 0 (0%) Scaling/ Dryness 377 (95%) 94 (24%) 99 (83%) 0 (0%) Crusting 346 (87%) 87 (22%) 46 (38%) 0 (0%) Pruritus 337 (85%) 65 (16%) 46 (38%) 1 (1%) Stinging/ Burning 346 (87%) 101 (25%) 42 (35%) 0 (0%) Edema 275 (69%) 30 (8%) 11 (9%) 0 (0%) Erosions 271 (68%) 44 (11%) 14 (12%) 0 (0%) In these clinical trials, the intensity of the adverse reactions in subjects using Tolak Cream generally increased over the 4-week treatment period, usually reaching maximal levels at 4 weeks of treatment and then diminishing to baseline levels within 4 weeks after cessation of treatment. In Trials 1 and 2, 11% of Tolak Cream-treated and 3% of vehicle-treated subjects discontinued treatment because of adverse reactions. Of these subjects, the majority had adverse reactions at the application site. Eye swelling, leading to discontinuation, occurred in one subject with Tolak Cream use . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topical fluorouracil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : leukocytosis, pancytopenia, thrombocytopenia, eosinophilia, neutrophil toxic granulation Eye disorders : corneal disorder, conjunctival disorder, eye irritation, conjunctivitis, lacrimation Gastrointestinal disorders : stomatitis General Disorders and Administration Site Conditions : medicinal taste Infections and Infestations : herpes simplex Neoplasms : chronic lymphocytic leukemia, non-melanoma skin cancer Nervous system disorders : insomnia, irritability Psychiatric disorders : emotional distress Skin and subcutaneous tissue disorders : blistering, allergic contact dermatitis, photosensitivity, pain, scarring, skin irritation, rash, ulceration, hyperpigmentation, alopecia, bullous pemphigoid, ichthyosis, suppuration, swelling, soreness, telangiectasia, tenderness, urticaria

4 CONTRAINDICATIONS Tolak Cream is contraindicated: During pregnancy [see Warnings and Precautions (5.5 , 8.1) ] In patients with dihydropyrimidine dehydrogenase (DPD) deficiency [see Warnings and Precautions (5.6) ] Pregnancy ( 4.1 , 8.1 ). Dihydropyrimidine dehydrogenase (DPD) deficiency ( 4.2 ). 4.1 Pregnancy Tolak Cream may cause fetal harm when administered during pregnancy and is contraindicated in women who are pregnant. 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. 4.2 Dihydropyrimidine Dehydrogenase Deficiency Tolak Cream is contraindicated in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

11 DESCRIPTION Tolak (fluorouracil) Cream, 4% contains 40 mg of fluorouracil per gram of white cream for topical application. It is a nucleoside metabolic inhibitor. Chemically, fluorouracil is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. The molecular formula of 5-fluorouracil is C 4 H 3 FN 2 O 2 , and its molecular weight is 130.1. Its structural formula is: Tolak Cream contains the following inactive ingredients: arlacel-165, butylated hydroxytoluene, cetyl alcohol, anhydrous citric acid, glycerin, isopropyl myristate, methyl gluceth-10, methylparaben, propylparaben, purified water, peanut oil, sodium hydroxide, stearic acid, and stearyl alcohol. Tolak Cream formulation has an alkaline pH at 8.3 to 9.2. Chemical Structure

2 DOSAGE AND ADMINISTRATION Prior to application of Tolak Cream, wash, rinse, and dry the treatment areas. Apply Tolak Cream once daily in an amount sufficient to cover the lesions of the face, ears, and/or scalp with a thin film, using the fingertips to gently massage the medication uniformly into the skin. Apply Tolak Cream for a period of 4 weeks as tolerated. Thoroughly wash hands following Tolak Cream application. Tolak Cream is for topical use only. Do not apply to eyes, nose, mouth or mucous membranes. Not for ophthalmic, oral or intravaginal use. Apply Tolak Cream after washing, rinsing, and drying the treatment area(s) ( 2 ). Apply Tolak Cream once daily in an amount sufficient to cover the lesions of the face, ears, and/or scalp with a thin film, using the fingertips to gently massage the medication uniformly into the skin ( 2 ). Tolak Cream should be applied for a period of 4 weeks as tolerated ( 2 ). Wash hands thoroughly following Tolak Cream application ( 2 ). Tolak Cream is for topical use only. Do not apply to eyes, nose, mouth or mucous membranes ( 2 ). Not for ophthalmic, oral, or intravaginal use ( 2 ).

1 INDICATIONS AND USAGE Tolak (fluorouracil) Cream is indicated for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp. Tolak (fluorouracil) Cream, 4%, is a nucleoside metabolic inhibitor indicated for the topical treatment of actinic keratosis lesions of the face, ears, and scalp ( 1 ).

7 DRUG INTERACTIONS Subjects using systemic steroids, immunosuppressants, and immunomodulators were generally excluded from the clinical studies of Tolak Cream, as were subjects who used retinoids, topical steroids, glycolic acid products, alpha-hydroxy products, and chemical peeling products in the treatment areas. No clinical trials were designed to specifically evaluate drug interactions.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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 DNA and to a lesser extent inhibits the formation of 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. 12.3 Pharmacokinetics A systemic absorption study of topically applied Tolak Cream was performed in 21 patients with at least 3 actinic keratosis lesions (4 mm or greater in diameter). The steady state concentration of 5-fluorouracil in plasma was examined at 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours after the last dose of a 4-week regimen in subjects with actinic keratosis after "area application" to area(s) in which actinic keratosis lesions were identified at baseline. Areas were defined as the whole region of the left cheek, right cheek, chin and forehead, bald scalp, and right and left ears, where actinic keratosis was identified at baseline. Thus, for example, if an actinic keratosis lesion was identified on the left cheek, Tolak Cream was to be applied as a thin film to the whole area of the left cheek. Eight patients had undetectable levels of plasma 5-fluorouracil (the lower limit of quantification was 1.00 ng/ml) in all plasma samples following treatment with Tolak Cream. Among patients with detectable plasma 5-fluorouracil levels, the highest level of plasma 5-fluorouracil was generally observed at 1 hour post-dose. The mean observed maximum concentration (± standard deviation) of plasma 5-fluorouracil was 3.66 (±1.58) ng/mL with the range between 1.11 – 7.35 ng/mL. The catabolism of 5-fluorouracil results in inactive degradation products (such as CO 2 , urea, α-fluoro-β-alanine).

12.1 Mechanism of Action 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 DNA and to a lesser extent inhibits the formation of 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.

12.3 Pharmacokinetics A systemic absorption study of topically applied Tolak Cream was performed in 21 patients with at least 3 actinic keratosis lesions (4 mm or greater in diameter). The steady state concentration of 5-fluorouracil in plasma was examined at 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours after the last dose of a 4-week regimen in subjects with actinic keratosis after "area application" to area(s) in which actinic keratosis lesions were identified at baseline. Areas were defined as the whole region of the left cheek, right cheek, chin and forehead, bald scalp, and right and left ears, where actinic keratosis was identified at baseline. Thus, for example, if an actinic keratosis lesion was identified on the left cheek, Tolak Cream was to be applied as a thin film to the whole area of the left cheek. Eight patients had undetectable levels of plasma 5-fluorouracil (the lower limit of quantification was 1.00 ng/ml) in all plasma samples following treatment with Tolak Cream. Among patients with detectable plasma 5-fluorouracil levels, the highest level of plasma 5-fluorouracil was generally observed at 1 hour post-dose. The mean observed maximum concentration (± standard deviation) of plasma 5-fluorouracil was 3.66 (±1.58) ng/mL with the range between 1.11 – 7.35 ng/mL. The catabolism of 5-fluorouracil results in inactive degradation products (such as CO 2 , urea, α-fluoro-β-alanine).

20220906

6

3 DOSAGE FORMS AND STRENGTHS Cream: 40 mg of fluorouracil per gram (4%) of white cream in 40 gram tubes. Cream: 40 mg of fluorouracil per gram of cream (4%) ( 3 ).

TOLAK FLUOROURACIL FLUOROURACIL FLUOROURACIL Water Peanut Oil Isopropyl Myristate Methyl Gluceth-10 Glyceryl Monostearate Polyethylene Glycol 4500 Cetyl Alcohol Glycerin Stearyl Alcohol Stearic acid Butylated Hydroxytoluene Methylparaben Anhydrous Citric Acid Propylparaben Sodium Hydroxide

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate long-term studies in animals to evaluate carcinogenic potential of fluorouracil have not been conducted. Studies with the active ingredient of Tolak, fluorouracil, have shown mutagenic effects in in vitro and in vivo tests and impairment of fertility in in vivo animal studies. 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. Although no evidence for mutagenic activity of fluorouracil was observed in 3 studies utilizing the Ames test, mutagenic activity was observed 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 demonstrated positive results in the micronucleus test using bone marrow cells of male mice. Fluorouracil demonstrated clastogenic activity in vitro in Chinese hamster fibroblasts at concentrations of 1.0 and 2.0 µg/mL and was associated with chromatid gaps, breaks, and exchanges. In human lymphocytes, fluorouracil increased sister chromatid exchange in vitro. Additionally, an increase in numerical and structural chromosome aberrations have been observed in peripheral lymphocytes of patients treated with 5-fluorouracil. In rats, chromosomal abnormalities and changes in chromosome organization in spermatogonia have been observed after intraperitoneal administration of 125 to 250 mg/kg of fluorouracil. Spermatogonial differentiation was also inhibited and resulted in transient infertility. Fluorouracil was inactive, however, at oral doses of 5 to 80 mg/kg/day 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. In female rats, fluorouracil administered intraperitoneally at doses of 25 and 50 mg/kg during the preovulatory phase of oogenesis resulted in a significant reduction in the incidence of fertile matings, a delay in the development of preimplantation and postimplantation embryos, an increased incidence of preimplantation lethality, and an induction of chromosomal anomalies in these embryos. In mice, single intravenous or intraperitoneal injections of fluorouracil were toxic to differentiated spermatogonia and spermatocytes (at 500 mg/kg) and produced abnormalities in spermatids (at 50 mg/kg).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate long-term studies in animals to evaluate carcinogenic potential of fluorouracil have not been conducted. Studies with the active ingredient of Tolak, fluorouracil, have shown mutagenic effects in in vitro and in vivo tests and impairment of fertility in in vivo animal studies. 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. Although no evidence for mutagenic activity of fluorouracil was observed in 3 studies utilizing the Ames test, mutagenic activity was observed 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 demonstrated positive results in the micronucleus test using bone marrow cells of male mice. Fluorouracil demonstrated clastogenic activity in vitro in Chinese hamster fibroblasts at concentrations of 1.0 and 2.0 µg/mL and was associated with chromatid gaps, breaks, and exchanges. In human lymphocytes, fluorouracil increased sister chromatid exchange in vitro. Additionally, an increase in numerical and structural chromosome aberrations have been observed in peripheral lymphocytes of patients treated with 5-fluorouracil. In rats, chromosomal abnormalities and changes in chromosome organization in spermatogonia have been observed after intraperitoneal administration of 125 to 250 mg/kg of fluorouracil. Spermatogonial differentiation was also inhibited and resulted in transient infertility. Fluorouracil was inactive, however, at oral doses of 5 to 80 mg/kg/day 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. In female rats, fluorouracil administered intraperitoneally at doses of 25 and 50 mg/kg during the preovulatory phase of oogenesis resulted in a significant reduction in the incidence of fertile matings, a delay in the development of preimplantation and postimplantation embryos, an increased incidence of preimplantation lethality, and an induction of chromosomal anomalies in these embryos. In mice, single intravenous or intraperitoneal injections of fluorouracil were toxic to differentiated spermatogonia and spermatocytes (at 500 mg/kg) and produced abnormalities in spermatids (at 50 mg/kg).

NDA022259

TOLAK

FLUOROURACIL

28105-421

HUMAN PRESCRIPTION DRUG

TOPICAL

PRINCIPAL DISPLAY PANEL - 40 g Tube Carton NDC 28105-421-40 Tolak ® (fluorouracil) Cream 4% Rx only For Topical Use Only Not for Ophthalmic, Oral or Intravaginal Use Contains Peanut Oil 40 g Topical Cream Hill Dermaceuticals, Inc. ® PRINCIPAL DISPLAY PANEL - 40 g Tube Carton

Manufactured and Distributed by: Hill Dermaceuticals, Inc. Sanford, Florida 32773

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Important Administration Instructions Advise patients of the following: Tolak Cream is for external use only. Do not apply to eyes, nose, mouth or mucous membranes. Avoid inadvertent transfer of Tolak Cream to other body areas, or to another person. Keep out of the reach of children. Fluorouracil, including Tolak may be fatal if ingested by pets. Avoid allowing pets to contact the Tolak container or the skin where Tolak has been applied. Store Tolak out of reach of pets. Safely discard or clean any cloth or applicator that may retain Tolak and avoid leaving any residues of Tolak on your hands, clothing, carpeting or furniture. Instruct patients to do the following: Apply after washing, rinsing, and drying the treatment area. Wash hands thoroughly after application. Hypersensitivity Reactions Inform patients that Tolak Cream contains peanut oil and that hypersensitivity reactions may occur with its use. Inform patients to discontinue Tolak Cream immediately and seek medical attention if signs of severe hypersensitivity occur [see Warnings and Precautions (5.2) ] . Ophthalmic Adverse Reactions Inform patients that ophthalmic adverse reactions can occur with Tolak Cream use. Advise patients that Tolak Cream is not for ophthalmic use. Advise patients to avoid application around the eyes. If accidental exposure occurs, advise patients to flush eye(s) with large amounts of water and seek medical care [see Warnings and Precautions (5.3) ] . Increased Sensitivity to UV Light Inform patients that topical fluorouracil is associated with photosensitivity reactions including severe sunburn. Advise patients to minimize exposure to sun, sun lamps, and tanning beds while using Tolak Cream. Advise patients that sunscreens may be applied after Tolak Cream application [see Warnings and Precautions (5.4) ] . Embryofetal Toxicity Inform females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for one month after the last dose of Tolak Cream and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5) ]. Systemic Toxicity in Patients with DPD deficiency Advise patient to stop using Tolak immediately and contact physician if abdominal (stomach) pain, bloody diarrhea, vomiting, fever, and/or chills occur with Tolak Cream use. Inform patient that these symptoms could be manifestations of a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) [see Warnings and Precautions (5.6) ] .

14 CLINICAL STUDIES The efficacy and safety of Tolak Cream was evaluated in two double-blind multi-center trials (Trial 1 and Trial 2) in subjects with at least 5 visible actinic keratosis lesions on the face, scalp, and/or ears. Subjects applied the assigned medication (Tolak Cream or vehicle placebo) to the face, and/or ears and/or scalp once or twice daily for four weeks as directed. Application of the medication involved field treatment of the whole area of the face and/or ears and/or scalp where actinic keratosis lesions were identified at baseline. Subjects receiving confounding treatments or medications were excluded. The effect of treatment was assessed at 4 weeks post-treatment. Subjects were almost all Caucasian, the mean age was approximately 68 years (range was from 33 to 89 years), and the mean number of actinic keratosis lesions was 14.4 in the Tolak group and 16.2 in the vehicle group in Trial 1, and 19.2 in the Tolak group and 23.2 in the vehicle group in Trial 2. The number and percentage of subjects with 100% clearing of their actinic keratosis lesions and with at least 75% clearing of their actinic keratosis lesions are shown in Table 2. Table 2 Subjects with 100% and at least 75% Clearing of Actinic Keratosis Lesions at 4 Weeks Post-Treatment Tolak Cream % (n/N) Vehicle % (n/N) Subjects with 100% Clearing of Actinic Keratosis Lesions Trial 1 54% (192/353) 4% (3/70) Trial 2 24% (12/50) 4% (2/50) Subjects with At Least 75% Clearing of Actinic Keratosis Lesions Trial 1 80% (284/353) 7% (5/70) Trial 2 74% (37/50) 10% (5/50) Examination of age (< 68 years versus ≥ 68 years) and gender subgroups did not identify differences in response to Tolak Cream among these subgroups. There were too few non-Caucasian subjects to adequately assess differences in effects among racial subgroups. After completing Trials 1 and 2, subjects who achieved 100% clearing of actinic keratosis lesions with Tolak Cream treatment were followed for 12 months for lesion recurrence. Table 3 presents the long term outcomes of these 204 subjects. Table 3 Recurrence of Actinic Keratosis Lesions within 12 Months After Completing Trial 1 or 2 Cleared Tolak Subjects N=204 Subjects remained clear 12 months after treatment 56 (27%) Subjects with recurrence within 12 months Subjects who applied other treatments for actinic keratosis were counted as having recurrence. 110 (54%) Subjects with no follow-up 38 (19%)

8.5 Geriatric Use No dose adjustment is required for elderly patients [see Clinical Studies (14) ] . The mean age of the 403 subjects treated with Tolak Cream in the clinical trials was 68 years. Of the Tolak Cream-treated subjects, 61% were 65 and over, while 28% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.3 Nursing Mothers Because many drugs are excreted in human milk and there is some systemic absorption of fluorouracil after topical administration, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue drug use, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Actinic keratosis is not usually observed in the pediatric population except in the case of rare genetic diseases. Tolak Cream is not intended for use in pediatric patients. Safety and effectiveness in children have not been established.

8.1 Pregnancy Teratogenic Effects: Pregnancy Category X [see Contraindications (4.1) ] . Cases of miscarriage and birth defects (including cleft lip and cleft palate) have been reported when pregnant women were exposed to a topical or parenteral fluorouracil product. In addition, ventricular septal defect and cases of miscarriage occurred when pregnant women applied a topical fluorouracil product to mucous membranes (Tolak Cream is not indicated for use on the mucous membrane). Animal reproduction studies have not been conducted with Tolak Cream. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats, and hamsters when given at doses equivalent to the usual human intravenous dose. However, the amount of fluorouracil absorbed systemically after topical administration to actinic keratosis is minimal [see Clinical Pharmacology (12.3) ] . 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. However, doses higher than 40 mg/kg resulted in spontaneous abortions. Based on the recommended human dose and instructions for use, it is not possible to calculate human dose equivalents for animal exposures in these studies.

Teratogenic Effects: Pregnancy Category X [see Contraindications (4.1) ] . Cases of miscarriage and birth defects (including cleft lip and cleft palate) have been reported when pregnant women were exposed to a topical or parenteral fluorouracil product. In addition, ventricular septal defect and cases of miscarriage occurred when pregnant women applied a topical fluorouracil product to mucous membranes (Tolak Cream is not indicated for use on the mucous membrane). Animal reproduction studies have not been conducted with Tolak Cream. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats, and hamsters when given at doses equivalent to the usual human intravenous dose. However, the amount of fluorouracil absorbed systemically after topical administration to actinic keratosis is minimal [see Clinical Pharmacology (12.3) ] . 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. However, doses higher than 40 mg/kg resulted in spontaneous abortions. Based on the recommended human dose and instructions for use, it is not possible to calculate human dose equivalents for animal exposures in these studies.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category X [see Contraindications (4.1) ] . Cases of miscarriage and birth defects (including cleft lip and cleft palate) have been reported when pregnant women were exposed to a topical or parenteral fluorouracil product. In addition, ventricular septal defect and cases of miscarriage occurred when pregnant women applied a topical fluorouracil product to mucous membranes (Tolak Cream is not indicated for use on the mucous membrane). Animal reproduction studies have not been conducted with Tolak Cream. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats, and hamsters when given at doses equivalent to the usual human intravenous dose. However, the amount of fluorouracil absorbed systemically after topical administration to actinic keratosis is minimal [see Clinical Pharmacology (12.3) ] . 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. However, doses higher than 40 mg/kg resulted in spontaneous abortions. Based on the recommended human dose and instructions for use, it is not possible to calculate human dose equivalents for animal exposures in these studies. 8.3 Nursing Mothers Because many drugs are excreted in human milk and there is some systemic absorption of fluorouracil after topical administration, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue drug use, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Actinic keratosis is not usually observed in the pediatric population except in the case of rare genetic diseases. Tolak Cream is not intended for use in pediatric patients. Safety and effectiveness in children have not been established. 8.5 Geriatric Use No dose adjustment is required for elderly patients [see Clinical Studies (14) ] . The mean age of the 403 subjects treated with Tolak Cream in the clinical trials was 68 years. Of the Tolak Cream-treated subjects, 61% were 65 and over, while 28% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

16 HOW SUPPLIED / STORAGE AND HANDLING 16.1 How Supplied Tolak (fluorouracil) Cream, 4% containing 40 mg of fluorouracil per gram of white cream is available in a 40 gram tube (NDC 28105-421-40). 16.2 Storage and Handling Store at 25°C (77°F), with excursion permitted from 15°C to 30°C (59°F - 86°F) [See USP Controlled Room Temperature]. Do not freeze.

16.2 Storage and Handling Store at 25°C (77°F), with excursion permitted from 15°C to 30°C (59°F - 86°F) [See USP Controlled Room Temperature]. Do not freeze.