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.

5.1 Application Site Adverse Reactions

Application site reactions (erythema, scaling/dryness, edema, crusting, erosions, stinging/burning, and pruritus) were observed in almost all patients during treatment of actinic keratosis on the face, ears, and/or scalp with topical fluorouracil [see Adverse Reactions (6.1)]. In the clinical trials of Tolak Cream, application site irritation returned to baseline (pre-treatment) levels within 4 weeks after discontinuing treatment.

Do not apply Tolak Cream directly into eyes, nose, mouth, or other mucous membranes because irritation, local inflammation and ulceration can occur.

5.2 Hypersensitivity Reactions

Allergic contact dermatitis (delayed type hypersensitivity reaction) has been noted for topical fluorouracil drugs. While application site reactions are observed in almost all patients during treatment of actinic keratosis with topical fluorouracil [see Adverse Reactions (6.2)], delayed type hypersensitivity should be suspected in the event of severe pruritus or eczema at the application site or at a distant site. Although the potential for a delayed hypersensitivity reaction to fluorouracil exists, patch testing to confirm hypersensitivity may be inconclusive.

Tolak Cream contains peanut oil. If signs of hypersensitivity occur, patients should discontinue Tolak Cream immediately and contact their healthcare provider.

5.3 Ophthalmic Adverse Reactions

Corneal and conjunctival disorders have occurred with topical fluorouracil use [see Adverse Reactions (6.2)]. Avoid application to the periocular area. To avoid transfer of the drug into the eyes and to the periocular area during and after application, patients should wash hands well after applying Tolak Cream. If accidental exposure occurs, the patient should flush eye(s) with large amounts of water and seek medical care as soon as possible.

5.4 Photosensitivity

Topical fluorouracil is associated with photosensitivity reactions including severe sunburn. Minimize exposure to ultraviolet rays including sunlight, sun lamps, and tanning beds during and immediately following treatment with Tolak Cream because the intensity of the photosensitivity reaction may be increased.

5.5 Embryofetal Toxicity

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). Furthermore, fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA), inhibits the formation of ribonucleic acid (RNA), and provokes unbalanced growth and death of cells. Therefore, Tolak Cream is contraindicated in pregnancy.

Advise females of reproductive potential to use effective contraception during Tolak use and for one month after the last dose of Tolak Cream.

5.6 Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency

Life-threatening systemic toxicity has been reported with the topical use of fluorouracil in a patient with DPD 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.

A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency may result in increased availability of fluorouracil to the anabolic pathway, which may lead to increased interference with DNA and RNA synthesis and increased cytotoxic activity and potential toxicities [see Clinical Pharmacology (12.1)]. Therefore, Tolak Cream is contraindicated in patients with DPD deficiency.

Patients should discontinue Tolak Cream if symptoms of fluorouracil's systemic toxicity develop.

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.

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

8.1 Pregnancy

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.

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 CO2, urea, α-fluoro-β-alanine).

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).

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.

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)].