Tolak (Fluorouracil): Uses, Dosage, Side Effects & Warnings

Uses

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 ).

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 ).

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 ).

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.

Warnings and precautions

Application site adverse reactions are likely to occur during and for 4 weeks after treatment of actinic keratosis with Tolak Cream ( 5.1 ). Hypersensitivity reactions may occur with Tolak Cream ( 5.2 ). Avoid treatment in the periocular area. Eye disorders, including corneal reactions have occurred with topical fluorouracil use. Avoid accidental transfer of the drug into eyes and to the periocular area. If accidental exposure occurs, seek medical care ( 5.3 ). Increased sensitivity to ultraviolet light may occur during and immediately after treatment with Tolak Cream ( 5.4 ). Fluorouracil may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception ( 5.5 ). Increased fluorouracil exposures may occur in DPD deficiency. Discontinue Tolak Cream if symptoms of fluorouracil's systemic toxicity develop ( 5.6 ). 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.

Side effects

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

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.

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.

Pregnancy

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.

Pediatric use

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.

Geriatric use

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.

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

Mechanism of action

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.

How supplied

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. 16.1 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).

Storage

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.

Patient 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) ] .

Active ingredients

Fluorouracil in 1 product

Tolak NDC products (1)

NDC	Strength & form	Labeler	Type
28105-421	Fluorouracil .04 g/g Cream	HILL DERMACEUTICALS, INC.	NDA

Frequently asked questions

What is Tolak used for?

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 ).

What are the side effects of Tolak?

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… See the full label for the complete list.

Who makes Tolak?

Tolak is listed by 1 labeler in the FDA NDC directory, including HILL DERMACEUTICALS, INC..