Nucleoside Metabolic Inhibitor

Tolak

Approved 18 Sept 2015TopicalCream

Indications

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 ).

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 ).

4.1Pregnancy 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.

4.2Dihydropyrimidine 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 ).

5.1Application 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.

At a glance

Brand name: Tolak
Active substance: fluorouracil
Pharmacologic class: Nucleoside Metabolic Inhibitor
Route: Topical
Dosage form: Cream
Applicant: Hill Dermaceuticals
Status: Prescription
FDA approval: 18 Sept 2015
Application: NDA022259-001

Contraindications

4.1Pregnancy Tolak

4.2Dihydropyrimidine Dehydrogenase Deficiency Tolak

Cream is contraindicated in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

Warnings and precautions

5.1Application Site Adverse Reactions

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 .

6.1Clinical 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 .

6.2Postmarketing 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

Tolak

Indications

Contraindications

4.1Pregnancy Tolak

4.2Dihydropyrimidine Dehydrogenase Deficiency Tolak

Warnings and precautions

5.1Application Site Adverse Reactions

At a glance

Two medicines in one question?

Tolak

Indications

Contraindications

4.1Pregnancy Tolak

4.2Dihydropyrimidine Dehydrogenase Deficiency Tolak

Warnings and precautions

5.1Application Site Adverse Reactions

At a glance

Two medicines in one question?

5.2Hypersensitivity Reactions

5.3Ophthalmic Adverse Reactions Corneal

5.4Photosensitivity

5.5Embryofetal Toxicity Cases

5.6Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Teratogenic Effects: Pregnancy Category

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Official product information