TOLAK

TOLAK- fluorouracil cream
HILL DERMACEUTICALS, INC.

1 INDICATIONS AND USAGE

Tolak (fluorouracil) Cream is indicated for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp.

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.

3 DOSAGE FORMS AND STRENGTHS

Cream: 40 mg of fluorouracil per gram (4%) of white cream in 40 gram tubes.

4 CONTRAINDICATIONS

Tolak Cream is contraindicated:

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 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

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.

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