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TOLAK is a brand name for Fluorouracil, supplied as a cream. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Tolak® (fluorouracil cream), 4% (w/w), is indicated for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp. 1.1 Pediatrics Actinic keratosis is not usually observed in the pediatric population except in the case of rare genetic diseases. Tolak® is not intended for use in pediatric…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations Tolak® is for topical use only. Not for ophthalmic, oral or intravaginal use. Airtight or occlusive dressing should be avoided. Tolak® can potentiate skin sensitivity to sunlight and cause severe sunburn.
2 Recommended Dose and Dosage Adjustment Tolak® is applied once daily in an amount sufficient to cover the lesions of the face, ears, and/or scalp with a thin film, gently massaged uniformly into the skin. Tolak® is applied for a period of 4 weeks as tolerated.
3)]. 3 Administration Tolak® is applied once a day to the AK lesions and surrounding areas, for 4 weeks. Tolak® should not be applied around the eyes, in the nose, mouth or mucous membranes; local inflammation and ulceration can occur.
Application of Tolak® is as follows: o Gently wash, rinse, and pat dry the skin areas to be treated. o Apply a thin film of the Tolak® to the areas to be treated. o Gently massage Tolak® evenly into the skin. o Avoid contact with other areas of the body, and transfer of Tolak® to other people.
o Wash hands well after application of Tolak®. 4 Missed Dose If a dose of this medication is missed, it is not necessary to make up the missed dose. Skip the missed dose and continue with the next scheduled dose.
1 Adverse Reaction Overview The following adverse reactions are discussed in more detail under WARNINGS AND PRECAUTIONS (6): Application Site Adverse Reactions Embryofetal toxicity Hypersensitivity Reactions Ophthalmic Adverse Reactions Photosensitivity Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency [also see CONTRAINDICATIONS (2)].
2 Clinical Trial Adverse Reactions 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® in 397 subjects with actinic keratosis in vehicle-controlled Phase III clinical studies (Trials 1 and 2). The population ranged in age from 33 to 94 years, was 80% male, and almost all were Caucasian.
Most subjects were treated with Tolak® once daily for 4 weeks. In Trials 1 and 2, 12% of Tolak®-treated and 4% of vehicle- treated subjects discontinued treatment because of adverse reactions. Of these subjects, the majority had adverse reactions at the application site.
Ophthalmic adverse reactions (eye Tolak® Product Monograph Page 9 of 23 irritation and periorbital edema), leading to discontinuation, occurred in one subject for periorbital edema and two subjects for eye irritation with Tolak® use.
The most common adverse reactions reported in clinical trials with Tolak® throughout the 4- week treatment and the 4-week post-treatment periods, wereadverse reactions related to tolerability, including erythema, scaling/dryness, edema, crusting, erosions, stinging/burning, and pruritus.
These adverse reactions are likely to be related to the pharmacologic action of 5- fluorouracil in the clearing of actinic keratosis lesions. The severity of the local adverse reactions in subjects using Tolak® generally increased over the 4-week treatment period, usually reaching maximal scores at 4 weeks of treatment and resolving within 4 weeks after cessation of treatment.
2)]. In the clinical trials of Tolak®, application site irritation resolved within 4 weeks after discontinuing treatment. Tolak® should not be applied directly into eyes, nose, mouth, or other mucous membranes because irritation, local inflammation and ulceration can occur.
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® is not indicated for use on the mucous membrane).
Studies in animals have demonstrated that parenteral fluorouracil caused teratogenic and lethal embryo-fetal effects at sub-therapeutic doses. Therefore, Tolak® is contraindicated in pregnancy [see CONTRAINDICATIONS (2)]. Females of childbearing potential must use effective contraception during therapy.
5)]. Hypersensitivity Reactions Allergic contact dermatitis (delayed type hypersensitivity reaction) has been noted for topical fluorouracil drugs. 3)], delayed type hypersensitivity should be suspected in the event of severe pruritus or eczema at the application site or at a distant site.
If signs of hypersensitivity occur, patients should discontinue Tolak® immediately and contact their healthcare provider. Tolak® contains peanut oil. 5 parts per million. Physicians should use caution in prescribing Tolak® for peanut-sensitive individuals [see CONTRAINDICATIONS (2)].
3)]. 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®. If accidental exposure occurs, the patient should flush eye(s) with large amounts of water and seek medical care as soon as possible.
1)]. In patients with dihydropyrimidine dehydrogenase (DPD) deficiency [see WARNINGS AND PRECAUTIONS (6)]. In patients with known hypersensitivity to any of its ingredients.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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The number and percentage of subjects with each of application site reactions at one or more post-baseline visit(s) during the clinical trials are shown in Table 1.
Table 1:
Number and Percentage of Subjects with Application Site Adverse Reactions with Tolak® Treatment in Clinical Trials 1 and 2 Tolak® N=397 n (%) Vehicle N=120 n (%) Adverse event/Severity 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%) Treatment-related AEs reported by at least 1% of the subjects in the Tolak® treated groups were application site reactions which included irritation, pain, errosion and inflammation; other treatment-related AEs reported were eye disorders (eye irritation and eye swelling), and insomnia.
Based on safety data from Trial 1, a randomized, double-blind well controlled trial in subjects with actinic keratosis, the safety profile for Tolak® was similar to that of its active comparator Efudex. Overall incidence of adverse events was comparable between the Tolak® (n=348) and Efudex (n=342) safety populations (34% and 36%, respectively).
The frequency of these adverse events excludes the tolerability assessments of erythema, scaling/dryness, crusting, pruritus, stinging/burning, edema, and erosions. 0) system organ class (SOC) of General disorders and administration site conditions were reported in 16% and 21% of subjects and adverse events of Infections and infestations SOC were reported in 6% and 7% of subjects in the Tolak® and Efudex groups, respectively.
All other adverse events specific as well as by SOC were reported in ≤ 2% of subjects treated with Tolak® Product Monograph Page 10 of 23 Tolak®. 2)]. 3 Post-Market Adverse Reactions 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
Photosensitivity Topical fluorouracil is associated with photosensitivity reactions including severe sunburn. Tolak® Product Monograph Page 7 of 23 Minimize exposure to ultraviolet rays including sunlight, sun lamps, and tanning beds during and immediately following treatment with Tolak® because the intensity of the photosensitivity reaction may be increased.
Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency Tolak® must not be used on patients with dihydropyrimidine dehydrogenase (DPD) deficiency [see CONTRAINDICATIONS (2)]. Life-threatening systemic toxicity has been reported with the topical use of fluorouracil in a patient with DPD deficiency.
Symptoms of serious side effects included severe stomach-area abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, and inflammation of the esophagus, stomach and small bowel.
A large percentage of fluorouracil is catabolized by the DPD enzyme. 2)]. Therefore, Tolak® is contraindicated in patients with DPD deficiency. Patients should discontinue Tolak® if symptoms of fluorouracil’s systemic toxicity develop.
1 Pregnant Women There is no clinical data regarding the use of Tolak® in pregnant women.
Because fluorouracil is a known human teratogen (Teratogenic Effects:
Pregnancy Category X), Tolak® must not be used during pregnancy [see CONTRAINDICATIONS (2)]. 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® is not indicated for use on the mucous membrane). Animal reproduction studies have shown that parenterally administered fluorouracil caused embryofetal toxicity at doses lower than the usual human intravenous dose [see WARNINGS AND PRECAUTIONS (6), Embryofetal toxicity and NON-CLINICAL TOXICOLOGY (14).
2 Breast-feeding Tolak® should not be used when breastfeeding or plan to breastfeed. It is unknown if the drug is excreted in human milk. 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.
3 Pediatrics Actinic keratosis is not usually observed in the pediatric population except in the case of rare genetic diseases. Tolak® is not intended […]