Included as part of the PRECAUTIONS section.
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]. 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
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],
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.
Ophthalmic Adverse Reactions
Corneal and conjunctival disorders have occurred with
topical fluorouracil use [see ADVERSE REACTIONS]. 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
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.
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
Toxicity In Patients With Dihydropyrimidine Dehydrogenase
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]. Therefore, Tolak Cream is
contraindicated in patients with DPD deficiency.
Patients should discontinue Tolak Cream if symptoms of
fluorouracil's systemic toxicity develop.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (PATIENT INFORMATION).
Advise patients of the
- 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.
Instruct patients to do the following:
- Apply after washing, rinsing, and drying the treatment
- Wash hands thoroughly after application.
- 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
Ophthalmic Adverse Reactions
- Inform patients that ophthalmic adverse reactions can
occur with Tolak Cream use.
- Advise patients that Tolak Cream is not for ophthalmic
- 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
Increased Sensitivity to UV
- 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].
- 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
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].
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
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
Use In Specific Populations
Pregnancy Category X [see CONTRAINDICATIONS]. 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]. 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.
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.
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.
No dose adjustment is required for elderly patients [see Clinical
Studies]. 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.