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

{ "type": "p", "children": [], "text": "Tolak (fluorouracil) Cream is indicated for the topical treatment of actinic keratosis lesions of the face, ears, and/or scalp. " }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Tolak Cream is for topical use only. Do not apply to eyes, nose, mouth or mucous membranes. Not for ophthalmic, oral or intravaginal use. " }

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

{ "type": "p", "children": [], "text": "Cream: 40 mg of fluorouracil per gram (4%) of white cream in 40 gram tubes." }

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.

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

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.

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.

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.

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 Cream.

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.

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: Incidence of Application Site Adverse Reactions Occurring with 4 Weeks of Tolak Cream Treatment in Clinical Trials 1 and 2</span> </caption> <col align="left" valign="top" width="24%"/> <col align="left" valign="top" width="19%"/> <col align="left" valign="top" width="19%"/> <col align="left" valign="top" width="19%"/> <col align="left" valign="top" width="19%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Tolak Cream<br/>N=397<br/>n (%)</th><th align="center" class="Rrule" colspan="2">Vehicle<br/>N=120<br/>n (%)</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="left" class="Rrule">Mild, Moderate or Severe</th><th align="left" class="Rrule">Severe Only</th><th align="left" class="Rrule">Mild, Moderate or Severe</th><th align="left" class="Rrule">Severe Only</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Erythema </td><td align="left" class="Rrule">394 (99%)</td><td align="left" class="Rrule">174 (44%)</td><td align="left" class="Rrule">102 (85%)</td><td align="left" class="Rrule">0 (0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Scaling/ Dryness</td><td align="left" class="Rrule">377 (95%)</td><td align="left" class="Rrule">94 (24%)</td><td align="left" class="Rrule">99 (83%)</td><td align="left" class="Rrule">0 (0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Crusting</td><td align="left" class="Rrule">346 (87%)</td><td align="left" class="Rrule">87 (22%)</td><td align="left" class="Rrule">46 (38%)</td><td align="left" class="Rrule">0 (0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pruritus</td><td align="left" class="Rrule">337 (85%)</td><td align="left" class="Rrule">65 (16%)</td><td align="left" class="Rrule">46 (38%)</td><td align="left" class="Rrule">1 (1%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Stinging/ Burning</td><td align="left" class="Rrule">346 (87%)</td><td align="left" class="Rrule">101 (25%)</td><td align="left" class="Rrule">42 (35%)</td><td align="left" class="Rrule">0 (0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Edema</td><td align="left" class="Rrule">275 (69%)</td><td align="left" class="Rrule">30 (8%)</td><td align="left" class="Rrule">11 (9%)</td><td align="left" class="Rrule">0 (0%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Erosions</td><td align="left" class="Rrule">271 (68%)</td><td align="left" class="Rrule">44 (11%)</td><td align="left" class="Rrule">14 (12%)</td><td align="left" class="Rrule">0 (0%)</td> </tr> </tbody> </table></div>

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.

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

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.

{ "type": "p", "children": [], "text": "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. " }

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.

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 (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.

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 C4H3FN2O2, and its molecular weight is 130.1. Its structural formula is:

{ "type": "p", "children": [], "text": "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 C4H3FN2O2, 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.

{ "type": "p", "children": [], "text": "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." }

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.

A systemic absorption study of topically applied Tolak Cream was performed in 21 patients with at least 3 actinic keratosis lesions (4 mm or greater in diameter). The steady state concentration of 5-fluorouracil in plasma was examined at 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours after the last dose of a 4-week regimen in subjects with actinic keratosis after "area application" to area(s) in which actinic keratosis lesions were identified at baseline. Areas were defined as the whole region of the left cheek, right cheek, chin and forehead, bald scalp, and right and left ears, where actinic keratosis was identified at baseline. Thus, for example, if an actinic keratosis lesion was identified on the left cheek, Tolak Cream was to be applied as a thin film to the whole area of the left cheek.

Eight patients had undetectable levels of plasma 5-fluorouracil (the lower limit of quantification was 1.00 ng/ml) in all plasma samples following treatment with Tolak Cream. Among patients with detectable plasma 5-fluorouracil levels, the highest level of plasma 5-fluorouracil was generally observed at 1 hour post-dose. The mean observed maximum concentration (± standard deviation) of plasma 5-fluorouracil was 3.66 (±1.58) ng/mL with the range between 1.11 – 7.35 ng/mL.

The catabolism of 5-fluorouracil results in inactive degradation products (such as CO2, urea, α-fluoro-β-alanine).

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 studies.

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 mg/kg).

The efficacy and safety of Tolak Cream was evaluated in two double-blind multi-center trials (Trial 1 and Trial 2) in subjects with at least 5 visible actinic keratosis lesions on the face, scalp, and/or ears. Subjects applied the assigned medication (Tolak Cream or vehicle placebo) to the face, and/or ears and/or scalp once or twice daily for four weeks as directed. Application of the medication involved field treatment of the whole area of the face and/or ears and/or scalp where actinic keratosis lesions were identified at baseline. Subjects receiving confounding treatments or medications were excluded. The effect of treatment was assessed at 4 weeks post-treatment. Subjects were almost all Caucasian, the mean age was approximately 68 years (range was from 33 to 89 years), and the mean number of actinic keratosis lesions was 14.4 in the Tolak group and 16.2 in the vehicle group in Trial 1, and 19.2 in the Tolak group and 23.2 in the vehicle group in Trial 2.

{ "type": "p", "children": [], "text": "The efficacy and safety of Tolak Cream was evaluated in two double-blind multi-center trials (Trial 1 and Trial 2) in subjects with at least 5 visible actinic keratosis lesions on the face, scalp, and/or ears. Subjects applied the assigned medication (Tolak Cream or vehicle placebo) to the face, and/or ears and/or scalp once or twice daily for four weeks as directed. Application of the medication involved field treatment of the whole area of the face and/or ears and/or scalp where actinic keratosis lesions were identified at baseline. Subjects receiving confounding treatments or medications were excluded. The effect of treatment was assessed at 4 weeks post-treatment. Subjects were almost all Caucasian, the mean age was approximately 68 years (range was from 33 to 89 years), and the mean number of actinic keratosis lesions was 14.4 in the Tolak group and 16.2 in the vehicle group in Trial 1, and 19.2 in the Tolak group and 23.2 in the vehicle group in Trial 2." }

The number and percentage of subjects with 100% clearing of their actinic keratosis lesions and with at least 75% clearing of their actinic keratosis lesions are shown in Table 2.

{ "type": "p", "children": [], "text": "The number and percentage of subjects with 100% clearing of their actinic keratosis lesions and with at least 75% clearing of their actinic keratosis lesions are shown in Table 2. " }

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2 Subjects with 100% and at least 75% Clearing of Actinic Keratosis Lesions at 4 Weeks Post-Treatment </span> </caption> <col align="left" valign="top" width="20%"/> <col align="center" valign="top" width="40%"/> <col align="center" valign="top" width="40%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule"></th><th align="center">Tolak Cream<br/> % (n/N)</th><th align="center" class="Rrule">Vehicle<br/>% (n/N)</th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Lrule Rrule" colspan="3" valign="top">Subjects with 100% Clearing of Actinic Keratosis Lesions </td> </tr> <tr> <td align="left" class="Lrule">Trial 1</td><td align="center">54% (192/353) </td><td align="center" class="Rrule">4% (3/70) </td> </tr> <tr> <td align="left" class="Lrule">Trial 2</td><td align="center">24% (12/50) </td><td align="center" class="Rrule">4% (2/50) </td> </tr> <tr> <td align="center" class="Lrule Rrule" colspan="3" valign="top">Subjects with At Least 75% Clearing of Actinic Keratosis Lesions </td> </tr> <tr> <td align="left" class="Lrule">Trial 1</td><td align="center">80% (284/353) </td><td align="center" class="Rrule">7% (5/70) </td> </tr> <tr class="Last"> <td align="left" class="Lrule">Trial 2</td><td align="center">74% (37/50) </td><td align="center" class="Rrule">10% (5/50) </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"85%\">\n<caption>\n<span>Table 2 Subjects with 100% and at least 75% Clearing of Actinic Keratosis Lesions at 4 Weeks Post-Treatment </span>\n</caption>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"center\" valign=\"top\" width=\"40%\"/>\n<col align=\"center\" valign=\"top\" width=\"40%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Lrule\"></th><th align=\"center\">Tolak Cream<br/> % (n/N)</th><th align=\"center\" class=\"Rrule\">Vehicle<br/>% (n/N)</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">Subjects with 100% Clearing of Actinic Keratosis Lesions </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\">Trial 1</td><td align=\"center\">54% (192/353) </td><td align=\"center\" class=\"Rrule\">4% (3/70) </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\">Trial 2</td><td align=\"center\">24% (12/50) </td><td align=\"center\" class=\"Rrule\">4% (2/50) </td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">Subjects with At Least 75% Clearing of Actinic Keratosis Lesions </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\">Trial 1</td><td align=\"center\">80% (284/353) </td><td align=\"center\" class=\"Rrule\">7% (5/70) </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule\">Trial 2</td><td align=\"center\">74% (37/50) </td><td align=\"center\" class=\"Rrule\">10% (5/50) </td>\n</tr>\n</tbody>\n</table></div>" }

Examination of age (< 68 years versus ≥ 68 years) and gender subgroups did not identify differences in response to Tolak Cream among these subgroups. There were too few non-Caucasian subjects to adequately assess differences in effects among racial subgroups.

{ "type": "p", "children": [], "text": "Examination of age (< 68 years versus ≥ 68 years) and gender subgroups did not identify differences in response to Tolak Cream among these subgroups. There were too few non-Caucasian subjects to adequately assess differences in effects among racial subgroups. " }

After completing Trials 1 and 2, subjects who achieved 100% clearing of actinic keratosis lesions with Tolak Cream treatment were followed for 12 months for lesion recurrence. Table 3 presents the long term outcomes of these 204 subjects.

{ "type": "p", "children": [], "text": "After completing Trials 1 and 2, subjects who achieved 100% clearing of actinic keratosis lesions with Tolak Cream treatment were followed for 12 months for lesion recurrence. Table 3 presents the long term outcomes of these 204 subjects." }

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3 Recurrence of Actinic Keratosis Lesions within 12 Months After Completing Trial 1 or 2</span> </caption> <col align="left" valign="top" width="70%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Cleared Tolak Subjects<br/> N=204</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Subjects who applied other treatments for actinic keratosis were counted as having recurrence.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Subjects remained clear 12 months after treatment</td><td align="center" class="Rrule">56 (27%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Subjects with recurrence within 12 months<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">110 (54%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Subjects with no follow-up</td><td align="center" class="Rrule">38 (19%)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"85%\">\n<caption>\n<span>Table 3 Recurrence of Actinic Keratosis Lesions within 12 Months After Completing Trial 1 or 2</span>\n</caption>\n<col align=\"left\" valign=\"top\" width=\"70%\"/>\n<col align=\"center\" valign=\"top\" width=\"30%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Lrule Rrule\"></th><th align=\"center\" class=\"Rrule\">Cleared Tolak Subjects<br/> N=204</th>\n</tr>\n</thead>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"2\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-1\" name=\"footnote-1\">*</a>\n</dt>\n<dd>Subjects who applied other treatments for actinic keratosis were counted as having recurrence.</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\">Subjects remained clear 12 months after treatment</td><td align=\"center\" class=\"Rrule\">56 (27%)</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Subjects with recurrence within 12 months<a class=\"Sup\" href=\"#footnote-1\" name=\"footnote-reference-1\">*</a></td><td align=\"center\" class=\"Rrule\">110 (54%)</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\">Subjects with no follow-up</td><td align=\"center\" class=\"Rrule\">38 (19%)</td>\n</tr>\n</tbody>\n</table></div>" }

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).

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.

Important Administration Instructions

Advise patients of the following:

Instruct patients to do the following:

Hypersensitivity Reactions

Ophthalmic Adverse Reactions

Increased Sensitivity to UV Light

Embryofetal Toxicity

Systemic Toxicity in Patients with DPD deficiency

Manufactured and Distributed by: Hill Dermaceuticals, Inc. Sanford, Florida 32773

{ "type": "p", "children": [], "text": "\nManufactured and Distributed by:\n Hill Dermaceuticals, Inc. Sanford, Florida 32773" }

Important: Tolak Cream is for use on skin only (topical). Do not get or apply Tolak Cream on your eyelids or in your eyes, nose, mouth, or in the vagina, because it may cause irritation and swelling in these areas.

{ "type": "p", "children": [], "text": "\nImportant: Tolak Cream is for use on skin only (topical). Do not get or apply Tolak Cream on your eyelids or in your eyes, nose, mouth, or in the vagina, because it may cause irritation and swelling in these areas. \n" }

What is Tolak Cream?

{ "type": "p", "children": [], "text": "\nWhat is Tolak Cream? \n" }

Tolak Cream is a prescription medicine used to treat skin lesions called actinic keratosis on the face, ears, or scalp.

{ "type": "p", "children": [], "text": "Tolak Cream is a prescription medicine used to treat skin lesions called actinic keratosis on the face, ears, or scalp." }

It is not known if Tolak Cream is safe and effective for use on other areas of the body or to treat problems other than actinic keratosis.

{ "type": "p", "children": [], "text": "It is not known if Tolak Cream is safe and effective for use on other areas of the body or to treat problems other than actinic keratosis." }

It is not known if Tolak Cream is safe and effective in children.

{ "type": "p", "children": [], "text": "It is not known if Tolak Cream is safe and effective in children." }

Who should not use Tolak Cream?

{ "type": "p", "children": [], "text": "\nWho should not use Tolak Cream?\n" }

Do not use Tolak Cream if:

{ "type": "p", "children": [], "text": "\nDo not use Tolak Cream if:\n" }

{ "type": "ul", "children": [ "\nyou are pregnant or may become pregnant. Tolak Cream may harm your unborn child. Stop using Tolak Cream and tell your doctor right away if you become pregnant while using Tolak Cream. \n", "your body does not make enough of (you are deficient in) the enzyme called dihydropyrimidine dehydrogenase (DPD). If you do not have enough of this enzyme, you may get serious side effects if you use Tolak Cream. Symptoms of serious side effects include: stomach-area abdominal pain, bloody diarrhea, vomiting, fever, and chills. " ], "text": "" }

What should I tell my doctor before using Tolak Cream?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before using Tolak Cream? \n" }

Before using Tolak Cream, tell your doctor about all your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore using Tolak Cream, tell your doctor about all your medical conditions, including if you:\n" }

{ "type": "ul", "children": [ "are allergic to any of the ingredients in Tolak Cream. Tolak Cream contains peanut oil. See the end of this leaflet for a list of all of the ingredients in Tolak Cream. ", "are pregnant or plan to become pregnant. See \"Who should not use Tolak Cream?\"\n\n\nFemales who are able to become pregnant should use an effective method of birth control during treatment with Tolak Cream and for one month after the last dose of Tolak Cream. Talk to your doctor about birth control methods that may be right for you during treatment with Tolak Cream.\n\n", "are breastfeeding or plan to breastfeed. It is not known if Tolak Cream passes into your breast milk. You and your doctor should decide if you will use Tolak Cream or breastfeed." ], "text": "" }

How should I use Tolak Cream?

{ "type": "p", "children": [], "text": "\nHow should I use Tolak Cream? \n" }

{ "type": "ul", "children": [ "Use Tolak Cream exactly as prescribed by your doctor. ", "Apply Tolak Cream 1 time each day, to the areas of your skin to be treated, for 4 weeks. Apply Tolak Cream as follows: \t\t\t\t\t\t\t\nGently wash, rinse, and pat dry the skin areas to be treated. \nApply a thin film of the Tolak Cream to the areas to be treated. \nGently massage Tolak Cream evenly into your skin. \nAvoid contact with other areas of your body, and transfer of Tolak Cream from your body to other people. \nWash your hands well after you apply Tolak Cream. \n\n" ], "text": "" }

What should I avoid while using Tolak Cream?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while using Tolak Cream? \n" }

{ "type": "ul", "children": [ "\nDo not cover the treated areas with an airtight dressing. • Avoid sunlight. Tolak Cream can make your skin sensitive to the sun. You could get severe sunburn. Limit your time in the sun during treatment with Tolak Cream. Talk to your doctor if you get sunburn.", "Do not breast feed or become pregnant while using Tolak. If you do become pregnant, stop using Tolak and tell your doctor right away.", "Tolak may be fatal to your pet if your pet licks or ingests Tolak.", "Avoid allowing pets to contact the Tolak container or your skin\twhere you applied Tolak.", "Store Tolak out of reach of pets.", "Safely discard or clean any cloth or applicator that may have Tolak residue.", "Avoid applying Tolak on your clothing, carpeting, or furniture.", "If your pet starts vomiting or starts having a seizure after your pet licks or ingests Tolak, seek immediate veterinary care for your pet." ], "text": "" }

What are the possible side effects of Tolak Cream?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of Tolak Cream? \n" }

Tolak Cream can cause serious side effects:

{ "type": "p", "children": [], "text": "\nTolak Cream can cause serious side effects: \n" }

{ "type": "ul", "children": [ "\nSkin reactions including possible allergic reactions. Most people using Tolak Cream get skin reactions in the treated areas. You may get skin reactions such as: \t\t\t\t\t\t\t\n\n\n\n\n\n\nredness \ndryness or scaling \ncrusting\nitching\n\n\n\nstinging or burning\nswelling\nskin loss (erosion)\n\n\n\n\n\n", "\nEye problems. Eye problems have happened with the use of medicines that contain fluorouracil that are applied to the skin. To help prevent getting Tolak Cream in your eyes, or transferring Tolak Cream from another part of your body to your eyes or to another person's eyes: \t\t\t\t\t\t\t\navoid applying Tolak Cream near or around your eyes\nwash your hands well after you apply Tolak Cream\n\n\nIf you accidentally get Tolak Cream in your eyes, or if Tolak Cream is accidentally transferred to another person's eyes, flush eyes with large amounts of water and get medical help as soon as possible.\n\n", "\nTolak Cream can cause serious side effects in people who do not have enough of the enzyme dihydropyrimidine dehydrogenase (DPD). See \"Who should not use Tolak Cream?\" and \"What should I tell my doctor before using Tolak Cream?\" Stop using Tolak Cream and call your doctor right away if you get any of the following symptoms during treatment with Tolak Cream: \t\t\t\t\t\t\t\n\n\n\n\n\n\n\nstomach-area (abdominal) pain \nbloody diarrhea \n\n\n\nvomiting \nfever \n\n\n\nchills\n\n\n\n\n\n" ], "text": "" }

Tell your doctor if you get any of these skin reactions and they are severe or do not go away.

{ "type": "p", "children": [], "text": "\nTell your doctor if you get any of these skin reactions and they are severe or do not go away.\n" }

These are not all the possible side effects of Tolak Cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of Tolak Cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store Tolak Cream?

{ "type": "p", "children": [], "text": "\nHow should I store Tolak Cream? \n" }

{ "type": "ul", "children": [ "Store Tolak Cream between 68°F to 77°F (20°C to 25°C). ", "Do not freeze Tolak Cream. ", "Do not use Tolak Cream after the expiration date printed on the tube. " ], "text": "" }

Keep Tolak Cream and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep Tolak Cream and all medicines out of the reach of children. \n" }

General information about the safe and effective use of Tolak Cream

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of Tolak Cream \n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Tolak Cream for a condition for which it was not prescribed. Do not give Tolak Cream to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Tolak Cream for a condition for which it was not prescribed. Do not give Tolak Cream to other people, even if they have the same symptoms that you have. It may harm them. " }

You can ask your pharmacist or doctor for information about Tolak Cream that is written for health professionals.

{ "type": "p", "children": [], "text": "You can ask your pharmacist or doctor for information about Tolak Cream that is written for health professionals. " }

What are the ingredients in Tolak Cream?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in Tolak Cream? \n" }

Active ingredient: fluorouracil

{ "type": "p", "children": [], "text": "Active ingredient: fluorouracil " }

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.

{ "type": "p", "children": [], "text": "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." }

Manufactured and Distributed by: Hill Dermaceuticals, Inc. Sanford, Florida 32773

{ "type": "p", "children": [], "text": "Manufactured and Distributed by: Hill Dermaceuticals, Inc. Sanford, Florida 32773 " }

For more information, go to www.hillderm.com or call 1-800-344-5707.

{ "type": "p", "children": [], "text": "For more information, go to www.hillderm.com or call 1-800-344-5707." }

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: August 2022

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: August 2022" }

NDC 28105-421-40

{ "type": "p", "children": [], "text": "NDC 28105-421-40" }

Tolak® (fluorouracil) Cream 4%

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Rx only

{ "type": "p", "children": [], "text": "Rx only" }

For Topical Use OnlyNot for Ophthalmic, Oral or Intravaginal Use

{ "type": "p", "children": [], "text": "For Topical Use OnlyNot for Ophthalmic, Oral or Intravaginal Use" }

Contains Peanut Oil

{ "type": "p", "children": [], "text": "Contains Peanut Oil" }

40 g

{ "type": "p", "children": [], "text": "40 g" }

Topical Cream

{ "type": "p", "children": [], "text": "Topical Cream" }

Hill Dermaceuticals, Inc.®

{ "type": "p", "children": [], "text": "Hill Dermaceuticals, Inc.®\n" }

Fluorouracil is indicated for the treatment of patients with:

{ "type": "p", "children": [], "text": "Fluorouracil is indicated for the treatment of patients with:" }

{ "type": "", "children": [], "text": "" }

Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. Individualize the dose and dosing schedule of fluorouracil based on tumor type, the specific regimen administered, disease state, response to treatment, and patient risk factors.

Withhold fluorouracil for any of the following:

Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or palmar-plantar erythrodysesthesia, resume fluorouracil administration at a reduced dose.

There is no recommended dose for resumption of fluorouracil administration following development of any of the following adverse reactions:

The 10 mL and 20 mL vials are only intended for preparation under appropriate conditions for cytotoxic drugs [see Reference (15)].

Store vial at room temperature. Under aseptic conditions, withdraw the calculated dose for an individual patient into a sterile syringe. Inspect the solution in syringe for particulate matter and discoloration prior to administration or further dilution. Discard syringe if the solution is discolored or contains particulate matter. Discard unused portion.

Note

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected. If a precipitate occurs in intact vials due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

Do not administer in the same intravenous line concomitantly with other medicinal products.

For bolus administration, store undiluted fluorouracil in the syringe for up to 4 hours at room temperature (25°C). Administer fluorouracil as an intravenous bolus through an established intravenous line.

Store diluted solutions of fluorouracil for up to 4 hours at room temperature (25°C) prior to administration to the patient. For intravenous infusion regimens, administer through a central venous line using an infusion pump.

Fluorouracil injection, USP, is supplied in single dose vials containing 500 mg/10 mL (50 mg/mL) and 1 g/20 mL (50 mg/mL) fluorouracil.

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None.

{ "type": "p", "children": [], "text": "None." }

Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, including fatal, adverse reactions.

Fluorouracil is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration, and severity of the observed adverse events in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. No fluorouracil dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency.

Consider testing for genetic variants of DPYD prior to initiating fluorouracil to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgement [see Clinical Pharmacology (12.5)]. Serious adverse reactions may still occur even if no DPYD variants are identified.

An FDA-authorized test for the detection of genetic variants of DPYD to identify patients at risk of serious adverse reactions due to increased systemic exposure to fluorouracil is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).

Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure, based on postmarketing reports. Reported risk factors for cardiotoxicity are administration by continuous infusion rather than intravenous bolus and presence of coronary artery disease. Withhold fluorouracil for cardiotoxicity. The risks of resumption of fluorouracil in patients with cardiotoxicity that has resolved have not been established.

Fluorouracil can cause hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause, based on postmarketing reports. Signs or symptoms of hyperammonemic encephalopathy began within 72 hours after initiation of fluorouracil infusion; these included altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level. Withhold fluorouracil for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resumption of fluorouracil in patients with hyperammonemic encephalopathy that has resolved have not been established.

Fluorouracil can cause neurologic toxicity, including acute cerebellar syndrome and other neurologic events, based on postmarketing reports. Neurologic symptoms included confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. There are insufficient data on the risks of resumption of fluorouracil in patients with neurologic toxicity that has resolved.

Fluorouracil can cause severe diarrhea. Withhold fluorouracil for Grade 3 or 4 diarrhea until resolved or decreased in intensity to Grade 1, then resume fluorouracil at a reduced dose. Administer fluids, electrolyte replacement, or antidiarrheal treatments as necessary.

Fluorouracil can cause palmar-plantar erythrodysesthesia, also known as hand-foot syndrome (HFS). Symptoms of HFS include a tingling sensation, pain, swelling, and erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as a continuous infusion than when fluorouracil is administered as a bolus injection, and has been reported to occur more frequently in patients with previous exposure to chemotherapy. HFS is generally observed after 8-9 weeks of fluorouracil administration but may occur earlier. Institute supportive measures for symptomatic relief of HFS. Withhold fluorouracil administration for Grade 2 or 3 HFS; resume fluorouracil at a reduced dose when HFS is completely resolved or decreased in severity to Grade 1.

Fluorouracil can cause severe and fatal myelosuppression which may include neutropenia, thrombocytopenia, and anemia. The nadir in neutrophil counts commonly occurs between 9 and 14 days after fluorouracil administration. Obtain complete blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as needed. Withhold fluorouracil until Grade 4 myelosuppression resolves; resume fluorouracil at a reduced dose when myelosuppression has resolved or improved to Grade 1 in severity.

Mucositis, stomatitis or esophagopharyngitis, which may lead to mucosal sloughing or ulceration, can occur with fluorouracil. The incidence is reported to be higher with administration of fluorouracil by intravenous bolus compared with administration by continuous infusion. Withhold fluorouracil administration for Grade 3 or 4 mucositis; resume fluorouracil at a reduced dose once mucositis has resolved or decreased in severity to Grade 1.

Clinically significant elevations in coagulation parameters have been reported during concomitant use of warfarin and fluorouracil. Closely monitor patients receiving concomitant coumarin-derivative anticoagulants such as warfarin for INR or prothrombin time in order to adjust the anticoagulant dose accordingly [see Drug Interactions (7)].

Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. In animal studies, administration of fluorouracil at doses lower than a human dose of 12 mg/kg caused teratogenicity. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy with fluorouracil [see Use in Specific Populations (8.1, 8.6), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)].

The following adverse reactions have been identified during postapproval use of 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.

Hematologic: pancytopenia [see Warnings and Precautions (5.7)]

Gastrointestinal: gastrointestinal ulceration, nausea, vomiting

Allergic Reactions: anaphylaxis and generalized allergic reactions

Neurologic: nystagmus, headache

Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased pigmentation of the skin; vein pigmentation

Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia

Psychiatric: euphoria

Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails)

Elevated coagulation times have been reported in patients taking fluorouracil concomitantly with warfarin. While pharmacokinetic data are not available to assess the effect of fluorouracil administration on warfarin pharmacokinetics, the elevation of coagulation times that occurs with the fluorouracil prodrug capecitabine is accompanied by an increase in warfarin concentrations. Thus, the interaction may be due to inhibition of cytochrome P450 2C9 by fluorouracil or its metabolites.

Pregnancy Category D

Risk Summary

There are no adequate and well-controlled studies with fluorouracil in pregnant women. Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. Administration of fluorouracil to rats and mice during selected periods of organogenesis, at doses lower than a human dose of 12 mg/kg, caused embryolethality and teratogenicity. Malformations included cleft palate and skeletal defects. In monkeys, maternal doses of fluorouracil higher than an approximate human dose of 12 mg/kg resulted in abortion. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Clinical Pharmacology (12.1)].

Animal Data

Malformations including cleft palate, skeletal defects and deformed appendages (paws and tails) were observed when fluorouracil was administered by intraperitoneal injection to mice at doses at or above 10 mg/kg (approximately 0.06 times a human dose of 12 mg/kg on a mg/m2 basis) for 4 days during the period of organogenesis. Similar results were observed in hamsters administered fluorouracil intramuscularly at doses lower than those administered in commonly used clinical treatment regimens. In rats, administration of fluorouracil by intraperitoneal injection at doses greater than 15 mg/kg (approximately 0.2 times a human dose of 12 mg/kg on a mg/m2 basis) for a single day during organogenesis resulted in delays in growth and malformations including micro-anophthalmos. In monkeys, administration of fluorouracil during organogenesis at doses approximately equal to a human dose of 12 mg/kg on a mg/m2 basis resulted in abortion; at a 50% lower dose, resorptions and decreased fetal body weights were reported.

It is not known whether fluorouracil or its metabolites are present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from fluorouracil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness in pediatric patients have not been established.

Reported clinical experience has not identified differences in safety or effectiveness between the elderly and younger patients.

Contraception

Females

Based on its mechanism of action, fluorouracil can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with fluorouracil and for up to 3 months following cessation of therapy [see Use in Specific Populations (8.1)].

Males

Fluorouracil may damage spermatozoa. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy with fluorouracil [see Nonclinical Toxicology (13.1)].

Infertility

Females

Advise females of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)].

Males

Advise males of reproductive potential that, based on animal data, fertility may be impaired while receiving fluorouracil [see Nonclinical Toxicology (13.1)].

Administer uridine triacetate within 96 hours following the end of fluorouracil infusion for management of fluorouracil overdose.

{ "type": "p", "children": [], "text": "Administer uridine triacetate within 96 hours following the end of fluorouracil infusion for management of fluorouracil overdose." }

Fluorouracil injection, USP, a nucleoside metabolic inhibitor, is a colorless to yellow aqueous, sterile, nonpyrogenic injectable solution for intravenous administration. Each mL contains 50 mg fluorouracil in water for injection, USP. The pH is adjusted to approximately 9.2 with sodium hydroxide. Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. Its structural formula is:

{ "type": "p", "children": [], "text": "Fluorouracil injection, USP, a nucleoside metabolic inhibitor, is a colorless to yellow aqueous, sterile, nonpyrogenic injectable solution for intravenous administration. Each mL contains 50 mg fluorouracil in water for injection, USP. The pH is adjusted to approximately 9.2 with sodium hydroxide. Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1H,3H)-pyrimidinedione. Its structural formula is:" }

C4H3FN2O2               M.W. 130.08

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Fluorouracil is a nucleoside metabolic inhibitor that interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA); these affect rapidly growing cells and may lead to cell death. Fluorouracil is converted to three main active metabolites: 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), 5-fluorouridine-5′- triphosphate (FUTP) and 5-fluoro-2′-deoxyuridine-5′-triphosphate (FdUTP). These metabolites have several effects including the inhibition of thymidylate synthase by FdUMP, incorporation of FUTP into RNA and incorporation of FdUTP into DNA.

Distribution

Following bolus intravenous injection, fluorouracil distributes throughout the body including the intestinal mucosa, bone marrow, liver, cerebrospinal fluid and brain tissue.

Elimination

Following bolus intravenous injection, 5 – 20 % of the parent drug is excreted unchanged in the urine in six hours. The remaining percentage of the administered dose is metabolized, primarily in the liver. The metabolites of fluorouracil (e.g., urea and α-fluoro-ß-alanine) are excreted in the urine over 3 to 4 hours.

Following bolus intravenous injection of fluorouracil, as a single agent, the elimination half-life increased with dose from 8 to 20 minutes.

The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of >80% of fluorouracil. Approximately 3-5% of White populations have partial DPD deficiency and 0.2% of White populations have complete DPD deficiency, which may be due to certain genetic no function or decreased function variants in DPYD resulting in partial to complete or near complete absence of enzyme activity. DPD deficiency is estimated to be more prevalent in Black or African American populations compared to White populations. Insufficient information is available to estimate the prevalence of DPD deficiency in other populations.

Patients who are homozygous or compound heterozygous for no function DPYD variants (i.e., carry two no function DPYD variants) or are compound heterozygous for a no function DPYD variant plus a decreased function DPYD variant have complete DPD deficiency and are at increased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse reactions due to increased systemic exposure to fluorouracil. Partial DPD deficiency can result from the presence of either two decreased function DPYD variants or one normal function plus either a decreased function or a no function DPYD variant. Patients with partial DPD deficiency may also be at an increased risk for toxicity from fluorouracil.

Four DPYD variants have been associated with impaired DPD activity in White populations, especially when present as homozygous or compound heterozygous variants: c.1905+1G>A (DPYD *2A), c.1679T>G (DPYD *13), c.2846A>T, and c.1129-5923C>G (Haplotype B3). DPYD*2A and DPYD*13 are no function variants, and c.2846A>T and c.1129-5923C>G are decreased function variants. The decreased function DPYD variant c.557A>G is observed in individuals of African ancestry. This is not a complete listing of all DPYD variants that may result in DPD deficiency [see Warnings and Precautions (5.1)].

Carcinogenicity studies have not been performed with fluorouracil. Fluorouracil was mutagenic in vitro in the bacterial reverse mutation (Ames) assay and induced chromosomal aberrations in hamster fibroblasts in vitro and in mouse bone marrow in the in vivo mouse micronucleus assay.

Administration of fluorouracil intraperitoneally to male rats at dose levels equal to or greater than 1.7-fold the human dose of 12 mg/kg induced chromosomal aberrations in spermatogonia and inhibition of spermatogonia differentiation resulting in transient infertility. In female rats, intraperitoneal administration of fluorouracil during the pre-ovulatory phases of oogenesis at dose levels equal to or greater than 0.33 times a human dose of 12 mg/kg resulted in decreased incidence of fertile matings, increased pre-implantation loss, and fetotoxicity.

"OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

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Fluorouracil injection, USP is supplied as follows:

<div class="scrollingtable"><table width="100%"> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Product Code</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Unit of Sale</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Each</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">101710</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63323-117-10</p> <p>Unit of 10</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">500 mg per 10 mL</p> <p>(50 mg per mL)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63323-117-00</p> <p>10 mL single-dose, flip-top vial</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">101720</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63323-117-20</p> <p>Unit of 10</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 g per 20 mL</p> <p>(50 mg per mL)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63323-117-01</p> <p>20 mL single-dose, flip-top vial</p> </td> </tr> </tbody> </table></div>

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. PROTECT FROM LIGHT. DO NOT FREEZE. Retain in carton until time of use.

Fluorouracil injection, USP, is a cytotoxic drug. Follow applicable special handling and disposable procedures [see References (15)].

The container closure is not made with natural rubber latex.

Advise:

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Lake Zurich, IL 60047

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www.fresenius-kabi.com/us

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45648J

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NDC 63323-117-00             101710

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Fluorouracil Injection, USP

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500 mg per 10 mL

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(50 mg per mL)

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For Intravenous Use

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Rx only

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10 mL

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Single-Dose Vial

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NDC 63323-117-10        101710

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Fluorouracil Injection, USP

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500 mg per 10 mL

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(50 mg per mL)

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For Intravenous Use

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Rx only

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10 x 10 mL

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Single-Dose Vials

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NDC 63323-117-01        101720

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Fluorouracil Injection, USP

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1 g per 20 mL

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(50 mg per mL)

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For Intravenous Use

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20 mL

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Single-Dose Vial        Rx only

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NDC 63323-117-20        101720

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Fluorouracil Injection, USP

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1 g per 20 mL

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(50 mg per mL)

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For Intravenous Use

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Rx only

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10 x 20 mL

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Single-Dose Vials

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