CLOTRIMAZOLE

ADVERSE REACTIONS Abnormal liver function tests have been reported in patients treated with clotrimazole lozenges; elevated SGOT levels were reported in about 15% of patients in the clinical trials (See PRECAUTIONS ). Nausea, vomiting, unpleasant mouth sensations and pruritus have also been reported with the use of the lozenge. To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

CONTRAINDICATIONS Clotrimazole Lozenges are contraindicated in patients who are hypersensitive to any of its components.

DESCRIPTION Each Clotrimazole lozenge USP contains 10 mg clotrimazole USP [1-(o-chloro-α,α-diphenylbenzyl) imidazole], a synthetic antifungal agent, for topical use in the mouth. Structural Formula: Chemical Formula: C 22 H 17 ClN 2 The lozenge dosage form is a large, slowly dissolving lozenge containing 10 mg of clotrimazole USP dispersed in croscarmellose sodium, dextrates, magnesium stearate, microcrystalline cellulose and povidone. clotrimazole-structure

DOSAGE AND ADMINISTRATION Clotrimazole Lozenges are administered only as a lozenge that must be slowly dissolved in the mouth. The recommended dose is one lozenge five times a day for fourteen consecutive days. Only limited data are available on the safety and effectiveness of the clotrimazole lozenge after prolonged administration; therefore, therapy should be limited to short term use, if possible. For prophylaxis to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation, the recommended dose is one lozenge three times daily for the duration of chemotherapy or until steroids are reduced to maintenance levels.

WARNING Clotrimazole Lozenges are not indicated for the treatment of systemic mycoses including systemic candidiasis.

DRUG ABUSE AND DEPENDENCE No data available.

OVERDOSAGE No data available.

CLINICAL PHARMACOLOGY Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by altering the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal in vitro against Candida albicans and other species of the genus Candida at higher concentrations. No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Candida albicans in the laboratory; however, individual organism tolerance has been observed during successive passages in the laboratory. Such in vitro tolerance has resolved once the organism has been removed from the antifungal environment. After oral administration of a 10 mg clotrimazole lozenge to healthy volunteers, concentrations sufficient to inhibit most species of Candida persist in saliva for up to three hours following the approximately 30 minutes needed for a lozenge to dissolve. The long term persistence of drug in saliva appears to be related to the slow release of clotrimazole from the oral mucosa to which the drug is apparently bound. Repetitive dosing at three hour intervals maintains salivary levels above the minimum inhibitory concentrations of most strains of Candida ; however, the relationship between in vitro susceptibility of pathogenic fungi to clotrimazole and prophylaxis or cure of infections in humans has not been established. In another study, the mean serum concentrations were 4.98 ± 3.7 and 3.23 ± 1.4 nanograms/mL of clotrimazole at 30 and 60 minutes, respectively, after administration as a lozenge.

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CLOTRIMAZOLE CLOTRIMAZOLE CLOTRIMAZOLE CLOTRIMAZOLE DEXTRATES MICROCRYSTALLINE CELLULOSE CROSCARMELLOSE SODIUM POVIDONE K30 MAGNESIUM STEARATE white to off-white 227;P

Carcinogenesis An 18 month dosing study with clotrimazole in rats has not revealed any carcinogenic effect.

ANDA215641

CLOTRIMAZOLE

CLOTRIMAZOLE

16571-686

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 16571- 686 -07 Clotrimazole Lozenges USP 10 mg 70 Lozenges label-70s

FOR TOPICAL ORAL ADMINISTRATION Rx only

Geriatric Use Clinical studies of clotrimazole did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Pediatric Use Safety and effectiveness of clotrimazole in children below the age of 3 years have not been established; therefore, its use in such patients is not recommended. The safety and efficacy of the prophylactic use of clotrimazole lozenges in children have not been established.

Use In Pregnancy Pregnancy Category C: Clotrimazole has been shown to be embryotoxic in rats and mice when given in doses 100 times the adult human dose (in mg/kg), possibly secondary to maternal toxicity. The drug was not teratogenic in mice, rabbits, and rats when given in doses up to 200, 180, and 100 times the human dose. Clotrimazole given orally to mice from nine weeks before mating through weaning at a dose 120 times the human dose was associated with impairment of mating, decreased number of viable young, and decreased survival to weaning. No effects were observed at 60 times the human dose. When the drug was given to rats during a similar time period at 50 times the human dose, there was a slight decrease in the number of pups per litter and decreased pup viability. There are no adequate and well controlled studies in pregnant women. Clotrimazole lozenges should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category C: Clotrimazole has been shown to be embryotoxic in rats and mice when given in doses 100 times the adult human dose (in mg/kg), possibly secondary to maternal toxicity. The drug was not teratogenic in mice, rabbits, and rats when given in doses up to 200, 180, and 100 times the human dose. Clotrimazole given orally to mice from nine weeks before mating through weaning at a dose 120 times the human dose was associated with impairment of mating, decreased number of viable young, and decreased survival to weaning. No effects were observed at 60 times the human dose. When the drug was given to rats during a similar time period at 50 times the human dose, there was a slight decrease in the number of pups per litter and decreased pup viability. There are no adequate and well controlled studies in pregnant women. Clotrimazole lozenges should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

HOW SUPPLIED Clotrimazole Lozenges USP 10 mg lozenge is supplied as white to off white, round, flat face beveled edge lozenge debossed with “227” on one side and “P” on the other side. NDC 16571-686-07: Bottle of 70 Lozenges with child-resistant closure. NDC 16571-686-14: Bottle of 140 Lozenges with child-resistant closure. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Avoid freezing.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Avoid freezing.

PRECAUTIONS Abnormal liver function tests have been reported in patients treated with clotrimazole lozenges; elevated SGOT levels were reported in about 15% of patients in the clinical trials. In most cases the elevations were minimal and it was often impossible to distinguish effects of clotrimazole from those of other therapy and the underlying disease (malignancy in most cases). Periodic assessment of hepatic function is advisable particularly in patients with pre-existing hepatic impairment. Since patients must be instructed to allow each lozenge to dissolve slowly in the mouth in order to achieve maximum effect of the medication, they must be of such an age and physical and/or mental condition to comprehend such instructions. Carcinogenesis An 18 month dosing study with clotrimazole in rats has not revealed any carcinogenic effect. Use In Pregnancy Pregnancy Category C: Clotrimazole has been shown to be embryotoxic in rats and mice when given in doses 100 times the adult human dose (in mg/kg), possibly secondary to maternal toxicity. The drug was not teratogenic in mice, rabbits, and rats when given in doses up to 200, 180, and 100 times the human dose. Clotrimazole given orally to mice from nine weeks before mating through weaning at a dose 120 times the human dose was associated with impairment of mating, decreased number of viable young, and decreased survival to weaning. No effects were observed at 60 times the human dose. When the drug was given to rats during a similar time period at 50 times the human dose, there was a slight decrease in the number of pups per litter and decreased pup viability. There are no adequate and well controlled studies in pregnant women. Clotrimazole lozenges should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pediatric Use Safety and effectiveness of clotrimazole in children below the age of 3 years have not been established; therefore, its use in such patients is not recommended. The safety and efficacy of the prophylactic use of clotrimazole lozenges in children have not been established. Geriatric Use Clinical studies of clotrimazole did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.