Clotrimazole

CLOTIC is indicated for the treatment of fungal otitis externa (otomycosis) due to Aspergillus species and Candida species in patients 18 years of age and older. Limitations of Use CLOTIC has only been studied in patients with intact tympanic membranes. The use of CLOTIC is not recommended for the treatment of otomycosis in patients with perforated tympanic membranes. CLOTIC is an azole antifungal indicated for the treatment of fungal otitis externa (otomycosis) due to Aspergillus species and Candida species in patients 18 years of age and older. ( 1 ) Limitations of Use CLOTIC has only been studied in patients with intact tympanic membranes. The use of CLOTIC is not recommended for the treatment of otomycosis in patients with perforated tympanic membranes

CLOTIC is for otic use only. ( 2 ) Instill the contents of one single-dose CLOTIC vial into the affected ear canal twice daily, morning and evening, preferably 12 hours apart for 14 consecutive days. ( 2 ) See full prescribing information for preparation and administration instructions 2.1 Recommended Dosage and Administration CLOTIC is for otic use only. Instill the contents of one single-dose CLOTIC vial into the affected ear canal twice daily morning and evening, preferably 12 hours apart, for 14 consecutive days.

2.2 Preparation and Administration Instructions Warm the solution by holding the vial in the hand for 1 to 2 minutes. This is to avoid dizziness which may result from the instillation of a cold solution into the ear canal. The patient should lie with the affected ear upward, and then instill the medication. Gently pull the outer ear lobe upward and outward. This will allow the ear drops to flow down into the ear canal. Maintain this position for 1 minute after the drug administration. Repeat, if necessary, for the opposite ear [see Instructions for Use ].

Otic solution: Each single-dose vial of CLOTIC (clotrimazole) otic solution, 1%, delivers approximately 0.17 mL of solution equivalent to 1.7 mg of clotrimazole. The solution is clear colorless to slightly yellow. Otic solution: Each single-dose vial of CLOTIC (clotrimazole) otic solution, 1%, delivers approximately 0.17 mL of solution equivalent to 1.7 mg of clotrimazole. ( 3 )

CLOTIC is contraindicated in patients with known hypersensitivity to clotrimazole. CLOTIC is contraindicated in patients with known hypersensitivity to clotrimazole. ( 4 )

5 WARNINGS AND PRECAUTIONS None. None. ( 5 )

The most common adverse reactions that occurred in ≥ 1 patient were headache, application site pain, tinnitus, tympanic membrane perforation, and paresthesia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Carwin Pharmaceutical Associates, LLC at phone 1-844-700-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In two randomized, placebo-controlled, phase 3 trials, 393 adult patients with otomycosis and intact tympanic membranes were treated with CLOTIC or placebo (Trial 1 and Trial 2) twice daily for a median duration of 14 days. There were 261 patients who received at least one dose of CLOTIC and 132 patients received at least one dose of placebo. These patients had a mean age of 51 years (range 19 to 89 years); 55% were male, 87% were White, and 26% were Hispanic or Latino ethnicity. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 1% (3/261) of patients receiving CLOTIC and 3% (4/132) of patients receiving placebo. Adverse reactions leading to discontinuation of CLOTIC were application site pain in two patients and tympanic membrane perforation in one patient. Most Common Adverse Reactions Selected adverse reactions that occurred in 1 or more patients receiving CLOTIC are presented in Table 1. Table 1: Selected Adverse Reactions Occurring in 1 or more Patients in Trials 1 and 2 Adverse Reactions CLOTIC N=261 n (%) Placebo N=132 n (%) Headache 4 (1.5) 2 (1.5) Application site pain 2 (0.8) 0 Tinnitus 2 (0.8) 0 Tympanic membrane perforation 2 (0.8) 1 (0.8) Paresthesia 1 (0.4) 0

8.1 Pregnancy Risk Summary Systemic absorption of clotrimazole following topical administration appears to be minimal, and maternal use of CLOTIC is not expected to result in fetal exposure to the drug. The background risk of major birth defects and miscarriage for the indicated population is unknown All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

8.2 Lactation Risk Summary Systemic absorption following topical administration of CLOTIC appears to be minimal, and breastfeeding is not expected to result in exposure of the child to CLOTIC. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CLOTIC and any potential adverse effects on the breast-fed infant from CLOTIC or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of CLOTIC in pediatric patients less than 18 years of age have not been established.

8.5 Geriatric Use Of the total number of patients with otomycosis who received CLOTIC in Trial 1 and Trial 2 (n=261), 78 (30%) were 65 years of age and older, while 23 (9%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

Risk Summary Systemic absorption of clotrimazole following topical administration appears to be minimal, and maternal use of CLOTIC is not expected to result in fetal exposure to the drug. The background risk of major birth defects and miscarriage for the indicated population is unknown All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

The safety and effectiveness of CLOTIC in pediatric patients less than 18 years of age have not been established.

Of the total number of patients with otomycosis who received CLOTIC in Trial 1 and Trial 2 (n=261), 78 (30%) were 65 years of age and older, while 23 (9%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

CLOTIC is a sterile preservative-free otic solution containing clotrimazole, an azole antifungal agent, at a concentration of 1% in polyethylene glycol (PEG) 400. The solution is clear colorless to slightly yellow. Each single-dose vial of CLOTIC delivers approximately 0.17 mL of solution equivalent to 1.7 mg of clotrimazole. Chemically, clotrimazole is 1-(o-chloro-α,α-diphenylbenzyl)imidazole, with the empirical formula C 22 H 17 ClN 2 , a molecular weight of 344.84, and the following structural formula. Chemical Structure

12.1 Mechanism of Action Clotrimazole is an azole antifungal agent [see Microbiology (12.4) ] .

12.2 Pharmacodynamics Clotrimazole exposure-response relationships and the time course of pharmacodynamic response are unknown.

12.3 Pharmacokinetics Systemic absorption following topical administration of CLOTIC is anticipated to be minimal. The plasma concentrations of clotrimazole were not measured following otic installation of 1.7 mg (0.17 mL) clotrimazole 1% solution twice daily.

12.4 Microbiology Mechanism of Action Clotrimazole, an azole antifungal agent, inhibits the cytochrome P450 dependent enzyme lanosterol 14-α-demethylase encoded by Erg11 in yeasts and Cyp51A in molds. Erg11/Cyp51A is necessary for the conversion of lanosterol to ergosterol, which is an essential sterol component of fungal cytoplasmic membrane. Disruption in ergosterol biosynthesis causes damage to the cell membrane by increasing its permeability, resulting in cell lysis and death. Clotrimazole inhibition of lanosterol 14-α-demethylase also leads to an accumulation of 14-α-methylsterols; the methylsterols may affect the electron transport system, thereby inhibiting growth of fungi. Resistance Resistance to azoles, including clotrimazole, has been associated with decreased affinity for the target enzyme (Erg11 in Candida spp. and Cyp51A in Aspergillus spp.), increase in target copy number, alteration of the ergosterol biosynthetic pathway and overexpression of efflux pumps. Antimicrobial Activity CLOTIC has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1) ] : Fungal Aspergillus spp. Candida spp.

Clotrimazole is an azole antifungal agent [see Microbiology (12.4) ] .

Clotrimazole exposure-response relationships and the time course of pharmacodynamic response are unknown.

Systemic absorption following topical administration of CLOTIC is anticipated to be minimal. The plasma concentrations of clotrimazole were not measured following otic installation of 1.7 mg (0.17 mL) clotrimazole 1% solution twice daily.

, Mutagenesis, Impairment of Fertility Carcinogenesis No long-term studies of CLOTIC have been performed to evaluate carcinogenic potential. A 78-week oral (dietary) study of clotrimazole in rats did not show evidence of carcinogenicity at doses up to an equivalent of 150 mg/kg/day. Mutagenesis Clotrimazole has been studied in in vitro (bacterial) and in vivo (hamster spermatogonia) mutagenicity assays, and no evidence of mutagenic potential was found. Impairment of Fertility No reproduction toxicity studies were conducted with CLOTIC. Absorption of clotrimazole following topical administration is minimal.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Administration Instructions Advise patients that CLOTIC is for otic use only. Advise patients to warm the otic solution by holding the vial in the hand for 1 to 2 minutes before instilling it in the ear, to avoid dizziness [see Dosage and Administration (2.2) ] .

Store at 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature). Store unused vials in the foil pouch to protect from humidity. Do not open foil pouch until ready to use. Discard vial after use. Discard unused vials 30 days after first opening the pouch.