CLASSES

Topical Dermatological Antifungals

DEA CLASS

Rx

DESCRIPTION

Topical allylamine antifungal
Indicated for the interdigital tinea pedis, tinea cruris, and tinea corporis
Similar efficacy and adverse events profiles to topical azole antifungals

COMMON BRAND NAMES

Naftin, Naftin-MP

HOW SUPPLIED

Naftifine Hydrochloride/Naftin Topical Gel: 1%, 2%
Naftifine Hydrochloride/Naftin/Naftin-MP Topical Cream: 1%, 2%

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

No maximum dosage information is available.

No maximum dosage information is available.

No maximum dosage information is available for the 2% gel or 2% cream; safety and efficacy have not been established for all other formulations.

12 years: No maximum dosage information is available for the 2% gel or 2% cream; safety and efficacy have not been established for all other formulations.
2 to 11 years: No maximum dosage information is available for the 2% cream; safety and efficacy have not been established for all other formulations
< 2 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

For topical dermatologic use only; not for ophthalmic, oral, or intravaginal use.
Wash hands before and after application. When treating hand infections, do not wash patient's hands after application. Use gloves for topical application if required by universal precautions.
Rub topical cream or gel gently into the affected area(s). Apply an amount sufficient to cover the affected area and the immediate (approximately a 0.5 inch margin) surrounding skin. Avoid getting in the eyes, nose, mouth, or other mucous membranes.
Avoid occlusive dressing of the affected areas unless otherwise directed by the prescriber.
Improvement of dermal tinea infection is gradual, and improvements in the treated condition may continue for weeks after naftifine therapy is discontinued. The manufacturer recommends that patients not be considered therapeutic failures until 2 to 4 weeks of therapy have passed.

STORAGE

Naftin:
- Avoid extreme temperatures
- Protect from direct sunlight
- Store at controlled room temperature (between 68 and 77 degrees F)
- Store in a cool, well ventilated, dry place
Naftin-MP:
- Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

Naftifine is contraindicated in patients that have a known or suspected hypersensitivity to naftifine or any of the components of the formulation. If irritation, skin rash, or sensitivity occurs during use of naftifine, treatment should be discontinued and appropriate therapy administered. Avoid accidental exposure to unintended areas like the mucus membranes (e.g., mouth, nose, vaginal) or ocular exposure during treatment. Naftifine is for external use only.

According to the manufacturer, diagnosis of the mycoses should be performed by a tissue mount in potassium hydroxide and direct microscopic examination or by culture. Naftifine treatment may need to be continued for 4—6 weeks or longer, and patients should be informed to continue treatment for the full treatment period. If no clinical improvement is seen after 4 weeks of using topical naftifine, the patient should be re-evaluated. Patients should be informed to avoid the use of an occlusive dressing with naftifine (unless otherwise directed by their health care professional).

There are no available data on naftifine use during human pregnancy to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, no adverse effects on embryofetal development were observed with oral doses up to 37-times the maximum recommended human dose (MRHD) administered during organogenesis to pregnant rats or subcutaneous doses up to 4- and 7-times MRHD administered during organogenesis to pregnant rats and rabbits, respectively.[55334]

There is no information available on the presence of naftifine in human milk, the effects of the drug on the breast-fed infant, or the effects of the drug on milk production after topical application to women who are breast-feeding. The lack of clinical data precludes a clear determination regarding the risk of naftifine to a nursing infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for naftifine and any potential adverse effects on the breast-fed infant from naftifine or the underlying maternal condition. Based on data that roughly 3% of the drug is absorbed systemically, it was predicted that a breast-feeding infant may ingest 0.3 mcg/kg from human milk. To minimize infant exposure, advise lactating mothers to avoid topical naftifine application to the breast area. Clotrimazole and miconazole may be potential alternatives to consider during breast-feeding. However, assess the site of infection, local susceptibility patterns, and specific microbial susceptibility before choosing an alternative agent.[26994] [48145] [48147] [40267] [40140] [55334]

Safety and efficacy of the 1% naftifine gel and 1% naftifine cream have not been established in neonates, infants, children, nor adolescents. The 2% gel formulation is approved for use in pediatric patients as young as 12 years of age; this approval was based on the results of an open label trial, in which 22 pediatric patients (age 12 to 17 years) were exposed to approximately 4 grams of naftifine/day for 14 days. The 2% cream formulation is approved for use in children as young as 2 years of age for the treatment of tinea corporis, and 12 years for the treatment of tinea pedis and tinea cruris.

ADVERSE REACTIONS

agranulocytosis / Delayed / Incidence not known

erythema / Early / 0.5-0.5
contact dermatitis / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known

skin irritation / Early / 2.0-5.0
rash / Early / 0.5-0.5
pruritus / Rapid / 1.0
dizziness / Early / Incidence not known
headache / Early / Incidence not known

DRUG INTERACTIONS

There are no drug interactions associated with Naftifine products.

PREGNANCY AND LACTATION

There are no available data on naftifine use during human pregnancy to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, no adverse effects on embryofetal development were observed with oral doses up to 37-times the maximum recommended human dose (MRHD) administered during organogenesis to pregnant rats or subcutaneous doses up to 4- and 7-times MRHD administered during organogenesis to pregnant rats and rabbits, respectively.[55334]

There is no information available on the presence of naftifine in human milk, the effects of the drug on the breast-fed infant, or the effects of the drug on milk production after topical application to women who are breast-feeding. The lack of clinical data precludes a clear determination regarding the risk of naftifine to a nursing infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for naftifine and any potential adverse effects on the breast-fed infant from naftifine or the underlying maternal condition. Based on data that roughly 3% of the drug is absorbed systemically, it was predicted that a breast-feeding infant may ingest 0.3 mcg/kg from human milk. To minimize infant exposure, advise lactating mothers to avoid topical naftifine application to the breast area. Clotrimazole and miconazole may be potential alternatives to consider during breast-feeding. However, assess the site of infection, local susceptibility patterns, and specific microbial susceptibility before choosing an alternative agent.[26994] [48145] [48147] [40267] [40140] [55334]

MECHANISM OF ACTION

Naftifine exerts its antifungal effect by selective inhibition of the enzyme squalene 2,3-epoxidase, a key enzyme in ergosterol biosynthesis in fungi. Typically, squalene is transformed into ergosterol in the fungus. Ergosterol is a component of fungal membranes necessary for normal cell growth and function. The inhibition of the enzyme creates a deficiency in ergosterol and an accumulation of squalene. An abundance of squalene leads to cell death due to a decrease in phospholipid and glycoprotein synthesis and membrane destruction. Naftifine has fungicidal activity against dermatophytes, and exhibits fungistatic activity against Candida sp. At higher concentrations, naftifine can be fungicidal against Candida sp. Naftifine does not inhibit human sterol production. Naftifine has also been shown to possess local bactericidal properties against both gram-positive and gram-negative bacteria. The excellent anti-inflammatory properties of naftifine appear to be due to vasoconstriction via inhibition of inflammatory mediators, such as prostaglandins, leukotrienes, and histamine. Research also suggests that the allylamine antifungals, like naftifine, may enhance selected functions of polymorphonuclear leukocytes.

PHARMACOKINETICS

Naftifine is administered topically. Following topical application, measurable concentrations of naftifine are absorbed into the plasma and the drug penetrates the stratum corneum in sufficient quantities to inhibit growth of dermatophytes; however, it is not known if naftifine distributes into human milk or crosses the placenta. Roughly 14 to 29% of the absorbed dose is metabolized in the liver. Up to 64% of an absorbed dose and its metabolites is excreted in the urine and 36% in the bile. The metabolites have no pharmacologic activity. Unlike the imidazoles, the allylamine group of antifungals has limited effect on the cytochrome P450 enzyme system. Naftifine has a half-life of approximately 2 to 3 days.
 
Affected cytochrome P450 enzymes and drug transporters: None