ATC Class:D01AE22
VA Class:DE102
Naftifine hydrochloride is a synthetic allylamine antifungal agent.1, 3, 4, 5, 9, 11, 13, 14, 16, 21, 22, 23, 25, 29, 31, 35, 36, 37, 38, 41, 42, 43, 48, 63
Dermatophytoses and Cutaneous Candidiasis
Naftifine hydrochloride 1% topical cream or gel is used topically for the treatment of certain dermatophytoses (i.e., tinea cruris,1, 22, 23, 39, 45, 48, 49, 50, 51, 54, 55, 63 tinea corporis,1, 22, 39, 46, 48, 49, 50, 51, 54, 55, 63 tinea pedis,1, 15, 28, 47, 48, 49, 51, 54, 55, 63 and tinea manuum†51, 54, 55 ) caused by Trichophyton mentagrophytes ,1, 39, 47, 49, 50, 51, 53, 55, 63 T. rubrum , 1 T. verrucosum †, 50, 51, 53 T. violaceum ,50 Epidermophyton floccosum ,1, 39, 45, 47, 49, 50, 51, 53, 63 or Microsporum canis †.49, 50, 55 Naftifine topical gel has been used with some success in the treatment of tinea unguium (onychomycosis)†.57 The drug also has been effective when used topically for the treatment of cutaneous candidiasis†.47, 50, 51, 53, 54, 55, 56, 62
Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal; however, an oral antifungal may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection is chronic or does not respond to topical therapy, or the patient is immunocompromised because of coexisting disease or concomitant therapy.69, 70, 71, 72, 73 Many clinicians consider topical imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole) or topical allylamine antifungals (e.g., naftifine, terbinafine) the drugs of first choice for the topical treatment of tinea corporis or tinea cruris,70, 74 although other antifungals agents (e.g., ciclopirox olamine, butenafine hydrochloride, tolnafate, undecylenic acid) also can be effective in the treatment of these infections.69, 70, 71, 72, 73 Uncomplicated interdigital and vesiculobullous forms of tinea pedis generally can be treated effectively using topical therapy with an imidazole-derivative azole antifungal (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), an allylamine antifungal (e.g., naftifine, terbinafine), or other topical antifungal agents such as ciclopirox olamine, butenafine hydrochloride, tolnaftate, or undecylenic acid.69, 70, 71, 72, 73 However, an oral antifungal regimen usually is necessary for the treatment of hyperkeratotic areas on the palms and soles,70, 73 for chronic moccasin-type (dry-type) tinea pedis,69, 70, 72 and for the treatment of tinea unguium (onychomycosis).69, 70, 71, 72
Results of controlled studies indicate that naftifine hydrochloride 1% cream is equivalent in efficacy and safety to topical clotrimazole 1% cream,25, 32, 46, 47, 49 miconazole nitrate 1% cream,33 econazole nitrate 1% cream,22, 34, 51 or tolnaftate32 for the treatment of dermatophytoses. In clinical studies, 2-4 weeks of therapy with topical naftifine hydrochloride 1% cream resulted in a clinical and mycologic cure in 78-100% of patients with tinea cruris or tinea corporis22, 25, 33, 39, 45, 46, 49, 51, 53, 54 and 4-5 weeks of therapy resulted in a clinical and mycologic cure in 69-82% of patients with tinea pedis.15, 47, 49 Like imidazole-derivative azole antifungal agents (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole) and ciclopirox olamine, naftifine has an advantage over some other topical antifungal agents (e.g., nystatin, tolnaftate) in the treatment of mixed infections or for empiric treatment pending identification of the causative organism since the drug is active against both dermatophytes and Candida .56 However, in vitro on a weight basis, naftifine is considerably less active than imidazole derivatives against Candida .36, 37, 56
Naftifine hydrochloride is applied topically to the skin as a 1% cream1 or gel.63 The cream or gel should not be applied to the eye, and contact with the nose, mouth, and other mucous membranes should be avoided.1, 63 Occlusive dressings or wrappings should not be used, and hands should be washed after applying the cream.1, 63
For the treatment of tinea cruris, tinea corporis, or tinea pedis, a sufficient amount of naftifine hydrochloride topical cream1, 22, 33, 39, 46, 47, 49, 50, 51, 53, 54, 60 or gel63 should be applied and rubbed gently into the affected and surrounding skin areas; naftifine hydrochloride topical cream should be applied once daily1, 15, 33, 39, 53, 54, 60 and naftifine hydrochloride topical gel should be applied twice daily, in the morning and evening.
Clinical improvement usually occurs within the first week of treatment with naftifine hydrochloride topical cream.22, 25, 39, 45 Tinea cruris and tinea corporis generally are treated for 2-4 weeks22, 25, 39, 45, 46, 49 and tinea pedis for 4-6 weeks;15, 47, 49 severe infections may require more prolonged therapy.50, 60, 61 If clinical improvement does not occur after 4 weeks of treatment with naftifine hydrochloride topical cream or gel, the diagnosis should be reevaluated.1, 63
Topically applied naftifine hydrochloride appears to have a low order of toxicity and generally is well tolerated.1, 25, 32, 33, 34, 46, 47, 50, 54, 55 The major adverse effect reported with the drug is transient burning and stinging,1, 22, 32, 39, 46, 47, 50, 51, 55, 63 which occurred in 5-6% of patients during clinical studies.1, 63 Dryness,1, 23, 24, 47, 50, 51, 57 erythema,1, 23, 34, 49, 50, 63 pruritus,1, 22, 34, 39, 63 local irritation,1, 23, 24, 39, 45, 46, 47, 49, 50, 51 rash,63 and skin tenderness63 occurred in 0.5-3% of patients.1, 63 Although these local adverse effects generally are mild to moderate in severity,23, 32, 39, 45, 46, 47, 50, 51, 54, 56 they rarely are severe enough to require discontinuance of the drug.22, 24, 32, 45, 46, 47, 50, 54, 56
Contact dermatitis has been reported occasionally in patients receiving topical naftifine.20, 39, 49, 54, 56 In at least one case, the reaction appeared to be caused by the drug;20 in other reported cases, it was unclear whether the reaction was caused by the drug or the vehicle.20, 39, 54, 56 Results of patch tests in some patients who had contact dermatitis during naftifine therapy indicate that these individuals were sensitive to benzyl alcohol or some other ingredient contained in the vehicle.20, 54, 56 Controlled studies in guinea pigs and rabbits indicate that naftifine appears to have minimal potential for inducing allergic contact sensitization following topical application.44 In a dermatotoxicity study in healthy adults, topical application of a cream, gel, or solution containing naftifine to intact or irritated skin did not reveal evidence of local irritation, contact sensitization, phototoxicity, or photoallergic dermatitis.48
Adverse systemic effects have not been reported to date with topical naftifine.23
Precautions and Contraindications
Patients receiving topical naftifine hydrochloride therapy should be instructed to use the medication for the full, prescribed treatment period, even if symptoms improve, and to contact their physician if their skin condition does not improve after the prescribed period of treatment (i.e., up to 4 weeks).1 Patients also should be instructed to contact their physician if signs of increased irritation indicative of possible sensitization occur at the site of application.1, 63 If a reaction suggesting sensitivity or chemical irritation occurs during treatment with naftifine hydrochloride 1% cream or gel, the drug should be discontinued and an appropriate alternative anti-infective substituted.1, 63 Patients receiving topical naftifine therapy also should be instructed to avoid the use of occlusive dressings or wrappings (unless otherwise directed by the physician) and to keep the cream away from eyes, nose, mouth, and other mucous membranes.1, 63
Prior to initiation of naftifine therapy, the diagnosis should be confirmed either by direct microscopic examination of a potassium hydroxide mounting of infected tissue or by culture on an appropriate medium.1, 63
Naftifine is contraindicated in patients who have known hypersensitivity to the drug or any ingredient in the formulation.1, 63 Commercially available naftifine hydrochloride cream or gel is intended for topical application to the skin only and should not be applied to the eye .1, 63
Safety and efficacy of topical naftifine hydrochloride cream and gel in children1 younger than 12 years of age60 have not been established.1, 63
Mutagenicity and Carcinogenicity
Naftifine was not mutagenic1 in the rat hepatocyte DNA repair assay, mouse micronucleus test, or Chinese hamster V-79 cell test, or in the Salmonella microbial mutagen (Ames) test with metabolic activation.44 Long-term animal studies to determine the carcinogenic potential of naftifine have not been performed to date.1, 63
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using oral naftifine hydrochloride in doses 150 or more times the usual topical human dose have not revealed evidence of harm to the fetus.1, 44, 63 In in vitro studies using rat embryos exposed to the drug, there was no evidence of embryotoxicity at concentrations of 10 mcg/mL or less; however, adverse effects on embryonic growth and differentiation and morphologic abnormalities of a nonspecific pattern did occur at concentrations of 30 mcg/mL or greater.26, 29, 44 There are no adequate and controlled studies to date using topical naftifine in pregnant women, and the drug should be used during pregnancy only when clearly needed.1, 63
Reproduction studies in rats and rabbits using oral naftifine hydrochloride in doses 150 or more times the usual topical human dose have not revealed evidence of impaired fertility.1, 44, 63
Although naftifine is distributed into the milk of rats,43 it is not known whether the drug is distributed into human milk.1, 63 The manufacturer states that topical naftifine should be used with caution in nursing women;1, 63 however, it is unlikely that clinically important concentrations of naftifine could be achieved in breast milk following topical application of usual dosages to the skin.43, 60, 61
Naftifine hydrochloride usually is fungicidal in action against susceptible dermatophytes.1, 9, 14, 41, 42 The drug usually is fungistatic against Candida , including C. albicans ,1, 3, 42 but may be fungicidal at high concentrations.9, 14, 41, 42
The exact mechanism of action of naftifine's antifungal activity has not been fully determined.1, 3, 11, 16, 41, 43 The drug appears to interfere with sterol biosynthesis by inhibiting the enzyme squalene monooxygenase (squalene 2,3-epoxidase),1, 11, 13, 14, 16, 21, 41, 43 which results in decreased amounts of sterols, especially ergosterol, and a corresponding accumulation of squalene (the usual substrate of the enzyme) in the cells.1, 3, 10, 11, 16, 41 Accumulation of squalene appears to result in changes in membrane properties of susceptible fungi; these membrane changes do not appear to be directly responsible for the fungicidal or fungistatic action of the drug, especially against Candida ,3, 41 but cause secondary effects such as inhibition of phospholipid synthesis or inhibition of synthesis and extracellular transport of glycoproteins.41 Morphologic changes in Candida after exposure to naftifine include accumulation of lipid particles within the cytoplasm, alterations in the plasma membrane, and a thickening of the cell wall.5, 31
In vitro studies indicate that naftifine readily penetrates the cell envelope of Candida .3, 11 Therefore, naftifine's greater in vitro activity against dermatophytes compared with that against Candida appears to be related to the fact that sterol synthesis in the various fungi differs in susceptibility to the drug's blockade.3, 11, 14, 16 Naftifine and other allylamine derivatives appear to cause an immediate and total cessation of ergosterol synthesis in dermatophytes, whereas residual ergosterol synthesis may continue following exposure of some Candida species to the drugs.14
Squalene monooxygenase, similar to that contained in fungi, is involved in mammalian cholesterol synthesis; however, studies using rat liver indicate that the mammalian enzyme is 3-4 orders of magnitude (i.e., between 1000-10,000) times less sensitive than the fungal enzyme to the effects of naftifine and other allylamine derivatives.11, 13, 16
Although imidazole derivatives (e.g., clotrimazole, econazole, ketoconazole, miconazole) also appear to exert their antifungal activity by interfering with sterol biosynthesis, the mechanism of action of these antifungal agents differs from that of naftifine and other allylamine derivatives.11, 30, 43 The allylamine derivatives appear to affect sterol biosynthesis at an earlier stage than do imidazole derivatives and do not appear to affect C-14 demethylation of sterol intermediates (e.g., lanosterol).11, 41, 43 In addition, unlike imidazole derivatives, allylamine derivatives have no effect on the microsomal cytochrome P-450 systems in the liver, adrenal glands, or testes.11, 30, 43
Naftifine appears to have anti-inflammatory activity following topical application to skin.51, 52 Results of histamine wheal tests in healthy adults indicate that topical application of naftifine to the skin 2 hours prior to intracutaneous injection of histamine can inhibit erythema and wheal formation.51 Topical application to the skin of an alcoholic solution of naftifine also has effectively suppressed the erythema response to ultraviolet light.52 The anti-inflammatory effect of naftifine also was confirmed using a vasoconstrictor assay usually used to test the anti-inflammatory activity of topical corticosteroids.51
Naftifine hydrochloride is active against many fungi, including dermatophytes and yeasts.1, 2, 3, 4, 5, 8, 9, 12, 22, 23, 31, 37, 42 Limited data indicate that naftifine also may have some in vitro activity against gram-positive and -negative bacteria,58, 60, 61 but further studies are needed.61 Limited in vitro studies also indicate that the drug may have some activity against Leishmania .27
Results of in vitro susceptibility tests with naftifine do not appear to be affected by inoculum size,4 but are method dependent8 and are affected by pH.3, 4, 9, 11, 42 In vitro, naftifine is most active at pH 6.5-7 and relatively inactive at acidic pH;3, 11, 41, 42, 60 therefore, buffered media must be used for in vitro susceptibility testing of the drug since most fungi tend to acidify unbuffered media.11 The decreased antifungal activity of naftifine at low pH may be related to the fact that binding of naftifine to fungal cell membranes is pH dependent.41 Like other antifungal agents, results of naftifine in vitro susceptibility tests may not accurately reflect the in vivo susceptibility of some fungi (especially Candida ).42, 60, 61
Naftifine is active in vitro against Trichophyton mentagrophytes ,1, 2, 8, 38, 41, 42 T. rubrum ,1, 8, 38, 42 T. tonsurans ,1, 38 T. verrucosum ,42 T. violaceum ,8, 38 Epidermophyton floccosum ,1, 4, 8, 12, 38, 42 Microsporum audouinii ,1 M. canis ,1, 8, 38, 42 and M. gypseum .1, 8 Most susceptible strains of these dermatophytes are inhibited in vitro by naftifine hydrochloride concentrations of 0.01-0.4 mcg/mL.4, 8, 9, 12, 38, 42 In vitro on a weight basis, naftifine's activity against dermatophytes appears to be similar to or slightly greater than that of imidazole derivatives (e.g., clotrimazole, econazole, ketoconazole)4, 12, 37, 42 or tolnaftate.4, 42
Naftifine is active in vitro against Candida , including C. albicans ,1, 3, 4, 12, 36 C. krusei ,4 C. parapsilosis ,4, 12, 31, 41 and C. tropicalis ;12 however, the drug is much less active in vitro against these organisms than against dermatophytes.42 In addition, in vitro on a weight basis, naftifine is considerably less active against Candida than imidazole derivatives.36, 37, 56 A wide range of naftifine MIC values has been reported for Candida ; MICs of naftifine hydrochloride for C. albicans generally range from 1.5-100 mcg/mL.3, 4, 9 Naftifine is more active against C. parapsilosis than against C. albicans and C. tropicalis .12
Naftifine has some activity in vitro against Aspergillus ,4, 9, 12, 42 including A. flavus and A. fumigatus ,12 and the MIC of the drug reported for these organisms is 0.25-12.5 mcg/mL.4, 12 Sporothrix schenckii generally is inhibited in vitro by naftifine hydrochloride concentrations of 0.2-8 mcg/mL,4, 12 and Cryptococcus neoformans 12 and Petriellidium boydii 12 are inhibited by concentrations of 4-64 mcg/mL. Naftifine also is active in vitro against Blastomyces dermatitidis and Histoplasma capsulatum .12
Development of resistance to naftifine in organisms originally susceptible to the drug has not been reported to date;60, 61 however, the potential for resistance to the antifungal activity of the drug remains to be more fully evaluated with continued use.61
Following topical application of naftifine hydrochloride 1% cream or gel to intact skin of healthy adults, approximately 3-6% of the dose is absorbed systemically.1, 43, 63 Studies using radiolabeled naftifine indicate that following a single application of the drug, sufficient concentrations are retained in the upper skin layers to inhibit the growth of dermatophytes at this site for 24 hours.43
It is not known whether naftifine crosses the placenta.60 It also is not known whether naftifine is distributed into human milk;1, 63 however, the drug is distributed into the milk of rats43 following topical administration.60
Naftifine is metabolized to at least 3 metabolites by oxidation of the phenyl and naphthyl rings and by N -dealkylation.18 Following topical application of naftifine to intact skin in healthy adults, percutaneously absorbed naftifine and/or its metabolites are excreted in urine and feces.1, 18, 63 Approximately 40-60% of the absorbed dose is excreted in urine as unchanged drug and metabolites;18, 43 the remainder of the absorbed dose is excreted in feces via biliary elimination.18
Naftifine has a half-life of approximately 2-3 days following topical administration.1, 60, 63
Naftifine hydrochloride is a synthetic allylamine antifungal agent.1, 3, 4, 5, 9, 11, 13, 14, 16, 21, 22, 23, 25, 29, 31, 35, 36, 37, 38, 41, 42, 43, 48, 63 Naftifine is derived from naphthalenemethanamine8 and is structurally and pharmacologically related to terbinafine.64, 65, 66, 67, 68, 69 Several derivatives of naftifine and some other allylamine antifungal agents currently are being investigated but are not commercially available.11, 12, 13, 14, 16, 21, 23, 29, 30, 36, 43 The tertiary allylamine function appears to be necessary for the antifungal activity of naftifine and other allylamine derivatives.35 Naftifine's antifungal activity also appears to be related to the naphthalene ring system, with the side chain in the α-position, and the amino function and double bond.35
Naftifine hydrochloride occurs as a white to yellow, fine, crystalline powder60 and has solubilities of 0.68 mg/mL in water and 3.4 mg/mL in alcohol at 25°C.60 The drug has a pKa of 6.82.60 Naftifine hydrochloride is commercially available as a cream in a water-miscible base1 and as a gel containing alcohol 52% v/v;63 the cream has a pH of 4.5.60
Naftifine hydrochloride cream should be stored at a temperature less than 30°C1 and the gel should be stored at room temperature.63 The commercially available cream is stable for at least 24 months following the date of manufacture.60
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Cream | 1% | Naftin® | Merz |
Gel | 1% | Naftin® | Merz |
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