Tinactin Once-A-Day Cream Product Monograph

ADVERSE REACTIONS

Short-term studies indicate that Tinactin® Once-A-Day^TM Cream is well tolerated by the skin. During clinical trials conducted in Japan, 23 (2.56%) of 898 patients treated with butenafine cream reported side effects consisting mainly of irritation, pruritus and stinging. During North American clinical trials with

Tinactin® Once-A-Day^TM Cream, no patient discontinued therapy due to adverse events and 2/137 patients reported local adverse reactions judged by the investigator to be possibly, probably, or definitely related to drug therapy. The incidence of local adverse reactions was 0.7%.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

There has been no experience with overdosage of Tinactin® Once-A-Day^TM Cream. Treatment should include general supportive measures.

DOSAGE AND ADMINISTRATION

When clinically warranted, therapy with Tinactin® Once-A-Day^TM Cream may be initiated while results of culture and susceptibility tests are pending. Treatment should be adjusted according to the findings.

A thin layer of Tinactin® Once-A-Day^TM Cream should be applied (to avoid macerating effects) to the affected and immediate surrounding area in patients with the following condition:

Condition Frequency Duration

Tinea Pedis Once daily 4 weeks

The full course of therapy should be followed to reduce the possibility of recurrence. However, if there is no response within the recommended treatment period, the diagnosis should be re-evaluated.

The safety of Tinactin® Once-A-Day^TM Cream has not been established with treatment periods exceeding those recommended. Therefore, treatment must not exceed the recommended duration of therapy indicated above.

1. 1.

   Dosage Directions:

   a. Cleanse the skin with soap and water and dry thoroughly.

   b. Rub in a thin layer on affected (and immediately surrounding) area once daily.

   c. In applying medication, pay special attention to spaces between toes.

   d. Wear well fitting, ventilated shoes and cotton socks.

2. 2.

   Warnings

   a. For external use only.

   b. Do not use for infections of the scalp or nails.

   c. Do not use while pregnant or nursing except on the advice of a physician.

   d. Do not exceed recommended dosage.

   e. Do not use on children under 12 years of age unless under the advice of a physician.

   PHARMACOLOGICAL INFORMATION

DRUG SUBSTANCE

Proper Name: Butenafine Hydrochloride

Chemical Name: N-4-tert-Butylbenzyl-N-methyl-1 naphthalenemethylamine Hydrochloride

Structural Formula:

Code Name: KP-363

Molecular Formula: C₂₃H₂₇N-AHCl

Molecular Weight: 353.93

Description: White crystals or crystalline powder, odorless or with a faint characteristic odor

Melting Point: 210^o to 217^oC

Stability and Storage Recommendations:

Keep container closed when not in use. Store in a cool dry place between 15^o and 30^o C.

DRUG PRODUCT

Composition

Tinactin® Once-A-Day^TM Cream contains: Butenafine hydrochloride; propylene glycol dicaprylate;

glycerin; cetyl alcohol; glyceryl monostearate; white petrolatum; stearic acid; polyoxyethylene cetyl ether; benzyl alcohol; diethanolamine; sodium benzoate; purified water.

AVAILABILITY OF DOSAGE FORMS

Each gram of smooth, white cream contains 10 mg butenafine hydrochloride. It is available in a 24-gram tube.

INFORMATION FOR THE CONSUMER

1. 1. Treatment should be continued for one to two weeks after symptoms have disappeared (up to a maximum of four weeks of treatment). If no improvement is seen within two weeks, a physician should be consulted.
2. 2. Use Tinactin® Once-A-Day^TM Cream for the full treatment period even though symptoms have subsided.
3. 3. Notify the physician if the area of application reveals signs of increased irritation (redness, itching, burning, swelling or oozing).
4. 4. 4 Keep Tinactin® Once-A-Day^TM Cream away from the eyes, nose, mouth, and other mucous membranes. If contact with the eyes occurs, rinse thoroughly with water.
5. 5.

   Dosage Directions:

   a. Cleanse the skin with soap and water and dry thoroughly.

   b. Apply a thin layer on affected (and immediately surrounding) area once daily.

   c. In applying medication, pay special attention to spaces between toes.

   d. Wear well fitting, ventilated shoes and cotton socks.

6. 6.

   Warnings:

   a. For external use only.

   b. Do not use for infections of the scalp or nails.

   c. Do not use while pregnant or nursing except on the advice of a physician.

   d. Do not exceed recommended dosage.

   e. Do not use on children under 12 years of age unless under the advice of a physician.

   PHARMACOLOGY

ACTION AND CLINICAL PHARMACOLOGY

Butenafine is a potent, broad spectrum antifungal that is fungicidal against dermatophytes and molds. The mechanism of action of butenafine most likely involves specific inhibition of fungal ergosterol biosynthesis at the point of squalene epoxidation, leading to a deficiency of this essential component of the fungal cell membranes and to intracellular accumulation of the precursor squalene (Figure 1).

FIGURE 1

Synthesis Pathway for Ergosterol Biosynthesis and Sites of Inhibition by Allylamines, Imidazoles and Butenafine

PHARMACOLOGICAL EFFECTS

Animal Studies

Numerous in vivo and in vitro studies were performed to assess the pharmacological effects of butenafine

HCl. Butenafine HCl was administered subcutaneously in 50% aqueous Macrogol 400; intravenously in

Macrogol 400 or 40% propylene glycol; topically in 0.5% carboxymethyl cellulose; and dissolved in either Macrogol 400 or propylene glycol for in vitro studies. The results are summarized below.

• Effects on the Central and Peripheral Nervous Systems:

Subcutaneous administration of 1-100 mg/kg butenafine HCl to mice had no effect on the central and autonomic nervous systems. Topical administration of 0.3-3.0% butenafine HCl solutions to guinea pigs had no effect on the somatic nervous system.

A 10^-4 M solution of butenafine HCl produced no autonomic or smooth muscle effects in vitro when added to isolated ileum or trachea from guinea pig, jejunum or aorta from rabbit, and vas deferens or uterus from rat. This solution also produced no effects on the somatic nervous system of the rat when added to phrenic nerve diaphragm preparations.

• Effect on Respiratory and Cardiovascular Systems:

Intravenous administration of 1-30 mg/kg butenafine HCl to rats caused a transient decrease in heart rate with a 10 mg/kg dose and a transient decrease in respiratory rate with a 30 mg/kg dose. A decrease in blood pressure was observed in rats with subcutaneous administration of 10 mg/kg. No effect was seen on isolated atrial muscle from guinea pigs when a 10^-4 M solution of butenafine HCl was applied.

In dogs, an intravenous dose of 100 mg/kg, the highest dose administered, caused a slight increase in respiratory rate.

• Effect on the Gastrointestinal System:

Butenafine HCl had no effect on intestinal transport when given subcutaneously to mice at 1-100 mg/kg.

• Effect on the Urogenital System:

No diuretic effect was observed when butenafine HCl was given subcutaneously to mice at 1-100 mg/kg.

• Effect on the Endocrine System:

Butenafine HCl, at doses of 1-25 mg/kg, given to rats subcutaneously for six weeks had no effect on hormone levels or kinetics. A slight hypertrophy of the adrenal glands was observed in females.

• Effect on the Hematological System:

Mice and rats dosed subcutaneously with 1-100 mg/kg butenafine HCl showed no effect on blood coagulation. No hemolysis or effects on plasma were observed when blood from rabbits was exposed to

10^-4 M butenafine HCl, in vitro.

Other

Three of the primary metabolites of butenafine HCl (defined as M1, M2, M3) were isolated from the bile and urine of rats dosed with butenafine HCl subcutaneously. Degradants (D1, D2, D3) of butenafine HCl were produced by irradiation (D1) and heating (D2 and D3) of butenafine HCl at 215^o C for 20 minutes.

The metabolites and degradants were administered intraperitoneally and subcutaneously, respectively.

Doses of 10 and 100 mg/kg produced no effects on spontaneous movement in mice; however, M1 prolonged hexobarbital-induced sleeping time. Rats dosed intravenously with 1-100 mg/kg of butenafine

HCl metabolites or degradants showed transient decrease in blood pressure with M2 (100 mg/kg), decreased heart rate with M2 (30 mg/kg), M3 (100 mg/kg), and D2 (10 mg/kg), and increased respiratory rate with M1 and D2 (100 mg/kg). In vitro administration of M1 (10^-5 M), D1 (10^-5 M), and D2 (10^-4 M)

to isolated guinea pig ileum, inhibited the contraction of smooth muscle induced by various agonists.

ABSORPTION, DISTRIBUTION , METABOLISM, AND EXCRETION

The absorption of butenafine HCl is very slow and minimal following topical application to the skin. The drug remains in the skin predominantly in the unmetabolized (parent) form and is retained preferentially in the stratum corneum. Systemically absorbed drug is bound extensively to plasma proteins and is rapidly and nearly completely metabolized by methylation, dealkylation, and hydroxylation into five major metabolites which are characteristic for drugs of this class. The tissue concentration of parent compound and metabolites after subcutaneous administration was very high in intestinal contents and distributed primarily to liver, adrenals, pancreas, and fat. It is excreted predominantly as conjugated metabolites in the feces and urine, and high concentration in milk.

SUMMARY OF ANIMAL ADME STUDIES

HUMAN PHARMACOKINETICS

Studies in humans showed that absorption of butenafine through the skin of normal male volunteers is very low. In multiple dose studies utilizing exaggerated doses of 5 grams/day for seven days, the highest detectable plasma concentration of butenafine was 7.6 ng/ml.

CLINICAL STUDIES

Butenafine has been studied in tinea pedis in two North American clinical trials. In these studies, effective treatment was tabulated as a combination of laboratory results and clinical improvement. In the table below, the term “Mycological Cure” is defined as both negative KOH and negative culture. “Effective

Clinical Response” is defined as a Physician Global Assessment of “Cleared” or “Excellent”. “Effective

Treatment” is defined as a patient having both a “Mycological Cure” and a Physician Global Assessment of “Cleared” or “Excellent”.

The combined results of two North American vehicle-controlled studies of Tinactin® Once-A-Day^TM

Cream used once daily for four week in the treatment of tinea pedis are presented in the following table.

MICROBIOLOGY

IN VITRO

In in vitro susceptibility tests, butenafine HCl showed antimicrobial activity against a broad range of fungi including dermatophytes, filamentous and dematiaceous fungi, dimorphic fungi and yeast.

Butenafine exhibited particularly strong antifungal activity against dermatophytes. Tinactin® Once-A-

Day^TM Cream exhibits in vitro antifungal activity against a broad spectrum of organisms, although the clinical significance of these data is unknown. Fungicidal activity has been demonstrated in vitro against

Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Trichophyton tonsurans, Microsporum canis and fungistatic activity against Candida albicans.

MIC Values of Butenafine Hydroxhloride

for Several Pathogenic Fungi Circulation on

Sabouraud’s Dextrose Agar Medium at 27^oC or 37^oC (Yeasts)

* Growth medium adjusted to pH 5.0 through addition of 5N HCl.

IN VIVO

The therapeutic effects of butenafine HCl in various models of dermatophytosis in the guinea pig was compared with that of other antifungals and are summarized in Primary Therapeutic Studies in Animals.

In all but one of the studies reported below, the butenafine HCl solution used consisted of butenafine HCl dissolved in Macrogol 400:ethanol (75:25). The adsorption study employed 14Clabeled butenafine HCl initially dissolved in Tween 80 and then incorporated in a mixture of Macrogol 400: ethanol:water

(30:20:50).

• Effects on Tinea Dorsalis:

In guinea pigs with tinea dorsalis caused by Trichophyton mentagrophytes, Microsporum canis or

Candida albicans, 1.0% butenafine HCl was compared with naftifine, tolnaftate, clotrimazole, miconazole and bifonazole for efficacy. A 0.5% butenafine HCl cream applied twice a day and a 1.0% butenafine cream applied once a day had cure rates of 100% against T. mentagrophytes. Once percent naftifine and 1.0% tolnaftate creams when applied once a day had cure rates of 82% and 64%, respectively. Butenafine HCl, naftifine and tolnaftate had equal efficacy against M. canis while clotrimazole had lower efficacy. One percent butenafine HCl had equal efficacy to bifonazole but less activity than miconazole against C. albicans.

• Effects on Tinea Pedis:

Butenafine HCl was tested in a guinea pig model of tinea pedis caused by T. mantagrophytes, a mycosis that does not heal spontaneously. Treatment with 0.2 to 2.0% butenafine HCl creams or solutions were started on the 10th day after infection and lasted for 20-40 days. Dose-related effectiveness was seen against tinea pedis with once-daily application of 1.0% butenafine solution, and showed higher potency than either 1.0% naftifine, tolnaftate or clotrimazole solutions.

• Prophylactic Effects:

To establish the prophylactic effect of 1.0% butenafine HCl solution relative to 1.0% bifonazole solution, each compound was applied to the skin of guinea pigs. After 24, 48 and 72 hours following application, the region was infected with T. mentagrophytes. Butenafine HCl effectively prevented infection up to 17 days after a 48-hour, pre-infection application, whereas lesions appeared after eight days following a 24-hour, pre-infection application of bifonazole.

• Substantivity and Efficacy against T. mentagrophytes:

The permeability and retention (substantivity) of butenafine HCl in the skin of guinea pigs were examined following topical application of a 1.0% ¹⁴C-labeled butenafine HCl solution for six hours to the dorsal skin of guinea pigs. At six hours post-application, 50 µg/g or more of butenafine HCl was observed in the epidermis, including the horny layer in which dermatophytes are commonly found. At 24 hours post-application, 10 µg/g or more of butenafine HCl still remained in the epidermis, indicating high affinity and long retention. The concentration of butenafine HCl in the epidermis 24 hours post-topical application of a 1.0% solution was enough to inhibit the growth of T. mentagrophytes.

MICROBIOLOGY

IN VIVO

Summary of Primary Therapeutic Studies in Animals

B: bifonazole

C: clotrimazole

M: miconazole

N: naftifine

T: tolnaftate

TOXICOLOGY

ACUTE TOXICOLOGY

D1: 1-naphthalene methanol

D2: 1-(chloromethyl) naphthalene

D3: N-methyl-bis (1-naphthalenemethyl) aminehydrochloride

M1: 1-naphthoic acid

M2: N-4 (2-hydroxy-1,1-dimethylethyl) benzyl-N-methyl-1-naphthalenemethylamine

M3: N-1-naphthoxyl glycine 100

SUBCHRONIC TOXICITY STUDIES

CHRONIC STUDIES

MUTAGENICITY

In vitro mutagenicity testing (bacteria reverse mutation and CHL chromosome aberration) revealed no specific mutagenic or genotoxic properties of butenafine

CARCINOGENICITY

Long-term animal studies to determine carcinogenic potential have not been performed.

REPRODUCTION STUDIES

SPECIAL TOXICITY STUDIES

DERMAL SAFETY STUDIES IN MAN

Tinactin® Once-A-Day^TM Cream is not a primary irritant and appears to be devoid of allergenic sensitization or phototoxic/photoallergy potential on topical application.

A challenge patch of 0.2 ml Tinactin® Once-A-Day^TM Cream applied to the skin for 24 hours, 10 to 17 days after nine consecutive 24-hour patched applications of the same dose, did not product contact sensitization in 204 North American volunteers.

In 27 North American volunteers (22 female and 5 male) treated topically with Tinactin® Once-A-Day^TM

Cream, exposure to long-wave ultraviolet light did not produce any phototoxic reaction.

Thirty-one North American volunteers received a series of six applications (two per week) of 0.2 ml of

Tinactin® Once-A-Day^TM Cream on an occlusive dressing applied to the paraspinal area for 24 hours.

Following removal of the patch, the skin was exposed to twice the subject’s minimal erythema dose from a Xenon Solar Simulator. Fourteen days after the last exposure, the subjects were challenged with 0.2 ml

Tinactin® Once-A-Day^TM Cream applied to an untreated site of the skin for 24 hours and subsequently exposed to long ultraviolet light. Tinactin® Once-A-Day^TM Cream was shown to be devoid of any detectable photocontact allergenic potential.

BIBLIOGRAPHY

1. 1.

   Maeda T, Takase M, Ishibashi A, et al. Synthesis and antifungal activity of butenafine hydrochloride (KP-363), a new benzylamine antifungal agent. Yakugaku Zasshi 1991; 111:126-

   37.

2. 2. Nussbaumer P, Dorfstätter G, Grassberger MA, et al. Synthesis and structure-activity relationships of henyl-substituted benzylamine antimycotics: a novel benzylamine antifungal agent for systemic treatment. J Med Chem 1993; 36:2115-20.
3. 3.

   Stütz A. Synthesis and structure-activity correlations within allylamine antimycotics. Ann N Y

   Acad Sci 1988; 544:46-62.

4. 4. Schuster I. The interaction of representative members from two classes of antimycotics – the azoles and the allylamines – with cytochromes P-450 in steroidogenic tissues and liver. Xenobiotica 1985; 15:529-46.
5. 5.

   Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol

   1993;28:S28-S34.

6. 6. Arika T, Yokoo M, Hase T et al. Effects of butenafine hydrochloride, a new benzylamine derivative, on experimental dermatophytosis in guinea pigs. Antimicrob Agents Chemother 1990; 34:2250-3.
7. 7. Arika T, Yokoo M, Yamaguchi H. Topical treatment with butenafine significantly lowers relapse rates in an interdigital tinea pedis model in guinea pigs. Antimicrob Agents Chemother 1992; 36:2523-5.
8. 8. Arika T, Hase T, Yokoo M. Anti-Trychophyton mentagrophyes activity and percutaneous permeation of butenafine in guinea pigs. Antimicrob Agents Chemother 1993; 37:363-5.
9. 9.

   Fukushiro R, Urabe H, Kagawa S, et al. Butenafine hydrochloride, a new antifungal agent;

   clinical and experimental study. In: Yamaguchi H, Kobayashi GS, Takahashi H (eds). Recent progress in antifungal chemotherapy. New York: Marck Dekker, 1992:147-57.

10. 10. Odom R. Pathophysiology of dermatophyte infections. J Am Acad Dermatol 1993; 28:S2-S7.