Ketaconazole

KETACONAZOLE- ketoconazole aerosol, foam
Mylan Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

Ketoconazole foam, 2% is indicated for the topical treatment of seborrheic dermatitis in immunocompetent patients 12 years of age and older.

Limitations of Use

Safety and efficacy of ketoconazole foam for treatment of fungal infections have not been established.

2 DOSAGE AND ADMINISTRATION

Ketoconazole foam should be applied to the affected area(s) twice daily for four weeks.

Hold the container upright, and dispense ketoconazole foam into the cap of the can or other cool surface in an amount sufficient to cover the affected area(s). Dispensing directly onto hands is not recommended, as the foam will begin to melt immediately upon contact with warm skin. Pick up small amounts of ketoconazole foam with the fingertips, and gently massage into the affected area(s) until the foam disappears. For hair-bearing areas, part the hair, so that ketoconazole foam may be applied directly to the skin (rather than on the hair).

Avoid contact with the eyes and other mucous membranes. Ketoconazole foam is not for ophthalmic, oral or intravaginal use.

3 DOSAGE FORMS AND STRENGTHS

Ketoconazole foam, 2% contains 20 mg of ketoconazole, USP per gram, supplied in 50 g and 100 g containers.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Contact Sensitization

Ketoconazole foam may result in contact sensitization, including photoallergenicity [see Adverse Reactions (6.2)].

5.2 Flammable Contents

The contents of ketoconazole foam include alcohol and propane/butane, which are flammable. Avoid fire, flame and/or smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

5.3 Systemic Effects

Hepatitis has been seen with orally administered ketoconazole (1:10,000 reported incidence). Lowered testosterone and ACTH–induced corticosteroid serum levels have been seen with high doses of orally administered ketoconazole. These effects have not been seen with topical ketoconazole.

6 ADVERSE REACTIONS

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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be related to drug use and for approximating rates.

The safety data presented in Table 1 reflect exposure to ketoconazole foam in 672 subjects, 12 years and older with seborrheic dermatitis. Subjects applied ketoconazole foam or vehicle foam twice daily for 4 weeks to affected areas on the face, scalp, and/or chest. Adverse reactions occurring in > 1% of subjects are presented in Table 1.

Table 1: Adverse Reactions Reported by > 1% Subjects in Clinical Trials

Adverse Reactions

Ketoconazole Foam N = 672 n (%)

Vehicle Foam N = 497 n (%)

Subjects with an Adverse Reaction

188 (28%)

122 (25%)

Application site burning

67 (10%)

49 (10%)

Application site reaction

41 (6%)

24 (5%)

Application site reactions that were reported in < 1% of subjects were dryness, erythema, irritation, paresthesia, pruritus, rash and warmth.

6.2 Dermal Safety Studies

In a photoallergenicity study, 9 of 53 subjects (17%) had reactions during the challenge period at both the irradiated and non-irradiated sites treated with ketoconazole foam. Ketoconazole foam may cause contact sensitization.

6.3 Postmarketing Experience

The following adverse events have been identified during postmarketing use of ketoconazole foam:

Gastrointestinal disorders: Cheilitis

General disorders and administration site conditions: Application site pain and application site burn

Skin and subcutaneous tissue disorders: Skin burning sensation and erythema

Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on ketoconazole foam use in pregnant women to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. No reproductive studies in animals have been performed with ketoconazole foam. In animal reproduction studies with pregnant mice, rats and rabbits both embryotoxic and developmental effects (structural abnormalities) were observed following oral dosing of ketoconazole during organogenesis. Assuming equivalent systemic absorption of topical and oral ketoconazole doses and an ketoconazole foam maximum recommended human dose (MRHD) of 8 grams (equivalent to 160 mg ketoconazole), embryotoxic effects were observed at 0.8 to 2.4 times the MRHD and developmental effects were observed at 4.8 times the MRHD [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

The animal multiples of human exposure calculations are based on body surface area (BSA) comparisons of oral doses administered to animals and an ketoconazole foam maximum recommended human dose (MRHD) of 8 grams (equivalent to 2.67 mg ketoconazole/kg/day for a 60 kg individual or 98.8 mg ketoconazole/m2 /day).

Embryofetal development studies have been conducted in mice, rats and rabbits with orally administered ketoconazole. When orally administered to mice on gestational days 6 through 18 (covering the period of organogenesis), ketoconazole was embryotoxic (25 mg/kg and higher; 0.8 times the MRHD based on BSA comparisons) with a high incidence of resorptions, increased number of stillbirths and delayed parturition. Delays in maturation were also observed. There was no evidence of maternal toxicity or malformations at up to 50 mg/kg (1.5 times the MRHD based on BSA comparisons). No treatment related developmental effects were observed at 10 mg/kg (0.3 times the MRHD based on BSA comparisons).

In the presence of maternal toxicity in rats, orally administered ketoconazole was both embryotoxic (40 mg/kg and higher; 2.4 times the MRHD based on BSA comparisons), including increased resorbed fetuses and stillbirths, and teratogenic (80 mg/kg and higher; 4.8 times the MRHD based on BSA comparisons), including syndactylia, oligodactylia, waved ribs and cleft palate. Additionally, 100 mg/kg (6 times the MRHD based on BSA comparisons) ketoconazole orally administered on a single day during gestation (gestational days 9 through 12) was embryotoxic (increased resorptions). This same oral dose given on gestation day 12, 13, 14 or 15 induced external malformations including cleft palate, micromelia and digital anomalies (brachydactyly, ectrodactyly, syndactyly).

In pregnant rabbits orally administered ketoconazole, evidence of embryotoxicity (increased resorptions) was observed at 10 mg/kg (1.2 times the MRHD based on BSA comparisons) and higher and an increased incidence of skeletal abnormalities was observed at 40 mg/kg (4.8 times the MRHD based on BSA comparisons).

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