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Ketoconazole Gel, 2%

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Ketoconazole gel 2% is antifungal agent in a topical anhydrous gel vehicle for topical administration.

Ketoconazole is cis -1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H -imidazol-1-ylmethyl)-1,3 - dioxolan-4-yl]methoxy] phenyl]piperazine and has the following structural formula:

Each gram contains: 20 mg ketoconazole USP, dehydrated alcohol (34%), ascorbic acid, butylated hydroxytoluene, citric acid monohydrate, glycerin, hydroxypropyl cellulose, polyethylene glycol 400, PPG-15 stearyl ether, propylene glycol, FD&C yellow No. 6, and FD&C yellow No. 10.

Ketoconazole gel is a smooth, translucent to clear, amber gel.

2. INDICATIONS AND USAGE

Ketoconazole gel is indicated for the topical treatment of seborrheic dermatitis in immunocompetent adults and children 12 years of age and older.

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

3. DOSAGE AND ADMINISTRATION

Ketoconazole gel is for topical use only, and not for oral, ophthalmic, or intravaginal use.

Ketoconazole gel should be applied once daily to the affected area for 2 weeks.

4. CONTRAINDICATIONS

None.

5. MECHANISM OF ACTION

The mechanism of action of ketoconazole in the treatment of seborrheic dermatitis is unknown.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well controlled trials in pregnant women. Ketoconazole gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Reproductive toxicity studies have not been performed with ketoconazole gel. Ketoconazole was tested for its effects on offspring in the rat at oral doses of 10, 20, 40, 80, and 160 mg/kg. Ketoconazole was teratogenic (syndactylia and oligodactylia) at 80 mg/kg/day and embryotoxic at 160 mg/kg/day (76 and 152 times the human dose, respectively). However, these effects may be related to maternal toxicity, which was also seen at these dose levels.

Oral doses of 10, 20, 40, 80, and 160 mg/kg were studied in pre- and postnatal development studies in rats. Doses of 40 mg/kg (38 times the human dose) and above were associated with maternal toxicity, an increase in the length of gestation, and an increase in the number of stillborn fetuses. These doses of ketoconazole were also toxic to the offspring, resulting in a decrease in fetal/pup weights and viability.

6.2 Nursing Mothers

It is not known whether ketoconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ketoconazole is administered to a nursing woman.

If used during lactation and ketoconazole is applied to the chest, care should be taken to avoid accidental ingestion by the infant.

6.3 Pediatric Use

Safety and effectiveness in pediatric subjects below the age of 12 have not been established.

6.4 Geriatric Use

Of the 933 subjects in the three safety and efficacy trials, 193 (20.7%) were 65 and older, while 61 (6.5%) were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out.

7. WARNINGS AND PRECAUTIONS

7.1 Flammable Contents

Ketoconazole gel is flammable. Avoid being near fire, flame, or smoking during and immediately following application of ketoconazole gel.

7.2 Systemic Effects

Hepatitis and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topically administered ketoconazole.

7.3 Local Effects

Ketoconazole gel can cause local irritation at the application site. If irritation occurs or if the disease worsens, use of the medication should be discontinued and the health care provider should be contacted [see ADVERSE REACTIONS].

8. ADVERSE REACTIONS

8.1 Clinical Trial 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 clinical practice.

In the 3 safety and efficacy trials, 65 of 933 subjects (7%) experienced at least one treatment-related adverse event. The most common treatment-related adverse reaction was application site burning (4%). Treatment-related application site reactions that were reported in < 1% of subjects were: dermatitis, discharge, dryness, erythema, irritation, pain, pruritus, and pustules. Other treatment-related adverse reactions that were reported in < 1% of subjects were: eye irritation, eye swelling, keratoconjunctivitis sicca, impetigo, pyogenic granuloma, dizziness, headache, paresthesia, acne, nail discoloration, facial swelling.

8.2 Post-marketing Experience

Adverse events identified during post approval use of ketoconazole gel include burning sensation, pain, skin irritation, 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.

9. OVERDOSAGE

There has been no experience of overdose with ketoconazole gel. No incidents of accidental ingestion have been reported. A health care provider or poison control center should be contacted in the event of accidental ingestion.

10. DRUG INTERACTIONS

Formal drug interaction studies with XOLEGEL have not been performed. Coadministration of oral ketoconazole with CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, lovastatin and atorvastatin, may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. These effects have not been observed with topically administered ketoconazole.

11. PHARMACOKINETICS

In a pharmacokinetic absorption trial, eighteen subjects, both males and females, with severe seborrheic dermatitis (range 1-14% of body surface area) applied ketoconazole gel once daily for 2 weeks. The median total amount of gel applied was 4.6 g (range 1.65–46.3 g). Daily doses ranged from 0.05 to 3.47 g. Mean (± standard deviation [SD]) peak plasma levels were 1.35 (± 3.18) ng/mL on Day 7 (range from < 0.1 ng/mL, to 13.9 ng/mL), and 0.80 (± 1.22) ng/mL on Day 14 (range from < 0.1 ng/mL to 5.4 ng/mL). Median Tmax was 8 hours on Day 7 and 7 hours on Day 14. Mean (± SD) AUC0-24 values were 20.8 (± 44.7) ngwh/mL and 15.6 (± 26.4) ngwh/mL on Day 7 and 14, respectively.

The plasma levels from an oral dose of 200 mg ketoconazole taken with a meal are approximately 250 times higher than the resulting plasma levels of ketoconazole following topical application of ketoconazole gel.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: XOLEGEL, by Aqua Pharms.

b) Generic drugs: None.

2) How Supplied:

XOLEGEL® (ketoconazole, USP) Gel, 2% is supplied in 45-gram (NDC 16110-080-45) white-coated aluminum tubes with white caps, and is dispensed with FDA-Approved Patient Labeling.

3) Storage:

Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).

Contents are flammable.

Keep out of reach of children.

Rx only

Rev 05/12