ketoconazole 20 MG/ML Topical Foam [Extina]

INDICATIONS AND USAGE Ketoconazole shampoo, 2%, is indicated for the treatment of tinea (pityriasis) versicolor caused by or presumed to be caused by Pityrosporum orbiculare (also known as Malassezia furfur or M. orbiculare ). Note: Tinea (pityriasis) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk which may extend to the neck, arms and upper thighs. Treatment of the infection may not immediately result in normalization of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure. Although tinea versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora.

DOSAGE AND ADMINISTRATION Ketoconazole foam, 2% should be applied to the affected area(s) twice daily for four weeks. Hold the container upright, and dispense ketoconazole foam, 2% 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, 2% 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, 2% may be applied directly to the skin (rather than on the hair). Avoid contact with the eyes and other mucous membranes. Ketoconazole foam, 2% is not for ophthalmic, oral or intravaginal use. • Ketoconazole foam, 2% should be applied to the affected area(s) twice daily for four weeks ( 2 ). • Ketoconazole foam, 2% is not for ophthalmic, oral, or intravaginal use ( 2 ).

WARNINGS Because of the serious adverse reactions that have been reported in association with ketoconazole, including fatal hepatotoxicity, ketoconazole tablets are not indicated for treatment of onychomycosis, cutaneous dermatophyte infections, or Candida infections. Ketoconazole tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks. Hepatotoxicity Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity was reported both by patients receiving high doses for short treatment durations and by patients receiving low doses for long durations. The hepatic injury has usually, but not always, been reversible upon discontinuation of ketoconazole tablets treatment. Cases of hepatitis have been reported in children. At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST, total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR), and testing for viral hepatitides). Patients should be advised against alcohol consumption while on treatment. If possible, use of other potentially hepatotoxic drugs should be avoided in patients receiving ketoconazole tablets. Prompt recognition of liver injury is essential. During the course of treatment, serum ALT should be monitored weekly for the duration of treatment. If ALT values increase to a level above the upper limit of normal or 30 percent above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained. Liver tests should be repeated to ensure normalization of values. Hepatotoxicity has been reported with restarting oral ketoconazole (rechallenge). If it is decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring liver injury from the drug. QT Prolongation and Drug Interactions Leading to QT Prolongation Ketoconazole can prolong the QT interval. Coadministration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, lurasidone, cisapride, methadone, disopyramide, dronedarone, ranolazine. Ketoconazole can cause elevated plasma concentrations of these drugs which may prolong the QT interval, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. Adrenal Insufficiency Ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. This effect is not shared with other azoles. The recommended dose of 200 mg to 400 mg daily should not be exceeded. Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.). Adverse Reactions Associated with Unapproved Uses Ketoconazole has been used in high doses for the treatment of advanced prostate cancer and for Cushing's syndrome when other treatment options have failed. The safety and effectiveness of ketoconazole have not been established in these settings and the use of ketoconazole for these indications is not approved by FDA. In a clinical trial involving 350 patients with metastatic prostatic cancer, eleven deaths were reported within two weeks of starting treatment with high doses of ketoconazole tablets (1200 mg/day). It is not possible to ascertain from the information available whether death was related to ketoconazole therapy or adrenal insufficiency in these patients with serious underlying disease. Hepatoxicity, including fatal cases and cases requiring liver transplantation, have been reported in patients who received ketoconazole for treatment of onychomycosis, cutaneous dermatophyte infections, or Candida infections. Hypersensitivity Anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported.

CONTRAINDICATIONS Drug Interactions Coadministration of a number of CYP3A4 substrates such as dofetilide, quinidine, cisapride and pimozide is contraindicated with ketoconazole tablets. Coadministration with ketoconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious adverse reaction may occur. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and sometimes resulting in life-threatening ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. (See PRECAUTIONS : Drug Interactions .) Coadministration of ketoconazole tablets with lurasidone is contraindicated since it may result in an increase in lurasidone exposure and the potential for serious adverse reactions (see PRECAUTIONS : Drug Interactions ). Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. (See PRECAUTIONS : Drug Interactions .) Enhanced Sedation Coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam or alprazolam is contraindicated. (See PRECAUTIONS : Drug Interactions .) Myopathy Coadministration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin is contraindicated with ketoconazole tablets. (See PRECAUTIONS : Drug Interactions . ) Ergotism Concomitant administration of ergot alkaloids such as dihydroergotamine and ergotamine with ketoconazole tablets is contraindicated. (See PRECAUTIONS : Drug Interactions .) Liver Disease The use of ketoconazole tablets is contraindicated in patients with acute or chronic liver disease. Hypersensitivity Ketoconazole tablets USP, 200 mg is contraindicated in patients who have shown hypersensitivity to the drug.

CLINICAL PHARMACOLOGY Pharmacokinetics Absorption Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption. Mean peak plasma concentrations of approximately 3.5 mcg/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Oral bioavailability is maximal when the tablets are taken with a meal. Absorption of ketoconazole tablets is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as acid neutralizing medicines (e.g. aluminum hydroxide) and gastric acid secretion suppressors (e.g. H 2 -receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See Section PRECAUTIONS : Drug Interactions ) Absorption of ketoconazole under fasted conditions in these subjects is increased when ketoconazole tablets are administered with an acidic beverage (such as non-diet cola). After pretreatment with omeprazole, a proton pump inhibitor, the bioavailability of a single 200-mg dose of ketoconazole under fasted conditions was decreased to 17% of the bioavailability of ketoconazole administered alone. When ketoconazole was administered with non-diet cola after pretreatment with omeprazole, the bioavailability was 65% of that after administration of ketoconazole alone. Distribution In vitro , the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widely distributed into tissues; however, only a negligible proportion reaches the cerebrospinal fluid. Metabolism Following absorption from the gastrointestinal tract, ketoconazole tablets are converted into several inactive metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of ketoconazole. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, by hepatic microsomal enzymes. In addition, oxidative O-dealkylation and aromatic hydroxylation does occur. Ketoconazole has not been demonstrated to induce its own metabolism. Elimination Elimination from plasma is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Approximately 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract with about 57% being excreted in the feces. Special Populations Patients with Hepatic or Renal Impairment In patients with hepatic or renal impairment, the overall pharmacokinetics of ketoconazole was not significantly different when compared with healthy subjects. Pediatric Patients Limited pharmacokinetic data are available on the use of ketoconazole tablets in the pediatric population. Measurable ketoconazole plasma concentrations have been observed in pre-term infants (single or daily doses of 3 to 10 mg/kg) and in pediatric patients 5 months of age and older (daily doses of 3 to 13 mg/kg) when the drug was administered as a suspension, tablet or crushed tablet. Limited data suggest that absorption may be greater when the drug is administered as a suspension compared to a crushed tablet. Conditions that raise gastric pH may lower or prevent absorption (See Section PRECAUTIONS : Drug Interactions ). Maximum plasma concentrations occurred 1 to 2 hours after dosing and were in the same general range as those seen in adults who received a 200 to 400 mg dose. Electrocardiogram Pre-clinical electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QT c interval. Data from some clinical PK/PD studies and drug interaction studies suggest that oral dosing with ketoconazole at 200 mg twice daily for 3 to 7 days can result in an increase of the QT c interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma concentrations about 1 to 4 hours after ketoconazole administration. MICROBIOLOGY Mechanism of Action Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. Activity In Vitro & In Vivo Ketoconazole tablets USP, 200 mg are active against clinical infections with Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis.