Ketoconazole

INDICATIONS AND USAGE 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. Ketoconazole tablets are indicated for the treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole tablets should not be used for fungal meningitis because it penetrates poorly into the cerebrospinal fluid.

DOSAGE AND ADMINISTRATION There should be laboratory as well as clinical documentation of infection prior to starting ketoconazole therapy. The usual duration of therapy for systemic infection is 6 months. Treatment should be continued until active fungal infection has subsided. Adults The recommended starting dose of ketoconazole tablets is a single daily administration of 200 mg (one tablet). If clinical responsiveness is insufficient within the expected time, the dose of ketoconazole tablets may be increased to 400 mg (two tablets) once daily. Children In small numbers of children over 2 years of age, a single daily dose of 3.3 to 6.6 mg/kg has been used. Ketoconazole tablets have not been studied in children under 2 years of age.

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 side 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 alkaloid such as dihydroergotamine and ergotamine with ketoconazole tablets is contraindicated. (See PRECAUTIONS: DRUG INTERACTIONS). Liver Diseases 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.

ADVERSE REACTIONS 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 following adverse reactions were reported in clinical trials: Immune System Disorders : anaphylactoid reaction Endocrine Disorders : gynecomastia Metabolism and Nutrition Disorders : alcohol intolerance, anorexia, hyperlipidemia, increased appetite Psychiatric Disorders : insomnia, nervousness Nervous System Disorders : headache, dizziness, paresthesia, somnolence Eye Disorders : photophobia Vascular Disorders : orthostatic hypotention Respiratory, Thoracic and Mediastinal Disorders : epistaxis Gastrointestinal Disorders : vomiting, diarrhea, nausea, constipation, abdominal pain, abdominal pain upper, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration Hepatobiliary Disorders : hepatitis, jaundice, hepatic function abnormal Skin and Subcutaneous Tissues Disorders : erythema multiforme, rash, dermatitis, erythema urticaria, pruritus, alopecia, xeroderma Musculoskeletal and Connective Tissue Disorders : myalgia Reproductive System and Breast Disorders : menstrual disorder General Disorders and Administration Site Conditions : asthenia, fatigue, hot flush, malaise, edema peripheral, pyrexia, chills Investigations : platelet count decreased. Post-Marketing Experience The following adverse reactions have been identified during postapproval use of ketoconazole tablets. Because these reactions 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. The following adverse reactions were reported during post-marketing experience: Blood and Lymphatic System Disorders : thrombocytopenia Immune System Disorders : allergic conditions including anaphylactic shock, anaphylactic reaction, angioneurotic edema Endocrine Disorders : adrenocortical insufficiency Nervous System Disorders : reversible intracranial pressure increased (e.g. papilloedema, fontanelle bulging in infants) Hepatobiliary Disorders : serious hepatotoxicity including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death Skin and Subcutaneous Tissue Disorders : acute generalized exanthematous pustulosis, photosensitivity Musculoskeletal and Connective Tissue Disorders : arthralgia Reproductive System and Breast Disorders : erectile dysfunction; with doses higher than the recommended therapeutic dose of 200 or 400mg daily, azoospermia. To report SUSPECTED ADVERSE EVENTS, contact Amici at 1-866-760-2646 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Drug Interactions Ketoconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of ketoconazole. Similarly, ketoconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Ketoconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosages. Interaction studies have only been performed in adults. The relevance of the results from these studies in pediatric patients is unknown. Drugs that may decrease ketoconazole plasma concentrations Drugs that reduce the gastric acidity (e.g., acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 -receptor antagonists and proton pump inhibitors) impair the absorption of ketoconazole from ketoconazole tablets. These drugs should be used with caution when coadministered with ketoconazole tablets: Ketoconazole tablets should be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity. Acid neutralizing medicines (e.g., aluminum hydroxide) should be administered at least 1 hour before or 2 hours after the intake of ketoconazole tablets. Upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary. Coadministration of ketoconazole tablets with potent enzyme inducers of CYP3A4 may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. Examples include: Antibacterials: isoniazid, rifabutin (see also under 'Drugs that may have their plasma concentrations increased'), rifampicin. Anticonvulsants: carbamazepine (see also under 'Drugs that may have their plasma concentrations increased'), phenytoin. Antivirals: efavirenz, nevirapine. Therefore, administration of potent enzyme inducers of CYP3A4 with ketoconazole tablets is not recommended. The use of these drugs should be avoided from 2 weeks before and during treatment with ketoconazole tablets, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. Upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary. Drugs that may increase ketoconazole plasma concentrations Potent inhibitors of CYP3A4 (e.g., antivirals such as ritonavir, ritonavir-boosted darunavir and ritonavir-boosted fosamprenavir) may increase the bioavailability of ketoconazole. These drugs should be used with caution when coadministered with ketoconazole tablets. Patients who must take ketoconazole tablets concomitantly with potent inhibitors of CYP3A4 should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of ketoconazole, and the ketoconazole tablets dose should be decreased as deemed necessary. When appropriate, ketoconazole plasma concentrations should be measured. Drugs that may have their plasma concentrations increased by ketoconazole Ketoconazole can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with ketoconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4- metabolized drugs known to prolong the QT interval may be contraindicated with ketoconazole tablets, since the combination may lead to ventricular tachyarrhythmias, including occurrences of torsade de pointes, a potentially fatal arrhythmia. Examples of drugs that may have their plasma concentrations increased by ketoconazole presented by drug class with advice regarding coadministration with ketoconazole tablet …

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.

DESCRIPTION Ketoconazole tablets USP is a synthetic broad-spectrum antifungal agent available in scored white tablets, each containing 200 mg ketoconazole base for oral administration. Inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and methylcellulose. 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: Ketoconazole is a white to slightly beige, odorless powder, soluble in acids, with a molecular weight of 531.44g/moL. FDA approved dissolution test specifications differ from USP. image description

OVERDOSAGE In the event of acute accidental overdose, treatment consists of supportive and symptomatic measures. Within the first hour after ingestion, activated charcoal may be administered.

HOW SUPPLIED Ketoconazole tablets USP, 200 mg are white to off-white, round, flat faced bevel edge, scored tablets, debossed "A" over "35" on one side and plain with bisect on the other side. NDC: 71335-1849-1: 10 Tablets in a BOTTLE NDC: 71335-1849-2: 30 Tablets in a BOTTLE NDC: 71335-1849-3: 40 Tablets in a BOTTLE NDC: 71335-1849-4: 60 Tablets in a BOTTLE NDC: 71335-1849-5: 8 Tablets in a BOTTLE NDC: 71335-1849-6: 7 Tablets in a BOTTLE NDC: 71335-1849-7: 14 Tablets in a BOTTLE NDC: 71335-1849-8: 90 Tablets in a BOTTLE Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Keep out of reach of children. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504