Drug Facts
Composition & Profile
Identifiers & Packaging
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. They are supplied in bottles of 100 tablets (NDC 69292-224-01) with a child-resistant cap. 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 tight, light-resistant container as defined in the USP. Keep out of reach of children.; PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 200 mg (100 Tablet Bottle) image description
- 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. They are supplied in bottles of 100 tablets (NDC 69292-224-01) with a child-resistant cap. 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 tight, light-resistant container as defined in the USP. Keep out of reach of children.
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 200 mg (100 Tablet Bottle) image description
Overview
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
Indications & 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 & 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.
Warnings & Precautions
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 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 con prolong the QT interval. Co-administration 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 pf 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 (120 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. Hepatotoxicity, 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.
Boxed Warning
Because ketoconazole tablets have been associated with serious adverse reactions (see WARNINGS section), 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. Somepatients had no obvious risk factors for liver disease. Patients receiving this drug should be informed by the physician of the risk and should be closely monitored. See WARNINGS section.4 QT Prolongation and Drug Interactions Leading to QT Prolongation Co-administration 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 and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. See CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS : DRUG INTERACTIONS sections.
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
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 ). 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.
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