Ketoconazole 200 mg Tablet, 30-count — NDC 87564-051-30 (Billing 87564-0051-30)

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 can 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 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 re… [Excerpted — this section continues on DailyMed.]

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 hypotension 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.

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.

PRECAUTIONS General Ketoconazole tablets have been demonstrated to lower serum testosterone. Once therapy with ketoconazole tablets has been discontinued, serum testosterone levels return to baseline values. Testosterone levels are impaired with doses of 800 mg per day and abolished by 1600 mg per day.

Clinical manifestations of decreased testosterone concentrations may include gynecomastia, impotence and oligospermia. Information for Patients Patients should be instructed to report any signs and symptoms which may suggest liver dysfunction so that appropriate biochemical testing can be done. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, abdominal pain, jaundice, dark urine or pale stools (see WARNINGS section).

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 H2-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 drug… [Excerpted — this section continues on DailyMed.]