Ketoconazole (Page 2 of 6)

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, and cisapride. 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.

Hypersensitivity

Anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported.

Enhanced Sedation

Co-administration 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 CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions sections.)

Myopathy

Co-administration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin is contraindicated with ketoconazole tablets. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions sections.)

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

Drugs that affect the absorption, distribution, metabolism, and excretion of ketoconazole may alter the plasma concentrations of ketoconazole. For example, gastric acid suppressants (e.g., antacids, histamine H2 -blockers, proton pump inhibitors) have been shown to reduce plasma concentrations of ketoconazole.Ketoconazole is a substrate and potent inhibitor of CYP3A4. Therefore, the following drug interactions may occur when ketoconazole is co-administered with other drugs that interact with CYP3A4. (See Table 1 and Table 2 for an overview of these drug interactions; details are provided in the text that follows these tables.)

  • Ketoconazole may decrease the elimination of drugs metabolized by CYP3A4, thereby increasing their plasma concentrations. Increased exposure to these drugs may cause an increase or prolongation of their therapeutic and/or adverse effects. Concomitant use with ketoconazole tablets is contraindicated for drugs known to present a risk of serious side effects with increased exposure (see BOXED WARNING, CONTRAINDICATIONS section, and PRECAUTIONS: Drug Interactions, Table 1). For others, monitoring of plasma concentrations is advised when possible. Clinical signs and symptoms associated with these drugs should be monitored, with dosage adjusted as needed.
  • Inducers of CYP3A4 may decrease the plasma concentrations of ketoconazole (see Table 2). Ketoconazole may not be effective in patients concomitantly taking one of these drugs. Therefore, administration of these drugs with ketoconazole is not recommended.
  • Other inhibitors of CYP3A4 may increase the plasma concentrations of ketoconazole (see Table 2). Patients who must take ketoconazole concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of ketoconazole.
Table 1. Selected Drugs That Have Been Shown To or Are Predicted To Have Their Plasma Concentrations Altered By Ketoconazole *
*
This list is not all-inclusive.
Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is contraindicated.
Alprazolam, midazolam, triazolam HMG-CoA reductase inhibitors (lovastatin, simvastatin)
Cisapride Nisoldipine
Dofetilide Pimozide
Eplerenone Quinidine
Ergot alkaloids (ergotamine, dihydroergotamine)
Systemic exposure to these drugs is increased by ketoconazole: Careful monitoring, with possible adjustment in dosage, is recommended.
Alfentanil, fentanyl, sulfentanil Indinavir, saquinavir
Amlodipine, felodipine, nicardipine, nifedipine Methylprednisolone
Bosentan Rifabutin
Buspirone Sildenafil
Busulfan Sirolimus (co-administration not recommended)
Carbamazepine Tacrolimus
Cilostazol Telithromycin
Cyclosporine Tolterodine
Digoxin Trimetrexate
Docetaxel, paclitaxel Verapamil
Oral anti-coagulants Vinca alkaloids (vincristine, — vinblastine, vinorelbine)
Table 2. Selected Drugs That Have Been Shown To or Are Predicted To Alter The Plasma Concentration Of Ketoconazole
*This list is not all-inclusive.
Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended.
Carbamazepine Phenytoin
Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2 -blockers, proton pump inhibitors, sucralfate) Rifampin, rifabutin, isoniazid
Nevirapine
Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered
Ritonavir

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