Get your patient on Ketoconazole - Ketoconazole tablet (Ketoconazole)

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 ).

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.)

Coadministration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin is contraindicated with ketoconazole tablets. (See PRECAUTIONS: DRUG INTERACTIONS ).

Concomitant administration of ergot alkaloid such as dihydroergotamine and ergotamine with ketoconazole tablets is contraindicated. (See PRECAUTIONS: DRUG INTERACTIONS).

The use of ketoconazole tablets is contraindicated in patients with acute or chronic liver disease.

Ketoconazole tablets USP, 200 mg is contraindicated in patients who have shown hypersensitivity to the drug.

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.

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 ketonazole 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.H2-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.

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.

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 the piperazine rings, by hepatic microsomal enzymes. In addition, oxidative 0-dealkylation and aromatic hydroxylation does occur. Ketoconazole has not been demonstrated to induce its own metabolism.

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.

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 occured 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.

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 interval. Data from some clinical PK/PO 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 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.