Ketoconzole drug interactions

# Drug Interactions
Coadministration of a number of CYP3A4 substrates 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. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. See WARNINGS section, and PRECAUTIONS: Drug Interactions section for specific examples.

## 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.

## Kintecis of 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.

### Effects of ketoconazole on other drugs
Systemic exposure to the following drugs is significantly increased by coadministration of ketoconazole. Concomitant use of these drugs with ketoconazole tablets USP, 200 mg is contraindicated
Alprazolam, midazolam, triazolam
Co-administration of ketoconazole tablets with alprazolam, midazolam, or triazolam has resulted in elevated plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated or chronic administration of these agents. Concomitant administration of ketoconazole tablets with alprazolam, oral midazolam, and oral triazolam is contraindicated. (SeeCONTRAINDICATIONS and WARNINGS sections.) Special precaution and patient monitoring are required with concomitant parenteral midazolam, because the sedative effect may be prolonged.
Cisapride
Oral ketoconazole potently inhibits the metabolism of cisapride resulting in a mean eight-fold increase in AUC of cisapride, which can lead to prolongation of QT interval. Therefore concomitant administration of ketaconazole tablets with cisapride is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.)
Dofetilide
The class III antiarrhythmic dofetilide is known to prolong the QT interval. The potential increase in dofetilide plasma concentrations when administered concomitantly with ketoconazole could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes. Therefore, concomitant administration of ketoconazole tablets with dofetilide is contraindicated. (See BOXED WARNING,CONTRAINDICATIONS, and WARNINGS sections.)
Eplerenone
Ketoconazole increases the eplerenone AUC by roughly 5-fold, thereby increasing the risk for hyperkalemia and hypotension. Co-administration of ketoconazole and eplerenone is contraindicated. (See CONTRAINDICATIONS section.)
Ergot Alkaloids
Elevated concentrations of ergot alkaloids can cause ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine and ergotamine with ketoconazole tablets is contraindicated. (See CONTRAINDICATIONS section.)
HMG-CoA Enzyme Inhibitors (lovastatin, simvastatin)
Co-administration of ketoconazole with CYP3A4-metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin, may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of ketoconazole tablets with these HMG-CoA reductase inhibitors is contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.)
Nisoldipine
Pre-treatment with and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold increase in mean AUC and Cmax of nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone. Concomitant administration of ketoconazole with nisoldipine is contraindicated. (See CONTRAINDICATIONS section.)
Pimozide
Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of ketoconazole and pimozide could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes, and is therefore contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.)
Quinidine
The class IA antiarhythmic quinidine is known to prolong the QT interval. The potential increase in quinidine plasma concentrations when administered concomitantly with ketoconazole could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes. Therefore, concomitant administration of ketoconazole tablets with quinidine is contraindicated. (See BOXED WARNING,CONTRAINDICATIONS, and WARNINGS sections.)
Co-administration of ketoconazole with the following agents was shown or is expected to result in increased exposure to these drugs. Therefore, careful monitoring of plasma concentrations or adverse events of these drugs is recommended. Adjustment of dosage of these drugs may be needed
Alfentanil, sufentanil, fentanyl
In vitro data suggest that alfentanil, sufentanil and fentanyl are metabolized by CYP3A4. Concomitant administration of ketoconazole tablets and alfentanil, sufentanil, or fentanyl may increase plasma concentrations of the latter drugs.
Amlodipine, felodipine, nicardipine, nifedipine
CYP3A4 metabolized calcium channel blockers such as amlodipine, felodipine, nicardipine, and nifedipine should be used cautiously with ketoconazole tablets as ketoconazole may cause several-fold increases in plasma concentrations of these calcium channel blockers.
Bosentan
Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1- and 2.3  fold, respectively. No dosage adjustment of bosentan is needed but close monitoring for increased bosentan-associated adverse effects is recommended.
Buspirone
Concomitant administration of buspirone with ketoconazole may result in significant increases in plasma concentrations of buspirone. When administered with ketoconazole tablets, a low initial dose of buspirone with subsequent dosage adjustment based on clinical assessment is recommended.
Busulfan
Ketoconazole tablets may decrease the clearance and thus increase the systemic exposure to busulfan.
Carbamazepine
In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Close monitoring of plasma carbamazepine concentrations is recommended whenever ketoconazole is given to patients stabilized on carbamazepine therapy.
Cilostazol
Ketoconazole had been shown to increase both cilostazol AUC and Cmax by about two-fold when administered concurrently. Co-administration of ketoconazole with cilostazol resulted in increased incidences of adverse effects, such as headache. When ketoconazole tablets is administered concomitantly with cilostazol, the prescriber should consider up to a 50% reduction in cilostazol dosage.
Cyclosporine
Ketoconazole tablets may alter the metabolism of cyclosporine, thereby resulting in elevated cyclosporine plasma concentrations. Dosage adjustment may be required if cyclosporine or tacrolimus is given concomitantly with ketoconazole tablets.
Digoxin
Rare cases of elevated plasma concentrations of digoxin have been reported. It is not clear whether this was due to the combination of therapy. It is, therefore, advisable to monitor digoxin concentrations in patients receiving ketoconazole.
Docetaxel
In the presence of ketoconazole, the clearance of docetaxel in cancer patients was shown to decrease by 50%. When docetaxel and ketoconazole are administered together, dosage reduction in docetaxel may be necessary in order to minimize the incidence of toxicities associated with docetaxel.
Indinavir, saquinavir
Concomitant administration of ketoconazole and protease inhibitors metabolized by CYP3A4, such as indinavir and saquinavir, may increase plasma concentrations of these protease inhibitors. Dosage reduction of indinavir is recommended when administering ketoconazole concomitantly. No dosage adjustments are recommended when saquinavir and ketoconazole are coadministered for a short period of time.
Methylprednisolone
Ketoconazole tablets may alter the metabolism of methylprednisolone, resulting in elevated plasma concentrations of methylprednisolone. Dose adjustments may be required if methylprednisolone is given concomitantly with ketoconazole tablets.
Oral anti-coagulants
Oral imidazole compounds such as ketoconazole may enhance the anticoagulant effect of coumarin-like drugs, thus the anticoagulant effect should be carefully titrated and monitored.
Oral hypoglycemic agents
Because severe hypoglycemia has been reported in patients concomitantly receiving oral miconazole (an imidazole) and oral hypoglycemic agents, such a potential interaction involving the latter agents when used concomitantly with ketoconazole tablets (an imidazole) cannot be ruled out.
Rifabutin
Ketoconazole was shown to inhibit the CYP-mediated metabolism of rifabutin in vitro. Co-administration with ketoconazole tablets may result in elevated plasma concentrations of rifabutin.
Sildenafil
Ketoconazole had been shown to increase sildenafil plasma concentrations. When used concomitantly with ketoconazole tablets, a 50% reduction in sildenafil starting dose should be considered.
Sirolimus
Multiple-dose ketoconazole had been shown to increase sirolimus Cmax and AUC by 4.3-fold and 10.9-fold, respectively. The concomitant use of ketoconazole tablets and sirolimus is not recommended.
Tacrolimus
Ketoconazole had been shown to decrease the oral clearance of tacrolimus thereby leading to a 2-fold increase in tacrolimus oral bioavailability. Adjustment in tacrolimus dosage may be required if tacrolimus is given concomitantly with ketoconazole tablets.
Telithromycin
Ketoconazole increased the AUC of telithromycin by 1.5 to 2-fold. Use caution when administering telithromycin concurrently with ketoconazole tablets since this may result in an increased risk for telithromycin associated adverse events.
TolterodineIn the presence of ketoconazole, the apparent oral clearance of tolterodine decreased resulting in at least a two-fold increase in tolterodine. For patients receiving ketoconazole, a 50% reduction in the initial tolterodine dosage is recommended.
Trimetrexate
In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Patients treated concomitantly with trimetrexate and ketoconazole tablets should be carefully monitored for trimetrexate-associated toxicities.
Verapamil
Findings of in vitro metabolic studies indicate that verapamil is metabolized by enzymes including CYP3A4. Ketoconazole may increase verapamil serum concentrations. Caution should be taken when co-administering verapamil with ketoconazole tablets.
Vinca Alkaloids (vincristine, vinblastine, vinorelbine)
Ketoconazole may inhibit the metabolism of vinca alkaloids metabolized by CYP3A4. Close monitoring for toxicities associated with vincristine, vinblastine, or vinorelbine is recommended when co-administered with ketoconazole tablets.

## Effects of other drugs on ketoconazole

### Drugs affecting the absorption of ketoconazole
Gastric Acid Suppressors/Neutralizers
Studies have shown that absorption of ketoconazole is impaired when gastric acid production is decreased. Reduced plasma concentrations of ketoconazole were reported when ketoconazole tablets were administered with antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors (omeprazole, lansoprazole) and sucralfate. (See PRECAUTIONS, Drug Interactions (General) section.)

### Drugs that were shown or are expected to significantly reduce the systemic exposure to ketoconazole
Co-administration of ketoconazole with potent CYP3A4 enzyme inducers is not recommended.
Carbamazepine
Concomitant administration of ketoconazole tablets with carbamazepine may alter the metabolism of one or both of the drugs. Close monitoring for both plasma concentrations of carbamazepine and reduced ketoconazole efficacy is recommended.
Nevirapine
Ketoconazole AUC and Cmax decreased by a median of 63% and 40%, respectively, in HIV-infected patients who were given nevirapine 200 mg once daily for two weeks along with ketoconazole 400 mg daily. Concomitant administration of ketoconazole tablets and nevirapine is not recommended.
Phenytoin
Concomitant administration of ketoconazole with phenytoin may alter the metabolism of one or both of the drugs. Close monitoring for both plasma concentrations of phenytoin and reduced efficacy of ketoconazole tablets is recommended.
Rifampin, rifabutin, isoniazid
Concomitant administration of rifampin and rifabutin with ketoconazole tablets reduces the blood concentrations of the latter. INH (Isoniazid) was also reported to affect ketoconazole concentrations adversely. These antitubercular drugs should not be given concomitantly with ketoconazole tablets.

### Drugs that significantly increase the systemic exposure to ketoconazole
Ritonavir
Concomitant administration of ritonavir with ketoconazole tablets increases was shown to increase the oral bioavailability of ketoconazole. Therefore, when ritonavir is to be given concomitantly, higher doses (>200 mg/day) of ketoconazole tablets should not be used.

### Other drug interactions
Alcohol
Rare cases of a disulfiram-like reaction to alcohol have been reported. These experiences have been characterized by flushing, rash, peripheral edema, nausea, and headache. Symptoms resolved within a few hours.
Loratadine
After the co-administration of 200 mg oral ketoconazole twice daily and one 20 mg dose of loratadine to 11 subjects, the AUC and Cmax of loratadine averaged 302% (142 S.D.) and 251% ( 68 S.D.), respectively, of those obtained after cotreatment with placebo. The AUC and Cmax of descarboethoxyloratadine, an active metabolite, averaged 155% ( 27 S.D.) and 141% ( 35 S.D.), respectively. However, no related changes were noted in the QTc on ECG taken at 2, 6, and 24 hours after the coadministration. Also, there were no clinically significant differences in adverse events when loratadine was administered with or without ketoconazole.