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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
Psychiatric Disorders: insomnia, nervousness
Eye Disorders: photophobia
Vascular Disorders: orthostatic hypotension
Respiratory, Thoracic and Mediastinal Disorders: epistaxis
Musculoskeletal and Connective Tissue Disorders: myalgia
Reproductive System and Breast Disorders: menstrual disorder
The following adverse reactions have been identified during postapproval use of Nizoral 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)
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.
Read the Nizoral (ketoconazole) Side Effects Center for a complete guide to possible side effects
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 NIZORAL® 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.)
- NIZORAL® 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 NIZORAL® Tablets is contraindicated for drugs known to present a risk of serious side effects with increased exposure (see BOXED WARNING, CONTRAINDICATIONS section, and, 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). NIZORAL® may not be effective in patients concomitantly taking one of these drugs. Therefore, administration of these drugs with NIZORAL® is not recommended.
- Other inhibitors of CYP3A4 may increase the plasma concentrations of ketoconazole (see Table 2). Patients who must take NIZORAL® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of NIZORAL® .
Table 1: Selected Drugs That Have Been Shown To or Are Predicted To
Have Their Plasma Concentrations Altered By NIZORAL®*
|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)|
|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|
|Busulfan||Sirolimus (co-administration not recommended)|
|Oral anti-coagulants||Vinca alkaloids (vincristine, - vinblastine, vinorelbine)|
|* This list is not all-inclusive.|
Table 2: Selected Drugs That Have Been Shown To or Are Predicted To
Alter The Plasma Concentration Of NIZORAL®
|Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended.|
|Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate)||Rifampin, rifabutin, isoniazid|
|Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered|
|* This list is not all-inclusive.|
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 NIZORAL® Tablets is contraindicated:
Alprazolam, midazolam, triazolam
Co-administration of NIZORAL® 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 NIZORAL® Tablets with alprazolam, oral midazolam, and oral triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.) Special precaution and patient monitoring are required with concomitant parenteral midazolam, because the sedative effect may be prolonged.
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 NIZORAL® Tablets with cisapride is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.)
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 NIZORAL® Tablets with dofetilide is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.)
Ketoconazole increases the eplerenone AUC by roughly 5-fold, thereby increasing the risk for hyperkalemia and hypotension. Co-administration of NIZORAL® and eplerenone is contraindicated. (See CONTRAINDICATIONS section.)
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 NIZORAL® 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 NIZORAL® Tablets with these HMG-CoA reductase inhibitors is contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.)
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 is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of NIZORAL® 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.)
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 NIZORAL® 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 NIZORAL® 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 NIZORAL® Tablets as ketoconazole may cause several-fold increases in plasma concentrations of these calcium channel blockers.
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.
Concomitant administration of buspirone with ketoconazole may result in significant increases in plasma concentrations of buspirone. When administered with NIZORAL® Tablets, a low initial dose of buspirone with subsequent dosage adjustment based on clinical assessment is recommended.
NIZORAL® Tablets may decrease the clearance and thus increase the systemic exposure to busulfan.
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 NIZORAL® Tablets is administered concomitantly with cilostazol, the prescriber should consider up to a 50% reduction in cilostazol dosage.
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 NIZORAL® Tablets.
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.
In the presence of ketoconazole, the clearance of docetaxel in cancer patients was shown to decrease by 50%. When docetaxel and NIZORAL® are administered together, dosage reduction in docetaxel may be necessary in order to minimize the incidence of toxicities associated with docetaxel.
Concomitant administration of NIZORAL® 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.
NIZORAL® 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 NIZORAL® Tablets.
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.
Ketoconazole was shown to inhibit the CYP-mediated metabolism of rifabutin in vitro. Co-administration with NIZORAL® Tablets may result in elevated plasma concentrations of rifabutin.
Ketoconazole had been shown to increase sildenafil plasma concentrations. When used concomitantly with NIZORAL® Tablets, a 50% reduction in sildenafil starting dose should be considered.
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 NIZORAL® Tablets and sirolimus is not recommended.
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 NIZORAL® Tablets.
Ketoconazole increased the AUC of telithromycin by 1.5 to 2-fold. Use caution when administering telithromycin concurrently with NIZORAL® Tablets since this may result in an increased risk for telithromycin associated adverse events.
In 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.
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 NIZORAL® Tablets should be carefully monitored for trimetrexate-associated toxicities.
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 NIZORAL® Tablets.
Vinca Alkaloids (vincristine, vinblastine, vinorelbine)
NIZORAL® 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 NIZORAL® 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 NIZORAL® Tablets were administered with antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors (omeprazole, lansoprazole) and sucralfate. (See 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.
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.
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 NIZORAL® Tablets and nevirapine is not recommended.
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 NIZORAL® 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 NIZORAL® Tablets.
Drugs that significantly increase the systemic exposure to ketoconazole
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 NIZORAL® Tablets should not be used.
Other drug interactions
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.
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.
Read the Nizoral Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 8/2/2013
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