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NIZORAL®
(ketoconazole) Tablets
WARNING
NIZORAL® 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.
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. Patients receiving this drug should be informed by the physician of the risk and should be closely monitored. See WARNINGS section.
Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: DRUG INTERACTIONS sections.
NIZORAL® is a synthetic broad-spectrum antifungal agent available in scored white tablets, each containing 200 mg ketoconazole base for oral administration. Inactive ingredients are colloidal silicon dioxide, corn starch, lactose, magnesium stearate, microcrystalline cellulose, and povidone. Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl] piperazine and has the following structural formula:
 |
Ketoconazole is a white to slightly beige, odorless powder, soluble in acids, with a molecular weight of 531.44.
NIZORAL® 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.
NIZORAL® (ketoconazole) Tablets are indicated for the treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. NIZORAL® Tablets should not be used for fungal meningitis because it penetrates poorly into the cerebrospinal fluid.
There should be laboratory as well as clinical documentation of infection prior to starting ketoconazole therapy. The usual duration of therapy for systemic infection is 6 months. Treatment should be continued until active fungal infection has subsided.
The recommended starting dose of NIZORAL® (ketoconazole) Tablets is a single daily administration of 200 mg (one tablet). If clinical responsiveness is insufficient within the expected time, the dose of NIZORAL® Tablets may be increased to 400 mg (two tablets) once daily.
In small numbers of children over 2 years of age, a single daily dose of 3.3 to 6.6 mg/kg has been used. NIZORAL® Tablets have not been studied in children under 2 years of age.
NIZORAL® (ketoconazole) is available as white, scored tablets containing 200 mg of ketoconazole debossed “JANSSEN” and on the reverse side debossed “NIZORAL”. They are supplied in bottles of 100 tablets (NDC 50458-220-10).
Store at controlled room temperature 15°-25°C (59°-77°F).
Protect from moisture.
Keep out of reach of children.
Janssen Pharmaceuticals, Inc, Titusville, New Jersey 08560. Revised: July 2013
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.
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)
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.
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.)
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) |
| 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) |
| * 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. | |
| 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 | |
| * This list is not all-inclusive. | |
Systemic exposure to the following drugs is significantly increased by coÂadministration of ketoconazole. Concomitant use of these drugs with NIZORAL® Tablets is contraindicated:
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.)
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.
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.
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.
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.
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.
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.)
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 NIZORAL® 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 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.
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 NIZORAL® Tablets should not be used.
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.
NIZORAL® 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.
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 NIZORAL® Tablets 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 NIZORAL® 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.
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.
NIZORAL® 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 - 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.).
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.
Anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported.
Co-administration of NIZORAL® 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 NIZORAL® Tablets with oral triazolam, oral midazolam, or alprazolam is contraindicated. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS sections.)
Co-administration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin is contraindicated with NIZORAL® Tablets. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS sections.)
NIZORAL® Tablets have been demonstrated to lower serum testosterone. Once therapy with NIZORAL® 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.
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).
Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. Ketoconazole was not carcinogenic in an 18-month, oral study in Swiss albino mice or a 24-month oral carcinogenicity study in Wistar rats at dose levels of 5, 20 and 80 mg/kg/day. The high dose in these studies was approximately 1x (mouse) or 2x (rat) the clinical dose in humans based on a mg/m² comparison.
Pregnancy Category C: Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given in the diet at 80 mg/kg/day (2 times the maximum recommended human dose, based on body surface area comparisons). However, these effects may be related to maternal toxicity, evidence of which also was seen at this and higher dose levels.
There are no adequate and well controlled studies in pregnant women. NIZORAL® Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Ketoconazole has also been found to be embryotoxic in the rat when given in the diet at doses higher than 80 mg/kg during the first trimester of gestation.
In addition, dystocia (difficult labor) was noted in rats administered oral ketoconazole during the third trimester of gestation. This occurred when ketoconazole was administered at doses higher than 10 mg/kg (about one fourth the maximum human dose, based on body surface area comparison).
Ketoconazole has been shown to be excreted in the milk. Mothers who are under treatment with NIZORAL® Tablets should not breast feed.
NIZORAL® Tablets have not been systematically studied in children of any age, and essentially no information is available on children under 2 years. NIZORAL® Tablets should not be used in pediatric patients unless the potential benefit outweighs the risks.
In the event of acute accidental overdose, treatment consists of supportive and symptomatic measures. Within the first hour after ingestion, activated charcoal may be administered.
Coadministration of a number of CYP3A4 substrates is contraindicated with NIZORAL® 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.
The use of NIZORAL® Tablets is contraindicated in patients with acute or chronic liver disease.
NIZORAL® is contraindicated in patients who have shown hypersensitivity to the drug.
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.
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)
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.
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.)
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) |
| 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) |
| * 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. | |
| 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 | |
| * This list is not all-inclusive. | |
Systemic exposure to the following drugs is significantly increased by coÂadministration of ketoconazole. Concomitant use of these drugs with NIZORAL® Tablets is contraindicated:
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.)
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.
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.
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.
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.
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.
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.)
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 NIZORAL® 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 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.
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 NIZORAL® Tablets should not be used.
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.
NIZORAL®
(ketoconazole) Tablets
What is the most important information I should know about NIZORAL® Tablets?
NIZORAL® Tablets is not the only medicine available to treat fungal infections and should only be used when other medicines are not right for you. Talk to your healthcare provider to find out if NIZORAL® Tablets are right for you.
NIZORAL® Tablets can cause serious side effects, including:
What are NIZORAL® Tablets?
Who should not take NIZORAL® Tablets?
Before you take NIZORAL® Tablets, tell your healthcare provider if you:
Tablets or breastfeed. You should NOT do both.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Using NIZORAL® Tablets with certain other medicines may affect each other. Using NIZORAL® Tablets with other medicines can cause serious side effects.
How should I take NIZORAL® Tablets?
What should I avoid while taking NIZORAL® Tablets?
What are the possible side effects of NIZORAL® Tablets?
NIZORAL® Tablets may cause serious side effects, including:
The most common side effects of NIZORAL® Tablets include nausea, headache, diarrhea, stomach pain, and abnormal liver function tests.
These are not all the possible side effects of NIZORAL® Tablets. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store NIZORAL® Tablets?
General information about the safe and effective use of NIZORAL® Tablets.
Medications are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NIZORAL® Tablets for a condition for which it was not prescribed. Do not give NIZORAL® Tablets to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about NIZORAL® Tablets.
If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about NIZORAL® Tablets that is written for health professionals.
What are the ingredients in NIZORAL® Tablets?
Active ingredient: ketoconazole.
Inactive ingredients: colloidal silicon dioxide, corn starch, lactose, magnesium stearate, microcrystalline cellulose, and povidone.
