Side Effects of Nizoral (ketoconazole)

Nizoral(ketoconazole) is an azole antifungal medication used to treat certain seriousfungal infectionssuch as画眉,ringworm,jock itch,athlete's foot,dandruff,tinea versicolor, blastomycosis,histoplasmosis, and coccidiomycosis. It prevents growth of several types of fungi by preventing production of the membranes that surround fungal cells.

Common side effects of Nizoral include

• rash,
• itching,
• nausea,
• vomiting,
• abdominal pain,
• headache,
• dizziness,
• fatigue,
• impotence, and
• blood count abnormalities.

Serious side effects of Nizoral are rare and may include

• seriousallergicreactions (anaphylaxis),
• severedepression,
• 脱发,
• tingling sensations, and
• liverdysfunction (signs include unusualfatigue,loss of appetite,nauseaandvomiting, yellowing of the skin [jaundice],dark urine, and pale stools).

Drug interactionsof Nizoral include other medicines for infections,asthma,heartproblems,high blood pressure,depression,mental illness,cancer,malaria, orHIVbecause thesedrugscan affect Nizoral and can cause a serious heart problem.

If you take an antacid, take it 1 hour before or 2 hours after you take Nizoral. Tell your doctor if you also take a stomach acid reducer, such asNexium,Prevacid,Prilosec,Protonix,Zantac, and others.

There are no adequate and well controlled studies of Nizoral inpregnantwomen. Nizoral should be used duringpregnancyonly if the potential benefit justifies the potential risk to the fetus.

A small amount of ketoconazole is secreted inbreast milk.Nursingmothers should probably avoidbreastfeedingwhile using Nizoral.

Ketoconazole generally is well tolerated. Commonly reported side effects of ketoconazole are:

• rash,
• itching,
• nausea,
• vomiting,
• abdominal pain,
• headache,
• dizziness,
• fatigue,
• impotence, and
• blood count abnormalities.

Other important side effects of ketoconazole are rare; they include:

• serious allergic reactions (anaphylaxis),
• severedepression,
• 脱发, and
• tingling sensations.

Liver dysfunction also has been reported. Signs of liver problems include

• unusual fatigue,
• loss of appetite,
• nausea and vomiting,
• yellowing of the skin (jaundice),
• dark urine, and
• pale stools.

Development of these symptoms while taking ketoconazole should be reported to a physician.

Becauseclinical trialsare 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 andNutrition障碍:alcoholintolerance,anorexia,hyperlipidemia,increased appetite

Psychiatric Disorders:insomnia, nervousness

Nervous System Disorders:headache, dizziness, paresthesia, somnolence

Eye Disorders:畏光

Vascular Disorders:orthostatic hypotension

Respiratory, Thoracic and Mediastinal Disorders:epistaxis

Gastrointestinal Disorders:vomiting,diarrhea, nausea,constipation,abdominal pain, abdominalpainupper,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:无力、疲劳、热flush, malaise,edemaperipheral, pyrexia,chillsInvestigations:platelet countdecreased.

Post-Marketing Experience

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 includinganaphylactic 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 includinghepatitischolestatic, 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.)

1. Nizoral可能会降低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 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.
2. 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.
3. 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)
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.

表2:选择药物,或已被证明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)	利福平、异烟肼,利福
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.

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 withalprazolam, midazolam, ortriazolamhas 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.
• 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 Nizoral Tablets with cisapride is contraindicated.

Dofetilide

• The class III antiarrhythmicdofetilideis 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.

Eplerenone

• Ketoconazole increases theeplerenoneAUC by roughly 5-fold, thereby increasing the risk forhyperkalemiaandhypotension.
• Co-administration of Nizoral and eplerenone is contraindicated.

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 Nizoral Tablets is contraindicated.

HMG-CoA Enzyme Inhibitors (lovastatin, simvastatin)

• Co-administration of ketoconazole with CYP3A4-metabolized HMG-CoA reductase inhibitors such assimvastatin, andlovastatin, may increase the risk of skeletal muscle toxicity, includingrhabdomyolysis.
• Concomitant administration of Nizoral Tablets with these HMG-CoA reductase inhibitors is contraindicated.

Nisoldipine

• 预处理与and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold increase in mean AUC and Cmax ofnisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone.
• Concomitant administration of ketoconazole with nisoldipine is contraindicated.

Pimozide

• Pimozideis 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.

Quinidine

• The class IA antiarhythmicquinidineis 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.
• 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 andfentanylare metabolized by CYP3A4.
• Concomitant administration of Nizoral Tablets and alfentanil, sufentanil, orfentanylmay increase plasma concentrations of the latter drugs.

Amlodipine, felodipine, nicardipine, nifedipine

• CYP3A4 metabolizedcalcium channel blockerssuch asamlodipine,felodipine,nicardipine, andnifedipineshould be used cautiously with Nizoral 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 ofbosentan2.1- 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 ofbuspironewith 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.

Busulfan

• Nizoral Tablets may decrease the clearance and thus increase the systemic exposure tobusulfan.

Carbamazepine

• In vivostudies have demonstrated an increase in plasmacarbamazepineconcentrations in subjects concomitantly receiving ketoconazole.
• Close monitoring of plasma carbamazepine concentrations is recommended whenever ketoconazole is given to patients stabilized on carbamazepine therapy.
• CilostazolKetoconazole 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 asheadache.
• When Nizoral 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 ofcyclosporine, thereby resulting in elevated cyclosporine plasma concentrations.
• Dosage adjustment may be required if cyclosporine ortacrolimusis given concomitantly with Nizoral Tablets.

Digoxin

• Rare cases of elevated plasma concentrations of地高辛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 ofdocetaxelincancerpatients 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.

Indinavir, saquinavir

• Concomitant administration of Nizoral andprotease inhibitorsmetabolized by CYP3A4, such asindinavirandsaquinavir, 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

• Nizoral Tablets may alter the metabolism ofmethylprednisolone, resulting in elevated plasma concentrations of methylprednisolone.
• Dose adjustments may be required if methylprednisolone is given concomitantly with Nizoral Tablets.

Oral anti-coagulants

• Oral imidazole compounds such as ketoconazole may enhance theanticoagulanteffect of coumarin-like drugs, thus the anticoagulant effect should be carefully titrated and monitored.

Oral hypoglycemic agents

• Because severehypoglycemiahas been reported in patients concomitantly receiving oralmiconazole(an imidazole) and oralhypoglycemicagents, 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 ofrifabutinin vitro.
• Co-administration with Nizoral Tablets may result in elevated plasma concentrations of rifabutin.

Sildenafil

• Ketoconazole had been shown to increasesildenafilplasma concentrations.
• When used concomitantly with Nizoral Tablets, a 50% reduction insildenafilstarting dose should be considered.

Sirolimus

• Multiple-dose ketoconazole had been shown to increasesirolimusCmax and AUC by 4.3-fold and 10.9-fold, respectively.
• The concomitant use of Nizoral 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 Nizoral Tablets.

Telithromycin

• Ketoconazole increased the AUC oftelithromycinby 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.

Tolterodine

• In the presence of ketoconazole, the apparent oral clearance oftolterodinedecreased 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 vitrodata 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.

Verapamil

• Findings ofin vitrometabolic studies indicate thatverapamilis 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),sucralfate.

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, inHIV-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.

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 Nizoral Tablets should not be used.

Other drug interactions

Alcohol

• Rare cases of adisulfiram-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 ofloratadineto 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 onECGtaken 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.