Ketoconazole (Nizoral) Interactions
- Alfentanil
- Alfuzosin
- Alosetron
- Alprazolam
- Amphotericin B
Antacids
Anti-retroviral protease inhibitors
Antimuscarinics
- Aprepitant
- Aripiprazole
- Astemizole
- Atorvastatin
- Azelastine
- Bexarotene
- Bortezomib
- Bosentan
- Buprenorphine
- Caffeine
- Calcitriol
Calcium-Channel Blockers
- Celecoxib
- Cerivastatin
- Cevimeline
- Chlordiazepoxide
- Cilostazol
- Cisapride
- Clonazepam
- Clorazepate
- Conivaptan
Corticosteroids
- Cyclosporine
- Delavirdine
- Diazepam
- Didanosine, ddI
- Digoxin
- Dihydroergotamine
- Dofetilide
- Doxercalciferol
- Echinacea
- Entecavir
- Eplerenone
- Ergotamine
- Erlotinib
- Erythromycin
- Escitalopram
- Estazolam
- Ethanol
- Fentanyl
- Fexofenadine
- Flurazepam
- Fosphenytoin
- Galantamine
- Gefitinib
- Green Tea
- Guarana
H2-blockers
- Haloperidol
- Imatinib, STI-571
- Isoniazid, INH
- Levobupivacaine
- Levomethadyl
- Loratadine
- Lovastatin
- Methadone
- Methysergide
- Midazolam
- Modafinil
- Nateglinide
- Nevirapine
- Nystatin
- Paricalcitol
- Phenytoin
- Pimozide
- Pioglitazone
- Prazepam
Proton pump inhibitors (PPIs)
- Quazepam
- Quetiapine
- Quinidine
- Quinine
- Ramelteon
- Ranolazine
- Repaglinide
- Rifampin
- Rosiglitazone
- Simvastatin
- Sirolimus
- Sucralfate
- Sufentanil
Sulfonylureas
- Sunitinib
- Tacrolimus
- Telithromycin
- Terfenadine
- Theophylline, Aminophylline
- Trazodone
- Triazolam
- Trimetrexate
- Valdecoxib
- Venlafaxine
- Voriconazole
- Warfarin
- Went Yeast, Monascus purpureus
- Ziprasidone
- Zonisamide
Ketoconazole (Nizoral) Interactions
The combined use of amphotericin B with azole antifungals is controversial. Although it is rare for these classes of drugs to be used together, such combinations have been initiated in patients with serious, resistant fungal infections. For the most part, the combinations represent duplication of therapy whenever the drugs are used by similar routes (e.g., systemic or topical routes). There are in vitro and in vivo data in the literature to support neutral effects for the combination of azole antifungals with amphotericin B against various fungal species or even antagonism of amphotericin B efficacy versus the use of amphotericin alone. Mechanistically, the azole antifungals inhibit the synthesis of the fungal sterol ergosterol, while the therapeutic actions of polyene antifungals, such as amphotericin B, result from binding to ergosterol. Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. More data are needed to determine if combination treatment is beneficial, detrimental or provides no advantage in clinical infections. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available to indicate improved outcomes with co-treatment, unless coadministration represents attempts to resolve serious recalcitrant infection. In addition, clinicians should be alert for therapeutic failure if amphotericin B therapy was immediately preceded by therapy with azole antifungals; some data indicate that azole antifungal pretreatment may affect therapeutic response to amphotericin B.
Although it is rare for nystatin and azole antifungals to be used together, such combinations have been initiated in patients with resistant fungal infections or multiple-site infections. For the most part, the combinations represent duplication of therapy whenever the drugs are used by similar routes (e.g., systemic, vaginal or topical routes) and are usually avoided. Azole antifungals inhibit the synthesis of the fungal sterol ergosterol, while the therapeutic actions of polyene antifungals, such as nystatin, result from binding to ergosterol. Theoretically, azole antifungals could interfere with the action of nystatin by depleting polyene binding sites. However, topical preparations or mouthwashes containing nystatin may be used concurrently with azole antifungals in selected patients.
Systemic azole antifungals such as ketoconazole substantially increase the risk of developing myopathy, rhabdomyolysis, and acute renal failure in patients receiving the HMG-CoA reductase inhibitors that are significantly metabolized by CYP3A4 (e.g., atorvastatin, cerivastatin, lovastatin, simvastatin). Systemic azole antifungals inhibit CYP 3A4 and should not be used concurrently with simvastatin or lovastatin. Ketoconazole is a potent inhibitor of CYP3A4. If no alternative to a short course of treatment with a systemic azole antifungal is available, a brief suspension of lovastatin or simvastatin therapy during such treatment can be considered as there are no known adverse consequences to brief interruptions of long-term cholesterol-lowering therapy. Some statin manufacturers recommend dose adjustment of the statin. Atorvastatin is metabolized by intestinal enzymes to a lesser extent by CYP3A4 than lovastatin or simvastatin; the overall metabolism of atorvastatin may be less affected by systemic azole antifungals. CYP3A4 interactions are not likely to occur with fluvastatin or pravastatin. Since compounds in went yeast, Monascus purpureus/red yeast rice claim to have HMG-CoA reductase inhibitor activity, went yeast/red yeast rice should not be used in combination with azole antifungals. Topical azole antifungals are not expected to alter lovastatin or simvastatin concentrations.
Ketoconazole inhibits the metabolism of several drugs via its effects on the CYP3A4 isozyme of the cytochrome P-450 microsomal enzyme system. Ketoconazole causes elevated terfenadine serum concentrations, leading to a prolonged QT interval, and syncope. Astemizole is chemically related to terfenadine, and astemizole by itself has also been associated with syncope and a prolonged QT interval. Ketoconazole can also decrease the hepatic clearance of astemizole. Cardiac arrhythmias, including ventricular tachycardia, syncope, arrest, and death, have been associated with terfenadine toxicity. Astemizole and terfenadine are contraindicated in patients receiving ketoconazole and clinicians should note the exceptionally long half-life of astemizole. Astemizole should be discontinued at least 1 week before prescribing ketoconazole.
Although data are limited, it appears that ketoconazole may interfere with loratadine or fexofenadine metabolism. Unlike terfenadine, fexofenadine or loratadine have not been associated with QT prolongation or ventricular arrhythmias when coadministered with ketoconazole. In two separate fexofenadine interaction studies of 24 healthy subjects, fexofenadine 120 mg twice daily (twice the recommended dose) was coadministered with ketoconazole 400 mg once daily for seven days. No differences in adverse events or QTc interval were observed when subjects were administered fexofenadine alone or in combination with ketoconazole. Ketoconazole increased steady-state fexofenadine peak concentrations by 135% and increased AUC by 164%. Fexofenadine had no effect on the pharmacokinetics of ketoconazole. The mechanism of this interaction has been evaluated using in vitro, in situ, and in vivo animal models. These studies indicate that ketoconazole coadministration enhances fexofenadine gastrointestinal absorption. This observed increase in the bioavailability of fexofenadine may be due to transport-related effects, such as p-glycoprotein. In vivo animal studies also suggest that in addition to enhancing absorption, ketoconazole decreases fexofenadine gastrointestinal secretion. According to the manufacturer, the associated changes in fexofenadine plasma levels following ketoconazole were within the range of plasma levels achieved in adequate and well-controlled clinical trials. Given the magnitude of the increases in AUC and that the contribution of CYP 3A4 metabolism to the elimination of systemically absorbed fexofenadine has not been clearly elucidated, it is prudent to use caution and monitor patients receiving fexofenadine and ketoconazole until additional data are available.
Ketoconazole may inhibit the metabolism of cisapride, which may lead to cardiac toxicity. Ketoconazole causes marked elevations in cisapride concentrations and that QT prolongation and torsade de pointes have been associated with cisapride-ketoconazole combination therapy. The combination of cisapride and ketoconazole is contraindicated.
A disulfiram-like reaction has been reported when patients taking ketoconazole consume ethanol. Symptoms include facial flushing, difficult breathing, slight fever, and tightness of the chest. This reaction usually resolves spontaneously within 24 hours, with no lasting effects. Ethanol should be avoided during and for at least 48 hours following ketoconazole therapy.
Typically voriconazole would not be used in combination with other systemic azole antifungal agents due to similar mechanisms of action and indications for use (duplicate therapies). Ketoconazole has the potential to exhibit multiple hepatic cytochrome P450 interactions with voriconazole. Serum concentrations of voriconazole or ketoconazole may increase or decrease.
Ketoconazole inhibits the hepatic CYP3A4 isoenzyme; quinidine is metabolized by this isoenzyme. Coadministration of ketoconazole (CYP3A4 inhibitor) with quinidine results in increased quinidine serum concentrations, with potential to result in proarrhythmias. A case report has documented substantial elevations in serum quinidine concentrations after the addition of ketoconazole. The patient was receiving other drugs concomitantly and it is unclear if drug-induced arrhythmias occurred. Based on this information and manufacturer contraindications for quinidine coadministration with itraconazole and voriconazole, ketoconazole should also be considered contraindicated for patients receiving quinidine. Ketoconazole also decreases the oral clearance of quinine by 31% and reduces the AUC of the quinine metabolite 3-hydroxyquinine.
The significance of an interaction between ketoconazole and warfarin is unclear. The more active of the two warfarin isomers is metabolized via the hepatic isozyme CYP2C9 and the other isomer is metabolized by CYP1A2. Ketoconazole appears to preferentially inhibit the CYP3A4 isozyme. On this basis, no interaction would be expected, however, the hypoprothrombinemic effects of warfarin have been potentiated by the addition of ketoconazole. Clinical data regarding an interaction between ketoconazole and warfarin are limited. In a review of warfarin drug interactions, the authors concluded that no interaction existed between warfarin and ketoconazole.
Ketoconazole significantly impairs the systemic clearance of alprazolam; concurrent use is considered contraindicated. Ketoconazole has been shown to dramatically inhibit the hepatic metabolism of midazolam and triazolam in healthy volunteers. Whenever possible, these 2 benzodiazepines should not be administered to patients receiving ketoconazole. Because the interaction with midazolam occurred with oral midazolam, the significance of an interaction between ketoconazole and IV midazolam is uncertain but may be less significant due to absence of an effect on pre-systemic midazolam clearance. Ketoconazole could theoretically inhibit CYP3A4 metabolism of other oxidized benzodiazepines (e.g., chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, prazepam, quazepam). Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ketoconazole, as these benzodiazepines are not oxidatively metabolized.
Ketoconazole requires an acidic pH for oral absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect include antimuscarinics. Antimuscarinics have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be considered if antimuscarinic medications are required. Darifenacin, an antimuscarinic used in the treatment of overactive bladder, is metabolized by CYP3A4; the manufacturer of darifenacin recommends a maximum dosage of 7.5 mg daily when used in combination with systemic ketoconazole.
Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. Sucralfate has been shown to produce a 20% decrease in ketoconazole bioavailability when administered concomitantly. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required.
Ketoconazole can decrease the hepatic clearance of corticosteroids such as methylprednisolone or prednisolone, resulting in increased plasma concentrations. The interaction may be due to the inhibition of cytochrome P-450 3A4 isoenzyme by ketoconazole, and subsequent decreases in corticosteroid metabolism by the same isoenzyme. Prednisolone and prednisone pharmacokinetics appear less susceptible than methylprednisolone to CYP3A4 inhibitory interactions. Ketoconazole also can enhance the adrenal suppressive effects of corticosteroids. Ketoconazole may increase plasma concentrations of oral budesonide more than 7-fold due to inhibition of the CYP3A4 isoenzyme in the liver, as well as in the gut, and can enhance the cortisol suppression associated with budesonide administered via inhalation. Inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
Ketoconazole is known to inhibit the clearance of drugs metabolized via the hepatic mixed-function oxidase system. Ketoconazole causes plasma concentrations of cyclosporine to increase, enhancing the nephrotoxicity of cyclosporine. Although this interaction is documented, others have used ketoconazole to lower the daily maintenance dose of cyclosporine, thus reducing the overall cost of therapy; however, this approach is rarely used. Renal function and blood or plasma cyclosporine concentrations should be closely monitored if ketoconazole is added.
Didanosine, ddI, tablets and powder are administered with a buffer to neutralize stomach acidity in order to improve oral bioavailability. Ketoconazole, however, requires an acidic environment for absorption. Delayed-release didanosine capsules do not contain a buffering agent and would not be expected to interact with ketoconazole. If ketoconazole and didanosine tablets or powder must be administered to the same patient, ketoconazole should be taken at least 2 hours before or 2 hours after the didanosine dose.
Ketoconazole and rifampin each affect the pharmacokinetics of the other. Ketoconazole has been shown to reduce serum concentrations of rifampin but the clinical significance of this effect on rifampin concentrations is not known. More significant are the effects of rifampin on ketoconazole pharmacokinetics. Rifampin is a potent inducer of hepatic microsomal enzymes. When rifampin is used in combination with isoniazid, INH, isoniazid appears to intensify the effect of rifampin on the pharmacokinetics of other drugs, despite the fact that isoniazid is generally considered an inhibitor of drug metabolism. The effects of isoniazid with rifampin on ketoconazole have been significant enough to result in antifungal treatment failure. Ketoconazole doses may need to be increased if rifampin, or the combination of rifampin with isoniazid, is used concomitantly. However, it is generally not recommended that ketoconazole be used with INH or rifampin.
Conflicting data exist about the combination of ketoconazole and phenytoin. Phenytoin is a known hepatic enzyme inducer, while ketoconazole inhibits hepatic metabolism. Although data suggest no interaction occurs when these agents are administered concomitantly, metabolism of either or both medications may be altered. Serum concentrations of phenytoin can increase, and time to peak ketoconazole serum concentrations can be delayed. Serum phenytoin levels should be closely monitored if ketoconazole is added to phenytoin or fosphenytoin therapy.
Ketoconazole has been reported to decrease theophylline serum concentrations when theophylline was administered orally as sustained-release tablets, however, no interaction was noted when theophylline was administered IV. Since ketoconazole is well-known to inhibit the hepatic metabolism of many drugs and theophylline concentrations would be expected to increase, it is suspected that ketoconazole may have interfered with oral bioavailability of theophylline. As these results are based on a single case report, additional clinical data are necessary.
Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol. Reductions in endogenous serum calcitriol concentrations have been observed following the the administration of ketoconazole 300 - 1200 mg/day.
Ketoconazole has been shown to increase both cilostazol AUC and Cmax when administered concurrently. In some studies, coadministration of these agents with cilostazol resulted in increased incidences of adverse effects, such as headache. If systemic ketoconazole is administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%.
Modafinil is significantly metabolized by the CYP3A4 hepatic microsomal enzyme system. Azole antifungals are significant inhibitors of this isoenzyme and may reduce the clearance of modafinil.
Ketoconazole may decrease the systemic clearance of alfentanil, buprenorphine, fentanyl, levomethadyl, methadone, or sufentanil. Prolonged duration of opiate action, increased sedation, respiratory depression or other opiate side effects may occur. Close monitoring of patients is warranted.
Ketoconazole inhibits the hepatic cytochrome P450 isoenzyme 3A4 (CYP3A4); the manufacturers of pimozide consider the concomitant use of inhibitors of CYP3A4 to be contraindicated. There are rare reports of QT prolongation, ventricular arrhythmia and sudden death when a CYP3A4 inhibitor was added to the drug regimen in patients on pimozide.
Ketoconazole may inhibit the metabolism of levobupivacaine. Concurrent administration of ketoconazole and levobupivacaine may result in increased systemic levels of levobupivacaine resulting in toxicity.
It is recommended that ketoconazole not be given concurrently with sirolimus. Multiple-dose ketoconazole significantly increases sirolimus Cmax 4.3-fold, Tmax 38%, and AUC 10.9-fold. The terminal half-life of sirolimus is not affected; sirolimus does not inhibit ketoconazole metabolism.
Gastric acid pump-inhibitors have long-lasting effects on the secretion of gastric acid. For drugs whose bioavailability is influenced by gastric pH, the concomitant administration of lansoprazole, rabeprazole, or omeprazole can exert a significant effect on their absorption (i.e., decreased bioavailability). Drugs that could be affected in this way include ampicillin, iron salts, itraconazole and ketoconazole.
Ketoconazole may decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, nisoldipine, and verapamil) via inhibition of CYP3A4 metabolism. In a randomized, crossover study, ketoconazole increased the AUC of nisoldipine by 24-fold and the Cmax by 11-fold in 7 healthy male volunteers. Subjects received ketoconazole 200 mg PO daily for 5 days before receiving a single PO dose of immediate-release nisoldipine 5 mg. As compared to nisoldipine alone, ketoconazole pretreatment resulted in an increase in heart rate and decrease in blood pressure.
Bexarotene is extensively metabolized by the CYP3A4 hepatic isoenzyme. When significant CYP3A4 inhibitors like ketoconazole are administered concomitantly with bexarotene, the health care professional may need to observe the patient for increased toxicity from bexarotene.
The concomitant use of ketoconazole or itraconazole with dofetilide is contraindicated. Ketoconazole (400 mg/day PO) coadministered with dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and increase dofetilide AUC by 41% in males and 69% in females. This interaction is proposed to occur primarily by inhibition of cationic renal tubular secretion of dofetilide by ketoconazole, however, inhibition of CYP 3A4 metabolism may also contribute. Concurrent use of dofetilide with itraconazole is contraindicated due to the risk of serious cardiovascular events (i.e., QT prolongation). Fluconazole and voriconazole should be used with significant caution since they may theoretically increase dofetilide plasma concentrations via inhibition of CYP3A4 metabolism. The resultant increase in serum dofetilide concentrations could increase the risk of torsade de pointes.
Cevimeline is metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6. Concurrent administration of inhibitors of these enzymes, such as ketoconazole, may lead to increased cevimeline plasma concentrations.
Alosetron is partially metabolized by cytochrome P450 3A4 (CYP3A4). Concurrent administration of inhibitors of these enzymes, such as systemic ketoconazole may lead to increased alosetron plasma concentrations.
Zonisamide is metabolized by cytochrome P450 3A4 (CYP3A4). Concurrent administration of inhibitors of these enzymes, such as ketoconazole, may lead to increased zonisamide plasma concentrations.
Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4, and ketoconazole is a CYP3A4 inhibitor. In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone. Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients. Close monitoring of tacrolimus blood levels is warranted. This interaction has been used clinically to reduce the nephrotoxicity and high cost of tacrolimus therapy.
Ketoconazole is a known inhibitor of cytochrome P450 3A4 (CYP3A4). Interactions between various anti-retroviral protease inhibitors or delavirdine and ketoconazole may occur due to the effects of these agents on cytochrome P450 isoenzymes. Ketoconazole administered concurrently with indinavir resulted in a 68% increase in the AUC of indinavir. The manufacturer of indinavir recommends that indinavir dosages be reduced in patients receiving both indinavir and ketoconazole. Concurrent administration of ketoconazole and ritonavir results in 3- to 4-fold increases in ketoconazole concentrations. Ketoconazole doses > 200 mg/day are not recommended in combination with ritonavir, lopinavir; ritonavir (Kaletra™), or tipranavir.
Hepatic CYP3A4 is partially responsible for the metabolism of galantamine. The bioavailability of galantamine is increased by 30% when coadministered with the CYP3A4 inhibitor ketoconazole.
In one study, ketoconazole 200 mg daily did not alter the pharmacokinetics of celecoxib; however, abnormally high celecoxib plasma concentrations were noted in one of about 45 subjects. Since celecoxib is metabolized by the cytochrome P450 2C9 isoenzyme, clinicians should be aware of a potential interaction with ketoconazole; however, the clinical significance of this interaction is not established.
Concomitant use of nevirapine and ketoconazole is not recommended. The coadministration of nevirapine and ketoconazole results in a 15 - 30% increase in nevirapine plasma concentrations and a 63% and 40% reduction in ketoconazole AUC and Cmax, respectively.
Coadministration of ergotamine or dihydroergotamine with potent inhibitors of CYP3A4, such as ketoconazole, is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Similar interactions might occur with methysergide.
Concurrent use of itraconazole with haloperidol has resulted in increased serum haloperidol concentrations; inhibition of haloperidol metabolism is the suspected mechanism of the interaction. Neurologic side effects have been noted clinically in some patients as a result of impaired haloperidol elimination. Similar interactions may occur with either fluconazole, ketoconazole, or voriconazole.
Agents that inhibit cytochrome P450 3A4, such as ketoconazole, decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity. There was a significant increase in imatinib Cmax and AUC (26% and 40%, respectively) in healthy subjects when imatinib was given with a single dose of ketoconazole.
Erlotinib is metabolized primarily by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP1A2. Substances that are potent inhibitors of cytochrome P450 (CYP) 3A4 activity decrease the metabolism of erlotinib and increase erlotinib concentrations. This increase may be clinically relevant as adverse reactions to erlotinib are related to dose and exposure; therefore caution should be used when administering CYP3A4 inhibitors with erlotinib. Concomitant administration of ketoconazole with erlotinib increases mean erlotinib AUC by two-thirds.
Telithromycin is metabolized by CYP3A4. Unpublished data on file with the manufacturer indicate that ketoconazole and itraconazole, both of which are strong inhibitors of CYP3A4, can increase plasma concentrations of telithromycin by 2 and 1.5 times, respectively.
Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole produced a significant increase in exposure of valdecoxib. Plasma exposure (AUC) to valdecoxib was increased 38% when coadministered with ketoconazole. Significant increases in valdecoxib plasma levels are associated with fluid retention.
Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. Coadministration of bosentan with ketoconazole, a potent CYP3A4 inhibitor, has been shown to increase the plasma concentrations of bosentan by approximately 2-fold. No dosage adjustment of bosentan is needed, however, the potential for increased bosentan effects should be monitored.
Ketoconazole decreases the metabolism of caffeine via CYP1A2 and exaggerated effects of caffeine may be expected. During concomitant therapy with ketoconazole, it may be prudent to limit or avoid caffeine-containing products such as guarana and beverages including coffee, green tea, other teas, or colas in an effort to minimize caffeine-related side effects.
Escitalopram is metabolized by CYP3A4. Ketoconazole is a potent CYP3A4 inhibitor and may theoretically lead to elevated plasma levels of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease escitalopram clearance.
Concomitant use of ketoconazole and eplerenone is contraindicated. Ketoconazole, due to the inhibition of hepatic CYP3A4 isoenzymes, increases serum eplerenone concentrations by roughly 5-fold and, hence, increases the risk of developing hyperkalemia and hypotension.
Increased aripiprazole blood levels are expected when aripiprazole is coadministered with inhibitors of CYP3A4 such as ketoconazole. A dosage adjustment of aripiprazole is necessary when these drugs are used concomitantly, and conversely, when ketoconazole is discontinued in a patient taking aripiprazole.
Substances that are potent inhibitors of cytochrome P450 (CYP) 3A4 activity decrease the metabolism of gefitinib and increase gefitinib concentrations. This increase may be clinically relevant as adverse reactions to gefitinib are related to dose and exposure; therefore caution should be used when administering systemic ketoconazole with gefitinib.
Agents that inhibit cytochrome P450 (CYP) 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with systemic ketoconazole is not known.
Concomitant administration of aprepitant with strong CYP3A4 inhibitors, such as systemic azole antifungals may lead to elevated serum concentrations of aprepitant. Coadminister these drugs with caution. In clinical trials, ketoconazole has been shown to increase the AUC of aprepitant by 5-fold. The clinical significance of elevated aprepitant serum concentrations is unknown. Topical ketoconazole is unlikely to interact unless significant systemic absorption occurs.
Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents (i.e., sulfonylureas, repaglinide, nateglinide). The most likely mechanism of this interaction is ketoconazole-mediated inhibition of the metabolism of these agents. For instance, ketoconazole decreases tolbutamide clearance and enhances its hypoglycemic activity. Furthermore, when coadministered, ketoconazole increases the AUC and Cmax of repaglinide by 15% and 26%, respectively. Patients should be monitored for signs and symptoms of hypoglycemia if ketoconazole is added to oral hypoglycemic therapy. There is no evidence that an interaction occurs between oral hypoglycemics and topical azole antifungal preparations.
Ketoconazole appears to significantly inhibit the metabolism of pioglitazone. Coadministration of pioglitazone for seven days with ketoconazole (200 mg PO twice daily) resulted in a log-transformed AUC ratio of 1.34 of pioglitazone. It is recommended that patients receiving both pioglitazone and ketoconazole be evaluated more frequently with respect to glycemic control. In addition, itraconazole should be used cautiously with oral antidiabetic agents (e.g., pioglitazone). The combination of itraconazole and oral antidiabetic agents has resulted in severe hypoglycemia. Itraconazole may inhibit the metabolism of oral antidiabetic agents. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
If ketoconazole and rosiglitazone are to be coadministered, patients should be closely monitored. A pharmacokinetic study found that the administration of rosiglitazone (8 mg) to subjects who had been receiving ketoconazole (200 mg twice daily for 5 days) resulted in increased rosiglitazone AUC, peak plasma concentrations, and half-life, and decreased rosiglitazone clearance. The clinical significance (i.e., altered blood glucose concentrations) of this interaction is unknown. It is proposed that this interactions the result of ketoconazole induced CYP 2C8 and 2C9 inhibition of rosiglitazone metabolism.
In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with CYP3A4 inhibitors. It is likely that ketoconazole, a CYP3A4 inhibitor, may lead to substantial increases in trazodone plasma concentrations, with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered.
Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme system. The concurrent use of ziprasidone with ketoconazole, a potent CYP3A4 inhibitor, causes a 35 - 40% increase in the AUC and Cmax of ziprasidone. Decreased metabolism of ziprasidone may lead to clinically important side effects. When given with ketoconazole, the inhibition of ziprasidone metabolism did not further increase the QTc interval above the administration of ziprasidone alone.
Alfuzosin is primarily metabolized by CYP3A4 hepatic enzymes; potent inhibitors of CYP3A4 are expected to inhibit alfuzosin metabolism and increase systemic exposure to alfuzosin. The manufacturer for alfuzosin recommends that alfuzosin not be coadministered with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole or ritonavir.
Concomitant use of digoxin with either itraconazole or ketoconazole has resulted in increased digoxin serum concentrations. Both itraconazole and ketoconazole inhibit p-glycoprotein, an enzyme which metabolizes digoxin. Fluconazole and voriconazole do not inhibit p-glycoprotein. Plasma concentrations of digoxin should be monitored closely if itraconazole or ketoconazole is added.
Erythromycin is a known inhibitor and substrate of the hepatic cytochrome isozyme CYP3A4 and P-glycoprotein. Erythromycin may increase plasma concentrations of itraconazole. Following administration of erythromycin 1 g and itraconazole 200 mg as single doses, the mean Cmax and AUC of itraconazole increase by 44% and 35%, respectively. Similar interactions may occur when erythromycin is administered with systemic ketoconazole. Coadministration of erythromycin or azithromycin and voriconazole did not affect the Cmax or AUC of voriconazole. In addition, both itraconazole and ketoconazole potently inhibit CYP3A4. A retrospective cohort study evaluated the association of erythromycin with sudden death due to cardiac causes and whether strong CYP3A inhibitors (nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin) increased the risk. The study population was a Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death from cardiac causes. Strong CYP3A inhibitors were identified by their ability to produce a doubling or more of the AUC for a recognized CYP3A substrate. While there were no deaths associated with nitroimidazoles, the authors recommended that erythromycin not be administered with strong inhibitors of CYP3A. Voriconazole also has the ability to inhibit CYP3A4. The effect of voriconazole on the pharmacokinetic disposition of erythromycin or other macrolides has not been studied. Because fluconazole also inhibits CYP3A4 and becomes a more potent inhibitor at higher dosages (>=200 - 400 mg/day), the co-use of fluconazole and erythromycin should also be approached with caution.
Trimetrexate is extensively metabolized by CYP450 3A4. In vitro studies have shown that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole or fluconazole on trimetrexate metabolism, because of the similarities to ketoconazole, concurrent administration of trimetrexate and fluconazole or itraconazole may result in inhibition of trimetrexate metabolism.
Both entecavir and ketoconazole are secreted by active tubular secretion. In theory, coadministration of entecavir with ketoconazole may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
Ketoconazole is an inhibitor of CYP3A4. Care should be taken when dosing paricalcitol, a CYP3A4 substrate, with ketoconazole; dose adjustments of paricalcitol may be required. Plasma iPTH and serum calcium and phosphorous concentrations should be closely monitored if a patient taking paricalcitol initiates or discontinues therapy with ketoconazole.
The cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine. Ketoconazole is a significant inhibitor of CYP3A4 and caused increased quetiapine plasma concentrations when the drugs were coadministered. Fluconazole, itraconazole, and voriconazole are also known to inhibit CYP3A4 and may also increase plasma concentrations of quetiapine.
Venlafaxine is a substrate of the hepatic CYP450 isoenzyme CYP2D6 (major) and CYP3A4 (minor). Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4 and, normally, the potential for clinically significant drug interactions between CYP3A4 inhibitors and venlafaxine is small. However, in patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway may become more important and administration of potent CYP3A4 inhibitors can result in elevated venlafaxine plasma concentrations. Administration of venlafaxine and ketoconazole, a potent CYP3A4 inhibitor, to patients identified as CYP2D6 poor metabolizers resulted in a significant increase in venlafaxine mean AUC; there was no effect on venlafaxine half-life. Fluconazole, itraconazole, and voriconazole are also known to inhibit CYP3A4 and may also interact with venlafaxine in a similar manner.
Ramelteon should be used cautiously in combination with ketoconazole, which is a strong CYP3A4 inhibitor. When ketoconazole 200 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and ketoconazole, the AUC and Cmax of ramelteon increased by approximately 84% and 36%, respectively. Similar increases were seen in regard to the active metabolite of ramelteon, M-II. The patient should be monitored closely for toxicity from ramelteon.
Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors including systemic azole antifungals may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if systemic azole antifungals are coadministered with doxercalciferol.
The exact CYP450 isozymes responsible for the metabolism of azelastine have not been identified. However, during concomitant administration of orally administered azelastine and ketoconazole 200 mg twice daily for seven days, azelastine plasma levels were affected. Conversely, no effects on QTc were observed via electrocardiogram. Theoretically, systemic exposure of nasally administered azelastine may be increased by coadministration with ketoconazole, although an interaction has not been documented.
An open-label, non-randomized, 2-period, one-way crossover study in healthy male subjects evaluated the use of sorafenib (50 mg single dose) in combination with ketoconazole (400 mg given daily for seven days). Despite in vitro data indicating that sorafenib is metabolized by cytochrome P450 (CYP) isoenzyme CYP3A4 and UGT149 pathways, the study showed no clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities. Therefore, sorafenib may be safely coadministered with ketoconazole.
Coadministration of conivaptan (CYP3A4 substrate) with itraconazole or ketoconazole is contraindicated according to the manufacturer. Coadministration of oral conivaptan 10 mg with ketoconazole 200 mg has resulted in a 4-fold and 11-fold increase in the Cmax and AUC of conivaptan, respectively. The effect of coadministration of ketoconazole with intravenous conivaptan has not been studied. Intravenous conivaptan results in higher drug exposure than oral conivaptan. The clinical significance of increased conivaptan plasma concentrations is unknown. Due to the contraindication with itraconazole and ketoconazole, it is prudent for clinicians to avoid coadministering conivaptan with other systemic azole antifungals which inhibit CYP3A4 isoenzymes such as fluconazole, IV miconazole, and voriconazole.
Ranolazine is contraindicated in patients receiving drugs known to be moderate or potent CYP3A inhibitors including systemic azole antifungal agents. Ketoconazole (200 mg PO twice daily) increases the average steady-state plasma concentrations of ranolazine by 3.2-fold. Avoid coadministering ranolazine with ketoconazole or other systemic azole antifungals which significantly inhibit CYP3A4 isoenzymes such as fluconazole, itraconazole, IV miconazole, and voriconazole. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, prolonged QTc prolongation, and possibly torsade de pointes.
Concurrent administration of sunitinib with strong inhibitors of cytochrome P450 (CYP) 3A4 results in increased concentrations of sunitinib and its primary active metabolite. Concurrent administration of sunitinib and ketoconazole resulted in 49% and 51% increases in the combined (sunitinib and primary active metabolite) Cmax and AUC values, respectively, after a single dose of sunitinib in healthy volunteers. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended; otherwise, a reduction in the dose of sunitinib is recommended.
Ketoconazole is metabolized by CYP3A4. The effects of echinacea on CYP3A4 are complex. In vitro data suggest that echinacea can inhibit the CYP3A4 isoenzyme; however, the clinical significance of these data are not yet known, as some authors have reported the in vivo activity in humans to be minor. Other limited in vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. In 6 subjects administered echinacea plus intravenous midazolam a probe for CYP3A4), the systemic clearance of midazolam increased by 34% and the AUC decreased to 75%. However, when oral midazolam was administered, the oral availability increased leading to no change in the overall clearance of oral midazolam. The overall effects on orally administered drugs metabolized by CYP3A4 are unknown and may be negligible. It may be prudent to closely monitor for changes in efficacy or toxicity when echinacea is coadministered with drugs that are metabolized by CYP3A4, including ketoconazole, until more data are available.
[ Last revised: 6/14/2006 11:04:00 AM ]
References
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. Monahan BP, Ferguson CL, Killeavy ES et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1990;264:2788 - 90.
. First MR, Weiskittel P, Alexander JW et al. Concomitant administration of cyclosporin and ketoconazole in renal transplant recipients. Lancet 1989;2:1198 - 1201.
. Wells PS, Holbrook AM, Crowther NR et al. Interaction of warfarin with drugs and food. Ann Intern Med 1994;121:676 - 83.
. Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994;56:601 - 7.
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