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Interactions with Erythromycin

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If you are currently being treated with any of the following medications, you should not use Erythromycin without reading these interactions.

Tolterodine

ADJUST DOSE: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of tolterodine, which is partially metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of tolterodine should be considered. Although tolterodine is primarily metabolized by CYP450 2D6, there is some evidence that CYP450 3A4 may play a minor role, thus any alteration in its activity levels could conceivably affect the metabolism of tolterodine. The clinical significance of this interaction is yet unknown but may be greater in patients who are CYP450 2D6-deficient, or so-called poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent).

MANAGEMENT: The manufacturer recommends a maximum tolterodine dosage of 1 mg twice daily in patients receiving concomitant CYP450 3A4 inhibitors. Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to notify their physician if they experience an irregular heartbeat, severe blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, or GI upset.

Tadalafil

ADJUST DOSE: Coadministration with drugs that are potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of tadalafil, which is primarily metabolized by the isoenzyme. According to the product labeling for tadalafil, ketoconazole (400 mg daily), a selective and potent inhibitor of CYP450 3A4, increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of a single 20 mg dose of tadalafil by 22% and 312%, respectively, compared to administration of tadalafil alone. Ketoconazole (200 mg daily) increased the Cmax and AUC of a single 10 mg dose of tadalafil by 15% and 107%, respectively. Ritonavir (200 mg twice a day), another potent inhibitor of CYP450 3A4, increased the AUC of a single 20 mg dose of tadalafil by 124% with no change in Cmax.

MANAGEMENT: Tadalafil labeling recommends that the dosage not exceed 10 mg once every 72 hours in patients treated concomitantly with a potent CYP450 3A4 inhibitor, such as erythromycin, itraconazole, ketoconazole, protease inhibitors, and nefazodone. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

Vardenafil

ADJUST DOSE: Coadministration with erythromycin may significantly increase the plasma concentrations of vardenafil. The mechanism is erythromycin inhibition of CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of vardenafil. According to vardenafil labeling, coadministration of erythromycin (500 mg three times a day) and vardenafil (5 mg) resulted in a 3-fold increase in the peak plasma concentration (Cmax) and a 4-fold increase in the area under the concentration-time curve (AUC) of vardenafil.

MANAGEMENT: Patients treated with erythromycin should not receive more than a single 5 mg dose of vardenafil within a 24-hour period. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

Cilostazol

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 and/or 2C19 may increase the plasma concentrations of cilostazol and or its pharmacologically active metabolites, which are substrates of these isoenzymes. The possibility of prolonged and/or increased pharmacologic effects of cilostazol should be considered. In pharmacokinetic studies, pretreatment with a 400 mg priming dose of ketoconazole (a potent CYP450 3A4 inhibitor) one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg resulted in a 94% increase in cilostazol peak plasma concentration (Cmax) and a 117% increase in cilostazol systemic exposure (AUC). Coadministration of the less potent inhibitor erythromycin (500 mg every 8 hours) with a single 100 mg dose of cilostazol resulted in a 47% and 73% increase in cilostazol Cmax and AUC, respectively, while AUC of 4-trans-hydroxy-cilostazol (an active metabolite with 1/5 the pharmacologic activity) increased by 141% as a result of the inhibition of cilostazol metabolism via CYP450 3A4. Coadministration with 180 mg of diltiazem, a moderate CYP450 3A4 inhibitor, decreased cilostazol clearance by 30% and increased its Cmax by 30% and AUC by 40%. In contrast, cilostazol metabolism was not significantly affected when coadministered with omeprazole, a potent CYP450 2C19 inhibitor, but the systemic exposure to 3,4-dehydro-cilostazol (the most active metabolite of cilostazol) was increased by 69%.

MANAGEMENT: The manufacturer recommends a 50% dosage reduction of cilostazol (i.e., 50 mg twice a day) in patients receiving the CYP450 3A4 inhibitors ketoconazole, itraconazole, erythromycin, and diltiazem, or the 2C19 inhibitor omeprazole. Other potent inhibitors include clarithromycin, telithromycin, troleandomycin, fluconazole, miconazole, voriconazole, delavirdine, nefazodone, and protease inhibitors. Close clinical and laboratory monitoring is advised whenever a potent CYP450 3A4 and/or 2C19 inhibitor is added to or withdrawn from cilostazol therapy. Patients should be advised to contact their physician if they experience adverse effects of cilostazol such as headache, dizziness, nausea, diarrhea, or irregular heartbeat.

Eplerenone

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of eplerenone, which is primarily metabolized by the isoenzyme. In pharmacokinetic studies, administration of eplerenone (100 mg single dose) with the potent inhibitor ketoconazole (200 mg twice a day) resulted in a 1.7-fold increase in eplerenone peak plasma concentration (Cmax) and a 5.4-fold increase in systemic exposure (AUC), while administration with other 3A4 inhibitors (erythromycin 500 mg twice daily; verapamil 240 mg once daily; saquinavir 1200 mg three times daily; fluconazole 200 mg once daily) resulted in increases in eplerenone Cmax ranging from 1.4- to 1.6-fold and AUC from 2.0 to 2.9-fold.

MANAGEMENT: Eplerenone should not be used with potent inhibitors of CYP450 3A4 (e.g., itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, most protease inhibitors) and should be used cautiously with other inhibitors of the isoenzyme. The initial dosage of eplerenone should be reduced to 25 mg once daily during concomitant therapy with moderate inhibitors and titrated slowly based on therapeutic response.

Trazodone

ADJUST DOSE: Coadministration with potent CYP450 3A4 inhibitors such as clarithromycin, erythromycin, itraconazole, ketoconazole, and protease inhibitors may increase the plasma concentrations and pharmacologic effects of trazodone, which is primarily metabolized by the isoenzyme. In ten healthy volunteers, ritonavir (200 mg orally for 4 doses) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of trazodone (50 mg single dose) by 34% and 137%, respectively, compared to placebo. Trazodone elimination half-life was prolonged 122% with ritonavir, while apparent oral clearance decreased 52%. Sedation, fatigue, and performance impairment were also increased during coadministration with ritonavir, and three subjects experienced nausea, dizziness, and hypotension.

MANAGEMENT: A lower dosage of trazodone should be considered during coadministration with a potent CYP450 3A4 inhibitor if concomitant use cannot be avoided. Pharmacologic response to trazodone should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the trazodone dosage adjusted as necessary.

Sunitinib

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of sunitinib and its pharmacologically active metabolite, both of which are substrates of the isoenzyme. In healthy volunteers, concurrent administration of a single dose of sunitinib with the potent CYP450 3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase in the combined (i.e., sunitinib plus its primary active metabolite) peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) values, respectively, compared to administration of sunitinib alone.

MANAGEMENT: Alternative agents with no or minimal CYP450 3A4-inhibiting activity are recommended in patients treated with sunitinib. A dosage reduction for sunitinib to a minimum of 37.5 mg daily should be considered if it must be coadministered with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.

Eszopiclone

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of eszopiclone (the S-enantiomer of zopiclone), which is primarily metabolized by the isoenzyme. According to product labeling, coadministration of eszopiclone (3 mg) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 5 days) resulted in a 2.2-fold increase in systemic exposure (AUC) to eszopiclone. Peak plasma concentration (Cmax) and half-life were increased 1.4-fold and 1.3-fold, respectively. Theoretically, this interaction should also affect racemic zopiclone.

MANAGEMENT: The dosage of eszopiclone and zopiclone should be reduced when used with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.

Sildenafil (oral)

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of sildenafil, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of sildenafil should be considered. In 14 healthy volunteers, the potent CYP450 3A4 inhibitor ritonavir (500 mg twice a day for 7 days) increased mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of sildenafil (100 mg single dose) by 300% and 1000%, respectively, compared to sildenafil given alone. At 24 hours, sildenafil plasma levels were still approximately 200 ng/mL as opposed to about 5 ng/mL with sildenafil alone. In a parallel study, saquinavir (SGC 1200 mg three times a day for 7 days) increased single-dose sildenafil Cmax and AUC by 140% and 210%, respectively, in 14 healthy volunteers. No change in safety or tolerability of sildenafil was observed with either protease inhibitor. In six HIV-infected patients stabilized on triple antiretroviral therapy containing indinavir (800 mg three times a day), the AUC of a single 25 mg dose of sildenafil was 4.4 times higher than dose-normalized data from historical controls. The patients experienced headache, flushing, dyspepsia and rhinitis, and there was a mean maximal decrease in blood pressure of 14/10 mmHg. The interaction was also suspected in the death of a 47-year-old man who used sildenafil (25 mg) during treatment with ritonavir and saquinavir. Another CYP450 3A4 inhibitor, erythromycin (500 mg twice daily for 5 days), increased single-dose sildenafil AUC by 182%.

MANAGEMENT: Caution is advised if sildenafil is coadministered with potent CYP450 3A4 inhibitors. Dosage adjustments may be appropriate for sildenafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. For the treatment of erectile dysfunction, an initial sildenafil dosage of 25 mg should be considered in patients treated concomitantly with CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours). For the treatment of pulmonary arterial hypertension, no dosage adjustment for sildenafil is necessary during coadministration with erythromycin or saquinavir. However, use with very potent CYP450 3A4 inhibitors such as ritonavir, ketoconazole, or itraconazole is not recommended.

Solifenacin

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of solifenacin, which is primarily metabolized by the isoenzyme. According to product labeling, coadministration of solifenacin (10 mg) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of solifenacin by 1.5- and 2.7-fold, respectively, compared to administration of solifenacin alone.

MANAGEMENT: The dosage of solifenacin should not exceed 5 mg/day when used with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.

Amoxicillin, Carbenicillin, Oxacillin, Penicillin V, Bacampicillin, Cloxacillin, Dicloxacillin, Penicillin G potassium injection, Ticarcillin

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Vincristine

Coadministration of some macrolide antibiotics may lead to an earlier onset and/or an increased severity of neuromuscular side effects from vincristine sulfate. Both drugs are believed to be metabolized by a cytochrome CYP450 isoenzyme in the CYP450 3A subfamily, so the mechanism of the interaction is inhibition of hepatic vincristine metabolism. The clinical significance of this interaction has not been established. If these drugs are used concomitantly, close neurological observation is advised.

Modafinil

Coadministration with drugs that are inhibitors of the CYP450 3A4 isoenzyme may increase the plasma concentrations and pharmacologic effects of modafinil, which is partially metabolized by the isoenzyme. Conversely, the plasma levels of some of these inhibitors may decrease, since many of them are also substrates of CYP450 3A4, and modafinil has been shown to be a modest inducer of CYP450 3A4 in vitro. The clinical significance of this potential interaction is unknown. Clinical monitoring for altered effects of both modafinil and the CYP450 3A4 inhibitor may be appropriate following addition or withdrawal of one or the other drug. Dose adjustments may be required if an interaction is suspected.

Fexofenadine

Coadministration with erythromycin has been shown to increase the oral bioavailability of fexofenadine. The proposed mechanism is erythromycin inhibition of the intestinal efflux of fexofenadine via P-glycoprotein transporter. In addition, erythromycin may decrease biliary excretion of fexofenadine. In 24 healthy volunteers, coadministration of fexofenadine 120 mg twice a day and erythromycin 500 mg every 8 hours resulted in a 82% and 109% increase in the steady-state fexofenadine peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of fexofenadine alone. However, no increase in adverse effects or QTc interval were noted. No studies have been performed using clarithromycin or troleandomycin, but similar results are possible given their similarities to erythromycin. Fexofenadine had no effect on the pharmacokinetics of erythromycin.

Rosuvastatin

Coadministration with erythromycin may slightly decrease the plasma concentrations of rosuvastatin. The mechanism may involve an increase in gut motility caused by erythromycin. According to the product labeling for rosuvastatin, erythromycin (500 mg four times a day for 7 days) decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of rosuvastatin (80 mg single dose) by 31% and 20%, respectively. These reductions are not considered clinically significant.

Donepezil (oral)

Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of donepezil, which is primarily metabolized by these isoenzymes. In a 7-day crossover study in 18 healthy volunteers, the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily) increased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) of donepezil (5 mg once daily) by approximately 36% each. The clinical relevance of these increases is unknown.

Retapamulin topical

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of retapamulin, which is primarily metabolized by the isoenzyme. In healthy adult males, coadministration of the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally twice a day) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of retapamulin by 81% following topical application of retapamulin ointment 1% on abraded skin. However, dosage adjustments are not necessary due to the low systemic exposure to retapamulin following topical application.

Dihydroergotamine, Ergotamine, Methysergide, Methylergonovine, Cabergoline, Dihydroergotamine nasal

CONTRAINDICATED: Coadministration with certain macrolide antibiotics may significantly increase the plasma concentrations of ergot derivatives. The mechanism is macrolide inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of ergotamine and related drugs. Macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin and troleandomycin, and clinical ergotism has been reported in patients receiving ergotamine or dihydroergotamine with these agents. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4.

MANAGEMENT: Given the potential for ergot toxicity characterized by peripheral vasospasm, ischemia, thrombosis, tachycardia and hypertension, concomitant use of ergot derivatives with clarithromycin, erythromycin, or troleandomycin is considered contraindicated. Although clinical data have not been reported, some manufacturers also consider the combination of cabergoline with macrolides contraindicated or to be avoided on theoretical grounds. Azithromycin may be a safer alternative during therapy with ergot derivatives.

Ranolazine

CONTRAINDICATED: Coadministration with potent and moderately potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ranolazine, which is primarily metabolized by the isoenzyme. Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes. In pharmacokinetic studies, plasma levels of ranolazine (1000 mg twice a day) were increased 3.2-fold by the potent CYP450 3A4 inhibitor, ketoconazole (200 mg twice a day), and 1.8- to 2.3-fold by the moderately potent inhibitor diltiazem (180 to 360 mg/day). Plasma levels of ranolazine (750 mg twice a day) were increased about 2-fold by the CYP450 3A4 and P-glycoprotein inhibitor, verapamil (120 mg three times a day).

MANAGEMENT: Ranolazine should not be used in combination with potent or moderately potent CYP450 3A4 inhibitors, including but not limited to diltiazem, verapamil, nefazodone, delavirdine, azole antifungal agents, protease inhibitors, and ketolide and certain macrolide antibiotics.

Alfuzosin

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations and pharmacologic effects of alfuzosin, which is primarily metabolized by the isoenzyme. Severe hypotension could result. Repeated administration of 400 mg of ketoconazole, a potent CYP450 3A4 inhibitor, increased alfuzosin peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 2.3- and 3.2-fold, respectively, following a single 10 mg dose of alfuzosin.

MANAGEMENT: Concomitant use of alfuzosin with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics is considered contraindicated.

Conivaptan

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of conivaptan, which is primarily metabolized by the isoenzyme. The interaction has been studied with orally administered conivaptan and ketoconazole, a potent CYP450 3A4 inhibitor. According to the product labeling, coadministration of oral conivaptan 10 mg with ketoconazole 200 mg resulted in a 4-fold increase in the peak plasma concentration (Cmax) and an 11-fold increase in the area under the plasma concentration-time curve (AUC) of conivaptan. The consequences of increased conivaptan concentrations are unknown.

MANAGEMENT: The use of conivaptan with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics is considered contraindicated.

Pimozide (oral)

CONTRAINDICATED: Coadministration with the ketolide, telithromycin, as well as certain macrolide antibiotics may increase the plasma concentrations of pimozide. The mechanism is inhibition of pimozide metabolism via CYP450 3A4. High plasma levels of pimozide have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death. Macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and troleandomycin. In a study involving 12 healthy subjects, clarithromycin (500 mg orally every 12 hours for 5 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of pimozide (6 mg single oral dose) by 39% and 113%, respectively, compared to placebo. These alterations corresponded with significant prolongations of the maximum QTc interval that exceeded those produced by pimozide alone. Isolated cases of sudden death have been reported following addition of clarithromycin to ongoing pimozide therapy.

MANAGEMENT: The use of pimozide with telithromycin or macrolide antibiotics is considered contraindicated by the manufacturers, although azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4.

Terfenadine, Astemizole

CONTRAINDICATED: Coadministration with the ketolide, telithromycin, as well as certain macrolide antibiotics may significantly increase the plasma concentrations of astemizole and terfenadine. The mechanism is inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of astemizole and terfenadine. High plasma levels of these agents have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death. Macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and troleandomycin. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4. In a study of 9 healthy volunteers, erythromycin (500 mg every 8 hours for 7 days) increased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of the pharmacologically active metabolite of terfenadine (60 mg twice a day) by 107% and 170%, respectively, compared to administration of terfenadine alone. Three of the subjects also had accumulation of unmetabolized terfenadine. Electrocardiographic data revealed changes in the QT interval in a subset of subjects who demonstrated drug accumulation.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of astemizole and terfenadine, the use of these agents with clarithromycin, erythromycin, troleandomycin, or telithromycin is considered contraindicated. Loratadine, cetirizine, or fexofenadine may be safer alternatives during therapy with telithromycin or macrolides. Depending on organism susceptibility, azithromycin and dirithromycin may be appropriate alternatives during therapy with astemizole or terfenadine.

Cisapride (oral)

CONTRAINDICATED: Coadministration with the ketolide, telithromycin, as well as certain macrolide antibiotics may significantly increase the plasma concentrations of cisapride. The mechanism is inhibition of cisapride metabolism via CYP450 3A4. High plasma levels of cisapride have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death. Macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and troleandomycin. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4. In a study of 12 healthy volunteers, coadministration of clarithromycin (500 mg twice a day) and cisapride (10 mg four times a day) led to threefold increases in cisapride concentrations and an average QTc increase of 25 ms above pretreatment values. In contrast, monotherapy with cisapride was associated with a concentration-dependent QTc elevation that amounted to 6 ms during steady state. Repeated doses of telithromycin have been reported to increase steady-state cisapride peak plasma concentrations by 95%, resulting in significant increases in QTc interval.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of cisapride, the use of cisapride with clarithromycin, erythromycin, troleandomycin, or telithromycin is considered contraindicated. Depending on organism susceptibility, azithromycin and dirithromycin may be appropriate alternatives during therapy with cisapride.

Grepafloxacin

CONTRAINDICATED: Grepafloxacin can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of grepafloxacin with other medications that can prolong the QT interval is considered contraindicated.

Mesoridazine

CONTRAINDICATED: Mesoridazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Mesoridazine overdosage has been associated with ventricular arrhythmias and death.

MANAGEMENT: The concurrent use of mesoridazine with other medications that can prolong the QT interval is considered contraindicated.

Sparfloxacin

CONTRAINDICATED: Quinolones such as gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and sparfloxacin may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Torsade de pointes have been reported in a few patients receiving sparfloxacin alone and with antiarrhythmic agents like amiodarone and disopyramide. There have also been isolated case reports of clinically significant interactions with sotalol, a class III antiarrhythmic agent, for both gatifloxacin and moxifloxacin. Levofloxacin, lomefloxacin, norfloxacin, and ofloxacin alone have been associated with extremely rare cases of torsade de pointes and ventricular tachycardia.

MANAGEMENT: Product labelings for some quinolones recommend avoiding concomitant therapy with class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, ibutilide, sotalol) antiarrhythmic agents, as well as bepridil. Sparfloxacin is additionally contraindicated for use with any other medication that can prolong the QT interval such as cisapride, erythromycin, some antipsychotics, and tricyclic antidepressants.

Thioridazine (oral)

CONTRAINDICATED: Thioridazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Thioridazine treatment alone has been associated with several reported cases of torsade de pointes and sudden death.

MANAGEMENT: The concurrent use of thioridazine with other medications that can prolong the QT interval is considered contraindicated.

Ziprasidone

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of ziprasidone with other medications that can prolong the QT interval is considered contraindicated.

Desloratadine

Erythromycin and ketoconazole may increase the plasma concentrations of desloratadine and its metabolite. The probable mechanism is inhibition of CYP450 hepatic metabolism, although the isoenzymes responsible for desloratadine metabolism have not been identified. There were no clinically significant adverse effects associated with this interaction. Clinical monitoring of patient response and tolerance is recommended when erythromycin or ketoconazole are administered with desloratadine.

Arsenic trioxide

GENERALLY AVOID: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During clinical studies involving 40 patients receiving arsenic trioxide for acute promyelocytic leukemia, 16 of them (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of QTc was observed between 1 and 5 weeks after arsenic trioxide infusion and returned towards baseline by the end of 8 weeks. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: If possible, medications that are known to prolong the QT interval should be discontinued prior to initiating therapy with arsenic trioxide and withheld for at least several weeks after completion of therapy. Caution is advised if concomitant use cannot be avoided. Patients should have frequent ECGs and be monitored for arrhythmias when QT intervals are prolonged. An absolute QT interval exceeding 500 msec will require immediate action to correct concomitant risk factors, if any, as well as a thorough assessment of the need for continued therapy. Patients who develop syncope or arrhythmia should be hospitalized for clinical and laboratory monitoring. Arsenic trioxide should be temporarily discontinued until symptoms resolve, the QTc interval regresses to below 460 msec, and electrolyte abnormalities are corrected.

Balsalazide

GENERALLY AVOID: Balsalazide may be rendered less effective when administered with certain antibiotics. Balsalazide is acted upon in the lower gut by bacterial azoreduction to produce mesalamine, the therapeutically active ingredient. Although no studies have been done, it is theorized that oral antibiotics can interfere with this reduction to mesalamine.

MANAGEMENT: If the patient must receive oral antibiotics, consideration should be given to using another 5-aminosalicylate such as mesalamine.

Procainamide, Bepridil, Sotalol, Sotalol AF

GENERALLY AVOID: Class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The concurrent use of class IA or class III antiarrhythmic agents with other medications that can prolong the QT interval should preferably be avoided unless benefits are anticipated to outweigh the risks. Caution and clinical monitoring are recommended if these agents are prescribed together, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

Methotrexate

GENERALLY AVOID: Coadministration of methotrexate with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Methotrexate, especially at higher doses or with prolonged treatment, has been associated with hepatotoxicity including acute hepatitis, chronic fibrosis, necrosis, cirrhosis, and liver enzyme elevations.

MANAGEMENT: Concomitant use is generally not recommended unless the potential benefit outweighs the risk of hepatotoxicity. Baseline and regular monitoring of hepatic function is recommended.

Naltrexone (oral), Naltrexone (injection)

GENERALLY AVOID: Coadministration of naltrexone with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Naltrexone, especially in larger than recommended doses (more than 50 mg/day), has been associated with hepatocellular injury, hepatitis, and elevations in liver transaminases and bilirubin.

MANAGEMENT: Concomitant use is generally not recommended unless the potential benefit outweighs the risk of hepatotoxicity. Periodic monitoring of hepatic function is advisable.

Temsirolimus

GENERALLY AVOID: Coadministration of temsirolimus with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of sirolimus, a major active metabolite of temsirolimus and known substrate of CYP450 3A4. According to the product labeling, administration of temsirolimus in combination with the CYP450 3A4 inhibitor ketoconazole resulted in a 2.2-fold and 3.1-fold increase in sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of temsirolimus alone. No significant effect on the pharmacokinetics of temsirolimus was reported.

MANAGEMENT: The use of temsirolimus in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. If concomitant use is unavoidable, the manufacturer recommends reducing the temsirolimus dosage to 12.5 mg once a week. Based on pharmacokinetic studies, this dosage is predicted to adjust the sirolimus systemic exposure (AUC) to the range observed without inhibitors. However, clinical data are lacking. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the temsirolimus dosage is adjusted upward to the normally recommended dosage (i.e., 25 mg once a week) or the dosage used prior to initiation of the CYP450 3A4 inhibitor.

Dasatinib

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of dasatinib, which is primarily metabolized by the isoenzyme. In a drug interaction study of 18 patients with solid tumors, coadministration of dasatinib (20 mg once a day) with the potent inhibitor ketoconazole (200 mg twice a day) increased the dasatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 4- and 5-fold, respectively, compared to administration without ketoconazole. Data are not available for dasatinib in combination with other CYP450 3A4 inhibitors.

MANAGEMENT: The use of dasatinib in combination with potent CYP450 3A4 inhibitors like protease inhibitors, macrolide antibiotics, azole antifungals, and nefazodone should generally be avoided. Close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention) and a reduction of dasatinib dosage to a range of 20 to 40 mg daily should be considered if there are no alternatives and concomitant use with these agents is necessary.

Sirolimus

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or P-glycoprotein may significantly increase the plasma concentrations of sirolimus following oral administration. Sirolimus is a substrate of both CYP450 3A4 isoenzyme and P-glycoprotein efflux transporter, thus their inhibition in the intestine can enhance the absorption of sirolimus. In a study of 23 healthy volunteers, multiple-dose ketoconazole (200 mg/day orally for 10 days) led to increases in the sirolimus peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of approximately 4- and 11-fold, respectively, compared to administration of sirolimus alone. Single-dose sirolimus (5 mg) did not affect steady-state 12-hour plasma ketoconazole concentrations. In 24 healthy volunteers, coadministration of erythromycin ethylsuccinate (800 mg every 8 hours) and sirolimus (2 mg daily) increased sirolimus Cmax and AUC more than 4-fold each, while erythromycin Cmax and AUC also increased more than 1.5-fold each.

MANAGEMENT: The use of sirolimus in combination with potent inhibitors of CYP450 3A4 and/or P-glycoprotein such as protease inhibitors, macrolide antibiotics, and azole antifungal agents is not recommended.

Verapamil (oral), Clarithromycin, Itraconazole, Ketoconazole, Troleandomycin, Nefazodone, Ritonavir, Indinavir, Nelfinavir, Delavirdine, Amprenavir, Voriconazole, Atazanavir (oral), Fosamprenavir, Telithromycin

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of erythromycin, which is primarily metabolized by the isoenzyme. The use of erythromycin has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. In a population-based retrospective study of 1476 cases of confirmed sudden death from cardiac causes, concurrent use of erythromycin and a CYP450 3A4 inhibitor (mostly verapamil or diltiazem) was associated with a marked increase in the risk of sudden death from cardiac causes as compared to nonuse of CYP450 3A4 inhibitors, erythromycin, or amoxicillin; concurrent use of amoxicillin and CYP450 3A4 inhibitors; use of CYP450 3A4 inhibitors without erythromycin or amoxicillin; and concurrent use of erythromycin and calcium channel blockers that do not significantly inhibit CYP450 3A4 (e.g., nifedipine). In fact, the risk was five times as high as that for nonuse of CYP450 3A4 inhibitors, erythromycin, or amoxicillin.

MANAGEMENT: The concurrent use of erythromycin and potent inhibitors of CYP450 3A4 (e.g., itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, ketolide and certain macrolide antibiotics) should be avoided.

Eletriptan

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of eletriptan, which is primarily metabolized by the isoenzyme. According to the product labeling, eletriptan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by nearly 3-fold and 6-fold, respectively, during coadministration with ketoconazole (400 mg). The half-life increased from 5 hours to 8 hours. Likewise, erythromycin (1000 mg) increased eletriptan Cmax by 2-fold and AUC by nearly 4-fold, while half-life increased from about 5 hours to 7 hours. Clinically, this interaction may result in increased risk of vasospastic reactions associated with the use of 5-HT1 receptor agonists, such as coronary artery vasospasm, peripheral vascular ischemia, and colonic ischemia.

MANAGEMENT: Eletriptan should not be used within at least 72 hours of treatment with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, nefazodone, delavirdine, most protease inhibitors, and ketolide and certain macrolide antibiotics. Alternatively, other 5-HT1 receptor agonists that are not metabolized by CYP450 3A4 may be considered, such as frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan.

Lapatinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of lapatinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of lapatinib in combination with the CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 7 days) resulted in lapatinib systemic exposure (AUC) and half-life that were approximately 3.6- and 1.7-fold, respectively, of the control values.

MANAGEMENT: The use of lapatinib in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. If concomitant use is unavoidable, the manufacturer recommends reducing the lapatinib dosage to 500 mg once a day. Based on pharmacokinetic studies, this dosage is predicted to adjust the lapatinib systemic exposure (AUC) to the range observed without inhibitors. However, clinical data are lacking. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the lapatinib dosage is adjusted upward to the indicated dosage (i.e., 1250 mg once a day).

Dofetilide

GENERALLY AVOID: Like other class III antiarrhythmic agents, dofetilide can cause dose-related QT interval prolongation. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The use of dofetilide in conjunction with other medications that can prolong the QT interval has not been studied and is not recommended.

Fluvastatin

GENERALLY AVOID: Severe myopathy and rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors and erythromycin in severely ill patients. The suspected mechanism is inhibition of HMG-CoA reductase inhibitor metabolism by CYP450 3A4 isoenzymes.

MANAGEMENT: While these effects have not been reported with concomitant use of fluvastatin and erythromycin, alternative therapy should be considered. If patients do receive this combination, they should be instructed to report symptoms of muscular pain, weakness, tenderness, malaise, or fever. If such symptoms occur, creatine kinase should be measured. Fluvastatin and erythromycin should be discontinued if creatine kinase is elevated.

Pravastatin

GENERALLY AVOID: Severe myopathy and rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors and erythromycin in severely ill patients. The suspected mechanism is inhibition of HMG-CoA reductase inhibitor metabolism by CYP450 3A4 isoenzymes.

MANAGEMENT: While these effects have not been reported with concomitant use of pravastatin and erythromycin, the manufacturer recommends that alternative therapy be considered. If patients do receive this combination, they should be instructed to report symptoms of muscular pain, weakness, tenderness, malaise, or fever. If such symptoms occur, creatine kinase should be measured. Pravastatin should be discontinued if creatine kinase is elevated or if myopathy is suspected.

Clofarabine

GENERALLY AVOID: Since the liver is a known target organ for clofarabine toxicity (i.e., hepatomegaly, jaundice), concomitant use of agents known to induce hepatotoxicity may potentiate the risk of liver injury.

MANAGEMENT: The use of clofarabine with other agents that are potentially hepatotoxic (e.g., alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, HMG-CoA reductase inhibitors, and niacin; nucleoside reverse transcriptase inhibitors; thiazolidinediones) should be avoided if possible.

Carbamazepine (oral)

GENERALLY AVOID: Some macrolide antibiotics can significantly increase serum carbamazepine levels. The mechanism is probably inhibition of hepatic CYP450 3A4 isoenzymes. Severe carbamazepine toxicity has been reported.

MANAGEMENT: Alternative antimicrobial therapy, if available, is generally recommended for patients on carbamazepine. A macrolide that does not affect carbamazepine levels, such as azithromycin, may be substituted if clinically appropriate. If this combination must be used, carbamazepine levels should be monitored and the patient should be carefully observed for signs of carbamazepine toxicity. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians. The carbamazepine dosage may require reduction.

Lovastatin, Simvastatin, Atorvastatin, Cerivastatin, Red yeast rice

GENERALLY AVOID: Some macrolide antibiotics inhibit CYP450 3A4 and may elevate the plasma concentrations of HMG-CoA reductase inhibitors that are metabolized by the isoenzyme. Macrolides that may significantly inhibit CYP450 3A4 include troleandomycin, erythromycin, and clarithromycin. There have been case reports of patients treated with lovastatin or simvastatin who developed severe myopathy or rhabdomyolysis following the addition of a macrolide, usually erythromycin. Plasma levels of HMG-CoA reductase inhibitory activity were significantly elevated in these patients, up to several-fold in many cases. Similar pharmacokinetic changes have been reported in studies with erythromycin and simvastatin and, to a lesser extent, with clarithromycin or erythromycin and atorvastatin. The interaction was also suspected in a patient treated with atorvastatin (more than 1 year) and esomeprazole (6 weeks) who developed rhabdomyolysis with AV block two days after the addition of clarithromycin. The patient reported experiencing symptoms of increased fatigue, mild chest pain, and shortness of breath that coincided with the initiation of esomeprazole approximately six weeks prior to admission.

MANAGEMENT: Because of the increased risk of musculoskeletal toxicity associated with high levels of HMG-CoA reductase inhibitory activity in plasma, macrolide therapy should be carefully selected in patients treated with atorvastatin, cerivastatin, lovastatin, simvastatin, and red yeast rice (which contains lovastatin). Azithromycin and dirithromycin may be safer alternatives in these patients, since they are generally believed to have little, if any, effect on CYP450 3A4. However, azithromycin has been implicated in a single case of rhabdomyolysis during lovastatin treatment. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report to their physician any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated or if myopathy is suspected or diagnosed.

Disopyramide

GENERALLY AVOID: Some macrolide antibiotics may increase plasma levels of disopyramide. Life-threatening malignant arrhythmias and prolongation of the QT interval have been reported with erythromycin and clarithromycin.

MANAGEMENT: The concomitant use of these agents should be avoided with disopyramide. Monitoring of disopyramide levels may be useful if these drugs must be used together.

Cyclosporine

GENERALLY AVOID: The coadministration of certain macrolide antibiotics and cyclosporine may result in elevated blood concentrations of the latter and increase the risk of nephrotoxicity and neurotoxicity. Some macrolide antibiotics inhibit the CYP450 3A4 isoenzyme and may interfere with the hepatic and possibly intestinal metabolism of cyclosporine. There have been numerous reports of significant increases in cyclosporine peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC), as well as decreases in its clearance during concomitant administration with macrolide antibiotics, primarily erythromycin and clarithromycin. Macrolides that may significantly inhibit CYP450 3A4 include troleandomycin, erythromycin, and clarithromycin. Azithromycin and dirithromycin are generally believed to have little effect, if any, on CYP450 3A4, although azithromycin was implicated in a single case report.

MANAGEMENT: The concomitant administration of macrolides and cyclosporine should generally be avoided. Caution is advised if any of these agents must be used with cyclosporine. Cyclosporine blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of macrolide in patients who are stabilized on their cyclosporine regimen. Patients should be advised to notify their physician if they experience nausea, vomiting, diarrhea, abdominal pain, dizziness, fatigue, or headache.

Rifampin, Rifabutin

GENERALLY AVOID: The coadministration of clarithromycin and rifabutin at normally recommended dosages has been reported to have resulted in significantly altered pharmacokinetics for both drugs. In a study of 34 clinically stable subjects with advanced HIV infection (CD4 less than 200 cells/mm3), the addition of rifabutin in patients stabilized on clarithromycin therapy slowly decreased the clarithromycin area under the plasma concentration-time curve (AUC) and C(max) up to an average of 44% and 41%, respectively, at the end of 4 weeks of combination therapy. In patients stabilized on rifabutin therapy, the addition of clarithromycin significantly increased rifabutin AUC and C(max) after the first dose. After 4 weeks, average increases of 99% and 69%, respectively, were reported. This bidirectional interaction is consistent with rifabutin's cumulative inducing effect over time on the CYP450 enzymatic pathway as well as clarithromycin's immediate inhibiting effect on the pathway. In the study, the combination was tolerated by more than 90% of the patients. However, 66% of them experienced gastrointestinal problems including nausea, vomiting and diarrhea. An increased incidence of uveitis has also been reported with this combination. In addition, the combination of clarithromycin and rifampin 600 mg/day (with multiple other drugs) decreased clarithromycin serum levels by approximately 90%. Other macrolide antibiotics may interact in a similar manner with rifamycins.

MANAGEMENT: Some experts recommend that this combination be avoided since it may result in decreased efficacy of the macrolide and increased rifamycin toxicity (e.g, neutropenia, uveitis).

Fluoxetine, Sertraline, Paroxetine

GENERALLY AVOID: The use of some macrolide antibiotics has been associated with increased blood levels of some selective serotonin reuptake inhibitors (SSRIs), resulting in excessive serotonergic effects or serotonin syndrome. The mechanism is inhibition of the CYP450 3A4 isoenzyme, which metabolizes SSRIs.

MANAGEMENT: In cases where both drugs are necessary, one could consider using a macrolide antibiotic that does not inhibit CYP450 3A4, such as azithromycin or dirithromycin.

Calcium carbonate, Sodium bicarbonate, Aluminum hydroxide, Aluminum carbonate, Magnesium hydroxide, Magnesium oxide

Limited data suggest that concurrent administration of antacids may prolong the elimination half-life of erythromycin. The mechanism of interaction is unknown. In eight healthy volunteers, administration of erythromycin stearate 500 mg followed immediately with 30 mL of antacid (aluminum hydroxide/magnesium hydroxide/simethicone 200 mg/200 mg/20 mg per 5 mL) resulted in a doubling of the mean elimination rate constant compared to administration of the erythromycin stearate alone. Coadministration with antacid had no effect on the peak serum concentration (Cmax), total area under the concentration-time curve (AUC), or time to peak concentration (Tmax) of erythromycin. These changes are unlikely to be of clinical importance, and no special precautions appear to be necessary.

Loratadine

Macrolide antibiotics may increase the plasma concentrations of loratadine through inhibition of CYP450 3A4 or 2D6 enzymes. Loratadine levels may increase by 40% when coadministered with erythromycin. Clinical monitoring of patient response and tolerance is recommended when macrolides are administered with non-sedating antihistamines. Azithromycin and dirithromycin are not expected to affect loratadine levels and may be considered as alternatives.

Nifedipine

MONITOR: An interaction between clarithromycin and nifedipine was suspected in a case of vasodilatory shock. The proposed mechanism is clarithromycin inhibition of nifedipine metabolism via CYP450 3A4, resulting in increased plasma levels and pharmacologic effects of nifedipine. The case report describes a 77-year-old male with poorly controlled type 2 diabetes and primary arterial hypertension who developed clinical derangement, hyperglycemia, metabolic acidosis with hyperkalemia, shock, heart block, and multiorgan failure 2 days after clarithromycin was added to his antihypertensive regimen, which consisted of twice-a-day captopril 25 mg, doxazosin 8 mg, and sustained-release nifedipine 60 mg just prior to hospital admission. Invasive monitoring revealed hyperdynamic shock with decreased systemic vascular resistance. Theoretically, this interaction may also occur with other macrolide antibiotics that inhibit CYP450 3A4 such as erythromycin. In fact, erythromycin was administered intravenously during the patient's hospitalization and may have contributed to the good blood pressure control achieved prior to discharge during which he received half the pre-admission dosage of nifedipine with furosemide as his only antihypertensive medications.

MANAGEMENT: Caution is advised if nifedipine is prescribed with macrolides that inhibit CYP450 3A4. Pharmacologic response to nifedipine should be monitored more closely whenever a macrolide such as clarithromycin or erythromycin is added to or withdrawn from therapy, and the nifedipine dosage adjusted as necessary. Patients should be advised to contact their physician if they experience excessive adverse effects of nifedipine such as hypotension (as indicated by dizziness, lightheadedness, or fainting), irregular heart beats, peripheral edema, and dyspnea.

Valproic acid, Divalproex sodium

MONITOR: A single case has been reported in which a patient developed seizures associated with elevated blood valproate levels after erythromycin was added to a stable valproate regimen. The seizures and elevated valproate levels resolved after both drugs were withheld. The patient subsequently tolerated her usual valproate dosage. The mechanism is suspected to be inhibition of the hepatic metabolism of valproate.

MANAGEMENT: While more data are needed, clinicians are encouraged to be aware that this interaction is possible when macrolide antimicrobial agents and valproate are coadministered. Patients should be advised to notify their physicians if they experience weakness, fatigue, confusion, ataxia, increased seizures, nausea, or vomiting.

Prednisolone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisone, Cortisone, Triamcinolone (oral and injectable), Triamcinolone inhalation, Betamethasone, Fludrocortisone, Triamcinolone acetonide injection

MONITOR: At least one macrolide antibiotic, erythromycin, may enhance the pharmacologic effect of some corticosteroids. The mechanism is probably reduced metabolism of the corticosteroids. Data are available for methylprednisolone and prednisone. Other macrolides that are expected to behave like erythromycin include clarithromycin and troleandomycin. Azithromycin and dirithromycin are unlikely to lead to interactions with the corticosteroids.

MANAGEMENT: The patient should be monitored for corticosteroid toxicity during therapy. If clinically indicated, dosages should be adjusted downward.

Oxcarbazepine

MONITOR: Based on in vitro data, coadministration with oxcarbazepine may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 and 3A5 isoenzymes. The mechanism is accelerated clearance due to induction of CYP450 3A activities by oxcarbazepine. In one study, a single dose of oxcarbazepine (600 mg) had no effect on the pharmacokinetics of felodipine, a CYP450 3A4 substrate, while repeated doses (450 mg twice a day) decreased the peak plasma concentration and area under the concentration-time curve of felodipine (10 mg once daily) by 34% and 28%, respectively. Likewise, in a single case study, cyclosporine trough concentrations decreased to subtherapeutic levels a little over 2 weeks after addition of oxcarbazepine in a renal transplant patient. These results indicate that enzymatic induction occurs after multiple doses.

MANAGEMENT: Caution is advised if oxcarbazepine must be used concurrently with medications that undergo metabolism by CYP450 3A4 and/or 3A5, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oxcarbazepine is added to or withdrawn from therapy.

Dutasteride

MONITOR: Based on in vitro data, the coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of dutasteride, which is metabolized by this isoenzyme. No clinical drug interaction studies have been conducted. However, a population pharmacokinetic analysis found decreased clearance of dutasteride when it is coadministered with the CYP450 3A4 inhibitors, verapamil and diltiazem (37% and 44%, respectively). In contrast, no decrease in dutasteride clearance was seen during coadministration with amlodipine, a calcium channel blocker that is not a CYP450 3A4 inhibitor.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of dutasteride should be considered during chronic, concomitant therapy with CYP450 3A4 inhibitors, particularly potent inhibitors such as ketoconazole, itraconazole, ritonavir, nefazodone and erythromycin.

Bexarotene

MONITOR: Bexarotene serum concentrations may be increased when administered concomitantly with drugs that are inhibitors of the CYP450 3A4 enzyme system. Bexarotene is a substrate of CYP450 3A4 in vitro.

MANAGEMENT: The patient should be observed for clinical and laboratory evidence of altered safety and efficacy of bexarotene if a drug that inhibits CYP450 3A4 is added to or removed from the patient's medication regimen. Patients should be advised to notify their physician if they experience persistent nausea, vomiting, diarrhea, weakness, back pain, headache, or other unusual symptoms.

Gemifloxacin

MONITOR: Certain quinolones, including gemifloxacin, may cause dose-related prolongation of the QT interval in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with gemifloxacin treatment in over 6775 patients during clinical trials, including 653 patients concurrently receiving drugs known to prolong the QTc interval and 5 patients with hypokalemia. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Although the risk of a serious interaction is probably low, caution is recommended when gemifloxacin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Since the magnitude of QTc prolongation may increase with increasing plasma concentrations of gemifloxacin, the recommended dosage should not be exceeded, especially in patients with renal or hepatic impairment. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Norfloxacin, Ofloxacin, Levofloxacin

MONITOR: Certain quinolones, including levofloxacin, norfloxacin, and ofloxacin, may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During postmarketing surveillance, rare cases of torsade de pointes and ventricular tachycardia have been reported in patients taking levofloxacin, norfloxacin, and ofloxacin. The levofloxacin cases primarily involved patients with underlying medical conditions or taking concomitant medications that may have been contributory. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Although the risk of a serious interaction is probably low, caution is recommended when levofloxacin, norfloxacin, or ofloxacin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of the quinolone, recommended dosages and intravenous infusion rates should not be exceeded. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Moxifloxacin, Gatifloxacin

MONITOR CLOSELY: Certain quinolones, including gatifloxacin and moxifloxacin, may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During postmarketing surveillance, rare cases of torsade de pointes have been reported in patients taking gatifloxacin. These cases primarily involved patients with underlying medical conditions for which they were receiving concomitant medications known to prolong the QTc interval. Rare cases of tachycardia have been reported with moxifloxacin. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when gatifloxacin or moxifloxacin is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of the quinolone, recommended dosages and intravenous infusion rates should not be exceeded. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Colchicine

MONITOR CLOSELY: Coadministration with certain macrolide antibiotics may increase the serum concentrations of colchicine, which may result in toxicity. The proposed mechanism is macrolide inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of colchicine. Macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and troleandomycin. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4. In one case report, a patient with familial Mediterranean fever and amyloidosis involving the kidney, liver, and gastrointestinal tract was admitted to the hospital with life-threatening colchicine toxicity after a two-week course of oral erythromycin. During the year prior to admission, the patient had developed recurrent diarrhea and abdominal pain and demonstrated toxic levels of colchicine on two occasions. It is likely the patient had acute colchicine toxicity brought on by the addition of erythromycin and superimposed on chronic colchicine intoxication secondary to renal and hepatic impairment. The patient improved with supportive therapy and intensive hemodialysis and was discharged on day 70 of hospitalization. Another report describes two fatal cases of agranulocytosis due to presumed interaction between clarithromycin and colchicine. One patient had mild liver function test abnormalities, while the other patient had end-stage renal failure and was on continuous ambulatory peritoneal dialysis.

MANAGEMENT: Pharmacologic response and serum colchicine levels should be monitored more closely whenever clarithromycin, erythromycin, or troleandomycin is added to or withdrawn from therapy, and the colchicine dosage adjusted as necessary. This precaution may be particularly important in patients with underlying renal or hepatic impairment, since they are already at risk for colchicine toxicity. Patients should be advised to contact their physician if they experience early symptoms of toxicity such as abdominal pain, nausea, vomiting, or diarrhea. Azithromycin may be a safer alternative during therapy with colchicine, since it is not thought to significantly inhibit CYP450 3A4.

Halofantrine

MONITOR CLOSELY: Coadministration with CYP450 3A4 inhibitors may increase the plasma concentrations of halofantrine, resulting in an increased risk of QT interval prolongation and ventricular arrhythmias. The mechanism is inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of halofantrine. Halofantrine has been associated with QT interval prolongation, ventricular arrhythmias, and sudden death, even at recommended dosages.

MANAGEMENT: Caution and close monitoring is recommended if halofantrine is prescribed with CYP450 3A4 inhibitors, especially potent inhibitors such as itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, and most protease inhibitors. The manufacturer recommends performing an ECG before initiating halofantrine therapy and cardiac monitoring during and for 8 to 12 hours after completion of therapy.

Fentanyl topical, Fentanyl (buccal), Fentanyl citrate (oral transmucosal)

MONITOR CLOSELY: Coadministration with potent and moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of fentanyl, which is primarily metabolized by the isoenzyme. Increased fentanyl concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

MANAGEMENT: Patients receiving fentanyl in combination with potent or moderate CYP450 3A4 inhibitors (e.g., azole antifungal agents, protease inhibitors, ketolide and certain macrolide antibiotics, aprepitant, diltiazem, dalfopristin-quinupristin, delavirdine, imatinib, nefazodone, verapamil) should be carefully monitored, and dosage adjustments made accordingly if necessary. Patients and/or their caregivers should be advised to seek medical attention if potential signs and symptoms of toxicity occur such as dizziness, confusion, fainting, extreme sedation, bradycardia, slow or difficult breathing, and shortness of breath. Patients treated with transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed.

Dolasetron

MONITOR CLOSELY: Dolasetron can cause dose-related prolongation of the QT interval via its pharmacologically active metabolite, hydrodolasetron. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In clinical trials, ECG interval prolongations usually returned to baseline within 6 to 8 hours after administration but lasted more than 24 hours in some patients. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when dolasetron is administered concomitantly with drugs that prolong the QT interval (including cumulative high-dose anthracycline therapy), especially to patients with underlying risk factors. ECG monitoring may be appropriate in high-risk patients. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Methadone

MONITOR CLOSELY: Methadone may cause dose-related prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. High dosages of methadone alone have been associated with QT interval prolongation and torsade de pointes. In a retrospective study of 17 methadone-treated patients who developed torsade de pointes, the mean daily dose was approximately 400 mg (range 65 to 1000 mg) and the mean corrected QT (QTc) interval on presentation was 615 msec. The daily methadone dose correlated positively with the QTc interval. Fourteen patients had at least one predisposing risk factor for arrhythmia (hypokalemia, hypomagnesemia, concomitant use of a medication known to prolong the QT interval or inhibit the metabolism of methadone, and structural heart disease), but these were not predictive of QTc interval. It is not known if any of the patients had congenital long-QT syndrome.

MANAGEMENT: Caution is recommended when methadone is administered concomitantly with drugs that prolong the QT interval, particularly in the setting of chronic pain management or methadone maintenance for opioid dependency where high dosages may be employed, or if administered to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. If taking drugs that also cause central nervous system and/or hypotensive effects (e.g., psychotropic drugs like tricyclic antidepressants, phenothiazines, and neuroleptics), patients should be made aware of the possibility of additive effects with methadone and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Apomorphine

MONITOR: Coadministration of apomorphine with other agents that can prolong the QT interval may result in an elevated risk of ventricular arrhythmias including ventricular tachycardia and torsade de pointes. In addition, some of these agents may cause additive sedative and hypotensive effects with apomorphine. Apomorphine doses greater than 6 mg have been associated with minimal increases of the QT interval. The average QTc prolongation was 1 msec at 6 mg and 7 msec at 8 mg. Two patients experienced large increases of more than 60 msec with 2 mg and 6 mg doses. Torsade de pointes has not been reported with apomorphine alone at recommended doses. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when apomorphine is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. If taking drugs that also cause CNS or orthostatic effects, patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness) and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Interferon beta-1b, Interferon beta-1a

MONITOR: Coadministration of beta interferons with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Use of beta interferons has been associated with rare cases of liver injury, including autoimmune hepatitis and severe liver damage leading to hepatic failure, some of which required transplantation. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. Symptoms of liver dysfunction typically began from 1 to 6 months following the initiation of therapy. Asymptomatic elevation of hepatic transaminases (particularly SGPT) have also been reported but is common with interferon therapy.

MANAGEMENT: The risk of hepatic injury should be considered when beta interferons are used in combination with other agents that are potentially hepatotoxic (e.g., alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, HMG-CoA reductase inhibitors, and niacin; nucleoside reverse transcriptase inhibitors; thiazolidinediones). Liver function tests should be monitored at regular intervals and the interferon dosage reduced if SGPT rises above 5 times the upper limit of normal. The dosage may be gradually re-escalated when enzyme levels return to normal. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. If liver injury is suspected, interferon therapy should be promptly discontinued due to the potential for rapid progression to liver failure.

Felodipine

MONITOR: Coadministration of felodipine and erythromycin may increase felodipine serum concentrations. The presumed mechanism is inhibition of CYP450 3A4 metabolism by erythromycin. Troleandomycin and clarithromycin may also affect felodipine levels.

MANAGEMENT: When macrolide antibiotics are coadministered with felodipine, patients should be monitored for adverse effects such as flushing, ankle edema, or palpitations. Azithromycin and dirithromycin do not inhibit CYP450 and may be considered as alternatives.

Bosentan

MONITOR: Coadministration with bosentan may decrease the plasma concentrations of drugs that are substrate-inhibitors of the CYP450 2C9 and/or 3A4 isoenzymes. Conversely, the plasma levels of bosentan may increase. Bosentan is a substrate as well as inducer of CYP450 2C9 and 3A4, thus a mutual interaction may occur with drugs that are substrates as well as inhibitors of these isoenzymes. According to bosentan product labeling, ketoconazole (a potent CYP450 3A4 inhibitor) alone increased the plasma concentrations of bosentan (125 mg orally twice a day) by approximately 2-fold. It is conceivable that concomitant administration of both a CYP450 2C9 inhibitor and a CYP450 3A4 inhibitor may lead to even larger increases in plasma concentrations of bosentan.

MANAGEMENT: When drugs that are known substrate-inhibitors of CYP450 2C9 and/or 3A4 are coadministered with bosentan, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever bosentan is added to or withdrawn from therapy. The possibility of prolonged and/or increased pharmacologic effects of bosentan, including serious adverse effects such as hepatotoxicity, should also be considered. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. Concomitant administration of both a potent CYP450 2C9 inhibitor (e.g., fluconazole, amiodarone) and a potent CYP450 3A4 inhibitor (e.g., ketoconazole, itraconazole, ritonavir) is not recommended. Concomitant administration with combination 2C9/3A4 inhibitors (e.g., delavirdine, imatinib, miconazole, voriconazole) should probably be avoided also, if possible.

Theophylline, Oxtriphylline, Aminophylline

MONITOR: Coadministration with certain macrolide antibiotics may increase the serum concentrations of theophylline, which may result in toxicity. In one case report, a pediatric patient developed seizures in association with theophylline toxicity shortly after the addition of erythromycin. The proposed mechanism is macrolide inhibition of CYP450 3A4, the isoenzyme partially responsible for the metabolic clearance of theophylline. Data from pharmacokinetic studies suggest that the magnitude of the interaction is generally greatest with troleandomycin, followed by erythromycin. The interaction with clarithromycin appears to be mild and inconsistent. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4, and most studies have not found a significant effect on the pharmacokinetics of theophylline. However, a case report describes an unusual interaction with azithromycin in an elderly patient whereby reduced serum theophylline levels were repeatedly observed after the discontinuation of azithromycin. The changes were transient and did not require an adjustment in the theophylline dosage. Theophylline has been reported to decrease plasma concentrations of erythromycin by increasing its renal clearance.

MANAGEMENT: Pharmacologic response and serum theophylline levels should be monitored more closely whenever a macrolide antibiotic is added to or withdrawn from therapy, and the methylxanthine dosage adjusted as necessary. For patients with theophylline levels at the upper end of the therapeutic range (15 to 20 mcg/mL), some clinicians suggest an initial reduction of the methylxanthine dosage by 25% when given with erythromycin and 50% with troleandomycin. Patients should be advised to contact their physician if they experience signs and symptoms of theophylline toxicity such as nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat.

Valdecoxib

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2C9 and/or 3A4 may increase the plasma concentrations of valdecoxib, which is metabolized by these isoenzymes. According to the product labeling for valdecoxib, multi-dose administration of fluconazole (CYP450 2C9/3A4 inhibitor) and ketoconazole (CYP450 3A4 inhibitor) increased the area under the plasma concentration-time curve (AUC) of a single 20 mg dose of valdecoxib by 62% and 38%, respectively. Parecoxib, a prodrug of valdecoxib, may be similarly affected.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of valdecoxib or parecoxib, including serious adverse effects such as gastrointestinal ulceration and bleeding, should be considered during concomitant therapy with CYP450 2C9 or 3A4 inhibitors, particularly combination (2C9/3A4) inhibitors such as fluconazole, fluvoxamine, imatinib, and zafirlukast. Dose reductions of the COX-2 inhibitor may be required.

Aripiprazole

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of aripiprazole, which is metabolized by these isoenzymes. According to the manufacturer, ketoconazole (200 mg/day for 14 days), a potent CYP450 3A4 inhibitor, increased the area under the plasma concentration-time curve (AUC) of aripiprazole (15 mg single dose) and its active metabolite, dehydro-aripiprazole, by 63% and 77%, respectively. Quinidine (166 mg/day for 13 days), a potent CYP450 2D6 inhibitor, increased the AUC of aripiprazole (10 mg single dose) by 112% but decreased the AUC of dehydro-aripiprazole by 35%.

MANAGEMENT: Pharmacologic response to aripiprazole should be monitored more closely whenever a CYP450 2D6 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the aripiprazole dosage adjusted as necessary. The manufacturer recommends that aripiprazole dosage be reduced to one-half the normal dosage during concomitant administration with ketoconazole or quinidine, and additional dosage adjustments be based on clinical evaluation. No dosage recommendations are available for concomitant administration with less potent CYP450 2D6 or 3A4 inhibitors.

Aprepitant

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of aprepitant, which is primarily metabolized by the isoenzyme. According to the manufacturer, coadministration of the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 10 days) and a single 125 mg dose of aprepitant on day 5 resulted in a 5-fold increase in the area under the plasma concentration-time curve (AUC) and a 3-fold increase in the mean terminal half-life of aprepitant. In patients with mild to moderate hypertension, coadministration of the moderate inhibitor diltiazem (120 mg three times a day for 5 days) and aprepitant (approximately 230 mg once a day) resulted in a 2-fold increase in the AUC of aprepitant and a 1.7-fold increase in that of diltiazem. No clinically significant changes in ECG, heart rate, or blood pressure were observed beyond those induced by diltiazem alone.

MANAGEMENT: Caution is advised if aprepitant is used with CYP450 3A4 inhibitors, particularly potent ones like protease inhibitors, macrolide antibiotics, itraconazole, ketoconazole, and nefazodone. Pharmacologic response to aprepitant should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. In addition, many CYP450 3A4 inhibitors are also substrates of the isoenzyme, thus pharmacologic response to these agents should also be monitored during coadministration with aprepitant.

Galantamine

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of galantamine, which is partially metabolized by the isoenzyme. In multiple dose pharmacokinetic studies, a potent CYP450 3A4 inhibitor such as ketoconazole has been shown to increase the systemic exposure (AUC) of galantamine by 30%. Erythromycin and cimetidine, which are less potent inhibitors, have been shown to increase galantamine AUC by 10% and 16%, respectively.

MANAGEMENT: Pharmacologic response to galantamine should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the galantamine dosage adjusted as necessary. Patients should be advised to notify their physician if they experience excessive cholinergic symptoms such as severe nausea, vomiting, GI cramping, salivation, lacrimation, sweating, dizziness, or syncope.

Repaglinide (oral)

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of repaglinide, which is metabolized by the isoenzyme in the intestine and liver. In nine healthy volunteers, pretreatment with the CYP450 3A4 inhibitor clarithromycin (250 mg orally twice a day for 4 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of repaglinide (0.25 mg single oral dose) by 66% and 41%, respectively, compared to placebo. Increases in repaglinide Cmax and AUC values were observed in every subject. Clarithromycin also increased the mean elimination half-life of repaglinide by 21% (from 1.4 to 1.7 hours), as well as the mean incremental AUC from 0 to 3 hours of serum insulin by 51% and the maximum increase in the serum insulin concentration by 61%. No statistically significant differences were found in the blood glucose concentrations between the clarithromycin and placebo phases, and no subject developed symptomatic hypoglycemia as a result of the interaction. However, the lack of clinical adverse effects may be explained, at least partially, by frequent carbohydrate intake during the study and the use of a subtherapeutic dose of repaglinide.

MANAGEMENT: Because the antidiabetic effect of repaglinide is dose- and concentration-dependent, pharmacologic response to repaglinide should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitations. The repaglinide dosage may require adjustment if an interaction is suspected.

Buprenorphine (oral), Buprenorphine (injection)

MONITOR: Coadministration with drugs that are inhibitors of the CYP450 3A4 isoenzyme may increase the plasma concentrations and pharmacologic effects of buprenorphine, which is metabolized in the liver by CYP450 3A4. The risk of central nervous system and respiratory depression may be increased.

MANAGEMENT: Pharmacologic response to buprenorphine and vital signs should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the buprenorphine dosage adjusted as necessary. If clinically significant respiratory depression occurs, buprenorphine should be withdrawn.

Efavirenz

MONITOR: Coadministration with efavirenz may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is accelerated clearance due to induction of CYP450 3A4 activity by efavirenz.

MANAGEMENT: Caution is advised if efavirenz must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever efavirenz is added to or withdrawn from therapy.

Fluconazole

MONITOR: Coadministration with fluconazole may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by fluconazole. A case of carbamazepine (a CYP450 3A4 substrate) toxicity secondary to significantly increased serum drug concentrations was reported in a patient shortly after the addition of fluconazole. Other drugs metabolized by CYP450 3A4 whose plasma levels reportedly are increased by fluconazole include oral contraceptives (ethinyl estradiol and levonorgestrel), cyclosporine, tacrolimus, and cisapride. These interactions have usually been observed with higher dosages of fluconazole (200 mg/day or more).

MANAGEMENT: Caution is advised if fluconazole must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fluconazole is added to or withdrawn from therapy.

Fluvoxamine

MONITOR: Coadministration with fluvoxamine may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to competitive inhibition of CYP450 3A4 activity by fluvoxamine.

MANAGEMENT: Caution is advised if fluvoxamine must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fluvoxamine is added to or withdrawn from therapy.

Darifenacin

MONITOR: Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of darifenacin, which is a substrate of these isoenzymes. According to the product labeling, coadministration of darifenacin (30 mg once daily) with the mixed CYP450 inhibitor cimetidine resulted in a 42% increase in the mean darifenacin steady-state peak plasma concentration (Cmax) and a 34% increase in the systemic exposure (AUC) compared to administration of darifenacin alone. The potent CYP450 2D6 inhibitor paroxetine (20 mg) increased steady-state AUC of darifenacin (30 mg once daily) by 33%. Erythromycin, a CYP450 3A4 inhibitor, increased the mean steady-state Cmax and AUC of darifenacin (30 mg once daily) by 128% and 95%, respectively. Fluconazole, another 3A4 inhibitor, increased these values by 88% and 84%, respectively.

MANAGEMENT: Pharmacologic response to darifenacin should be monitored more closely whenever a CYP450 2D6 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the darifenacin dosage adjusted if necessary. Patients should be advised to contact their physician if they experience undue adverse effects of darifenacin such as severe abdominal pain or constipation for 3 or more days.

Aliskiren

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of aliskiren, which is primarily metabolized by the isoenzyme. According to the product labeling, plasma levels of aliskiren were increased approximately 80% by the potent CYP450 3A4 inhibitor ketoconazole at a dosage of 200 mg twice daily. A 400 mg once daily dose of ketoconazole was not studied but would be expected to further increase aliskiren blood levels.

MANAGEMENT: Pharmacologic response to aliskiren should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the aliskiren dosage adjusted if necessary. Patients should be advised to notify their physician if they experience excessive adverse effects of aliskiren such as dizziness, lightheadedness, diarrhea, abdominal pain, and gastroesophageal reflux.

Budesonide inhalation, Budesonide (oral)

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and systemic effects of budesonide, which is metabolized by the isoenzyme. According to budesonide labeling, potent inhibitors can increase the plasma levels of budesonide several fold. For example, an eight-fold increase in the systemic exposure (AUC) has been observed during coadministration of oral budesonide with ketoconazole. In a prospective study of a cystic fibrosis center patient population, 11 of 25 patients receiving high-dose itraconazole (400 to 600 mg/day) and budesonide inhalation therapy (800 to 1600 mcg/day) were found to have adrenal insufficiency (one developed Cushing's syndrome), compared to none in a group of 12 patients treated with itraconazole alone and none in a group of 30 cystic fibrosis patients retrospectively included as controls, 24 of whom had been treated with high-dose inhaled budesonide for several years. Adrenal function improved but did not normalize in 10 of the 11 patients during a follow-up of two to ten months after discontinuation of itraconazole and institution of hydrocortisone replacement therapy.

MANAGEMENT: The possibility of increased systemic pharmacologic effects of budesonide should be considered during concomitant therapy with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, voriconazole, nefazodone, protease inhibitors, and ketolide and macrolide antibiotics. Adrenal function should be monitored regularly during chronic use of these agents, and reduction of budesonide dosage may be necessary. Systemic glucocorticoid effects of budesonide during prolonged administration may include symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, glucose intolerance, irregular menstruations); adrenal suppression (which reduces patient's ability to respond to stress situations); immunosuppression; and osteoporosis.

Gefitinib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of gefitinib, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of gefitinib (250 mg single dose) with the potent inhibitor itraconazole (200 mg once a day for 12 days) increased the mean gefitinib systemic exposure (AUC) by 88% in healthy male volunteers. This increase may be clinically significant, as adverse events of gefitinib are related to dose and exposure.

MANAGEMENT: Caution is advised if gefitinib is administered with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, and most protease inhibitors. Pharmacologic response to gefitinib should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the dosage adjusted as necessary. Patients should be advised to contact their doctor if they experience possible symptoms of gefitinib toxicity such as severe diarrhea, nausea, dyspnea, cough, and fever.

Cinacalcet

MONITOR: Coadministration with ketoconazole or other potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of cinacalcet, which is partially metabolized by the isoenzyme. According to the product labeling, ketoconazole (200 mg twice a day for 7 days) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cinacalcet (90 mg single dose on day 5) by over 2-fold compared to administration of cinacalcet alone.

MANAGEMENT: Pharmacologic response to cinacalcet (i.e., parathyroid hormone and serum calcium levels) should be monitored more closely whenever ketoconazole or other potent inhibitors of CYP450 3A4 (e.g., itraconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics) are added to or withdrawn from therapy, and the cinacalcet dosage adjusted accordingly.

Ramelteon

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 and/or 2C9 may increase the plasma concentrations and pharmacologic effects of ramelteon, which is partially metabolized by these isoenzymes. In healthy volunteers, pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally twice daily for 4 days) increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of ramelteon (16 mg single oral dose on day 4) by 36% and 84%, respectively, compared to administration of ramelteon alone. Likewise, coadministration with fluconazole, a potent CYP450 2C9 inhibitor, resulted in an increase of approximately 150% in the Cmax and AUC of ramelteon following a single 16 mg oral dose. Similar pharmacokinetic changes were also observed with its biologically active metabolite, known as M-II.

MANAGEMENT: Caution is advised if ramelteon is prescribed with potent inhibitors of CYP450 3A4 (e.g., itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, ketolide and certain macrolide antibiotics) and/or CYP450 2C9 (e.g., fluconazole, gemfibrozil, imatinib, metronidazole, miconazole, sulfonamides). A reduction in the ramelteon dosage may be necessary in patients who experience excessive sedation.

Alosetron (oral)

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of alosetron, which has been shown in vitro to be partially metabolized by the isoenzyme. In 38 healthy female subjects, pretreatment with ketoconazole (200 mg twice a day for 7 days) increased the area under the plasma concentration-time curve (AUC) of alosetron (1 mg single oral dose) by 29% compared to administration of alosetron alone. Concomitant administration of alosetron with other CYP450 3A4 inhibitors has not been evaluated.

MANAGEMENT: Because alosetron is associated with potentially serious and life-threatening, dose-related gastrointestinal adverse effects, caution is advised during concomitant use with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. Patients should be advised to immediately discontinue alosetron and notify their physician if they experience constipation or signs and symptoms of ischemic colitis such as rectal bleeding, bloody diarrhea, and new or worsening abdominal pain. Alosetron should not be resumed if ischemic colitis is diagnosed. Ischemic colitis and other serious complications such as obstruction, perforation, impaction, and toxic megacolon have resulted in hospitalization, blood transfusion, surgery, and death.

Fluticasone nasal, Fluticasone inhalation

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the systemic exposure of fluticasone propionate administered intranasally or by oral inhalation due to inhibition of its metabolism. In eight healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol levels by 7%, and no effect on urinary excretion of cortisol compared to coadministration with placebo. Adverse effects were not reported. Coadministration of fluticasone nasal spray twice daily and erythromycin 500 mg twice daily did not affect fluticasone levels but reduced plasma cortisol levels by 2%. Coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone propionate pharmacokinetics.

MANAGEMENT: Caution is advised if fluticasone is prescribed with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. Patients should be monitored for systemic glucocorticoid effects including symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, irregular menstruations), adrenal suppression (which reduces patient's ability to respond to stress situations), immunosuppression, osteoporosis, glucose intolerance, and exacerbation of diabetes mellitus.

Almotriptan

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of almotriptan, which is metabolized by the isoenzyme. In healthy volunteers, pretreatment with the potent inhibitor ketoconazole (400 mg once a day for 3 days) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of almotriptan (12.5 mg single oral dose) by approximately 60%. Coadministration of almotriptan with verapamil (120 mg sustained-release tablets twice a day for 7 days), a moderate inhibitor, resulted in a 24% increase in Cmax and a 20% increase in AUC of almotriptan, which are not considered clinically significant.

MANAGEMENT: Caution is advised if almotriptan is used in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. The possibility of prolonged and/or increased pharmacologic effects of almotriptan, including serious adverse effects such as vasospastic reactions, should be considered during concomitant therapy. Patients should be advised to notify their doctor if they experience pain or tightness in the check, neck or jaw, irregular heartbeat or breathing, seizures, tremor, tingling, or nausea.

Erlotinib

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of erlotinib, which is primarily metabolized by the isoenzyme. According to product labeling, coadministration with the potent CYP450 3A4 inhibitor ketoconazole increased erlotinib area under the plasma concentration-time curve (AUC) by two-thirds compared to administration of erlotinib alone.

MANAGEMENT: Caution is advised if erlotinib must be used with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. A dosage reduction or temporary interruption of therapy should be considered in patients who experience undue adverse effects of erlotinib such as severe diarrhea (i.e., that which is unresponsive to loperamide or results in dehydration), severe skin reactions, or severe liver function test abnormalities.

Rifapentine

MONITOR: Coadministration with rifapentine may decrease the plasma concentrations of drugs that are substrates of the CYP450 2C8, 2C9, and/or 3A4 isoenzymes. The mechanism is accelerated clearance due to induction of those isoenzymes by rifapentine. Enzyme activities may be induced within 4 days of the first dose and return to normal 14 days after discontinuation of rifapentine. In vitro and in vivo enzyme studies have suggested rifapentine induction potential to be less than that of rifampin but greater than that of rifabutin. In addition, the magnitude of induction is dependent on dose and dosing frequency.

MANAGEMENT: When drugs that are known substrates of CYP450 2C8, 2C9, and/or 3A4 are coadministered with rifapentine, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever rifapentine is added to or withdrawn from therapy.

Saquinavir

MONITOR: Coadministration with saquinavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by saquinavir.

MANAGEMENT: Caution is advised if saquinavir must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever saquinavir is added to or withdrawn from therapy.

Troglitazone (oral)

MONITOR: Coadministration with troglitazone may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is accelerated clearance due to induction of CYP450 3A4 activity by troglitazone.

MANAGEMENT: Caution is advised if troglitazone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever troglitazone is added to or withdrawn from therapy.

Cimetidine

MONITOR: Concomitant use of cimetidine and erythromycin may result in higher-than-normal plasma levels of erythromycin through inhibition of CYP450 metabolism by cimetidine. One small study has reported an increase of 73% in the area under the plasma concentration-time curve. Bilateral hearing loss occurred in one patient who had renal dysfunction and was receiving a high dose of erythromycin. This interaction may occur with other macrolide antibiotics.

MANAGEMENT: The patient should be monitored for evidence of adverse effects such as nausea, vomiting, diarrhea, or abdominal pain. Ranitidine, nizatidine and famotidine do not inhibit CYP450 and would not be expected to affect erythromycin levels at recommended doses.

Bromocriptine

MONITOR: Erythromycin may decrease the hepatic metabolism of bromocriptine. Bromocriptine levels and risk of toxicity may be significantly increased.

MANAGEMENT: Patients should be monitored for signs of toxicity, including headache, hypotension, and nausea. A reduction in bromocriptine dosage may be necessary.

Zafirlukast

MONITOR: Erythromycin may decrease zafirlukast plasma concentrations. In one study (n=11) concomitant erythromycin 500 mg 3 times daily reduced zafirlukast levels by 40%. The mechanism and clinical significance are unknown. Reduced efficacy may result.

MANAGEMENT: The clinician should be aware of this interaction and observation for decreased zafirlukast efficacy is recommended if the combination is used.

Imatinib (oral)

MONITOR: Imatinib is a substrate of the CYP450 3A4 isoenzyme as well as a potent competitive inhibitor of the CYP450 2C9, 2D6 and 3A4 isoenzymes. Some drugs that are known inhibitors of CYP450 3A4 are also metabolized by one or more of the isoenzymes inhibited by imatinib. Theoretically, coadministration of imatinib with those drugs may result in mutually elevated plasma drug concentrations due to competitive and noncompetitive inhibition of CYP450 activities.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of imatinib, including serious adverse effects such as edema, hematologic toxicity and immunosuppression, should be considered during concomitant therapy, particularly with potent CYP450 3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nefazodone, and erythromycin. In addition, clinical and laboratory monitoring for potentially increased pharmacologic effects of coadministered medications is recommended, especially those with a narrow therapeutic range.

Tacrolimus (oral)

MONITOR: In vitro and in vivo data suggest that some macrolide antibiotics may increase serum concentrations and toxicity of macrolide immunosuppressants. The mechanism is inhibition of CYP450 3A4 hepatic metabolism.

MANAGEMENT: If these drugs are used concomitantly, plasma immunosuppressant concentrations and renal function should be carefully monitored. Dosage reductions of the macrolide immunosuppressant may be necessary. Azithromycin and dirithromycin may be considered as alternatives, as they are considered unlikely to inhibit CYP450 3A4.

Docetaxel

MONITOR: In vitro data suggest that some macrolide antibiotics may inhibit the hepatic CYP450 3A4 metabolism of docetaxel. Reports on the concomitant use of these agents in the clinical setting are lacking.

MANAGEMENT: This combination should be used cautiously. Azithromycin and dirithromycin may be considered as alternatives, as they have little effect, if any, on CYP450 and are not expected to affect docetaxel.

Diazepam, Alprazolam, Chlordiazepoxide, Clonazepam, Clorazepate, Flurazepam, Triazolam, Halazepam, Estazolam, Quazepam, Diazepam rectal

MONITOR: Macrolide antibiotics may increase and prolong the CNS effects of certain benzodiazepines. The mechanism is inhibition of CYP450 3A4 hepatic oxidation of the benzodiazepines. Midazolam, triazolam, and alprazolam have been specifically studied in this regard. Lorazepam, oxazepam, and temazepam are hepatically conjugated and are not expected to interact. Azithromycin and dirithromycin do not inhibit CYP450 isoenzymes.

MANAGEMENT: Patients receiving this combination should be monitored for excessive or prolonged sedation. Non-interacting benzodiazepines or antimicrobials may be considered as alternatives.

Digoxin (oral)

MONITOR: Macrolide antibiotics may increase plasma concentrations of orally administered digoxin in about 10% of the population. Data are available for erythromycin and clarithromycin. The mechanism may be related to altered intestinal flora effect on gut-wall metabolism or absorption and/or inhibition of renal P glycoprotein secretion of digoxin. A similar interaction may be expected with other macrolides. The risk of an interaction may be less with digoxin solution in capsules because absorption occurs in the upper GI tract.

MANAGEMENT: Clinical monitoring of patient response and tolerance, including laboratory serum digoxin levels is recommended. Patients should be advised to notify their physicians if they experience nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.

Mefloquine

MONITOR: Mefloquine is a myocardial depressant and can cause ECG abnormalities. Theoretically, coadministration with other agents that can affect cardiac conduction (e.g., antiarrhythmic agents, beta blockers, calcium channel blockers, certain antihistamines, tricyclic antidepressants, phenothiazines, some neuroleptics) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential. Parenteral studies in animals have shown that mefloquine possesses 20% of the antifibrillatory action of quinidine and can cause 50% of the increase in PR interval reported with quinine. ECG alterations reported with mefloquine include sinus bradycardia, sinus arrhythmia, first degree AV block, prolongation of the QTc interval, and abnormal T waves. According to mefloquine labeling, there has been one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol).

MANAGEMENT: Caution and clinical monitoring are recommended if mefloquine is used concurrently with other medications that can prolong the QT interval or otherwise affect cardiac conduction. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of arrhythmia such as dizziness, palpitations, or syncope.

Pioglitazone (oral)

MONITOR: Pioglitazone is metabolized by CYP450 3A4 microsomal enzymes in the liver. The clinician should be aware of the potential for an interaction when pioglitazone is used in combination with another medication that inhibits and is also metabolized by CYP450 3A4.

MANAGEMENT: Monitoring for clinical and laboratory evidence of altered safety and efficacy of both drugs if pioglitazone is added to or removed from the patients medication regimen is recommended. Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations) and to notify their physician if it occurs.

Toremifene

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4, 3A5 and/or 3A6 enzymatic pathways may increase the plasma concentrations of toremifene, which is metabolized by these isoenzymes. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of toremifene should be considered.

MANAGEMENT: Clinical and laboratory monitoring for altered efficacy and safety of toremifene (e.g., hypercalcemia, elevated liver enzymes, leukopenia, or thrombocytopenia) may be appropriate whenever a CYP450 inhibitor is added to or withdrawn from therapy.

Cevimeline

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of cevimeline, which is metabolized by CYP450 3A4.

MANAGEMENT: Dosage adjustments and clinical monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be monitored for and advised to report prolonged and/or increased effects of cevimeline, including cholinergic adverse effects such as sweating, diarrhea, salivation and urinary frequency.

Citalopram (oral)

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of citalopram, which is partially metabolized by CYP450 3A4. While clinical data are lacking, the possibility of increased pharmacological effects and/or serotonin syndrome should be considered.

MANAGEMENT: Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever an enzyme inhibitor is added to or withdrawn from therapy. Close monitoring is recommended for signs and symptoms of excessive serotonergic activity such as CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia.

Zonisamide

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of zonisamide, which is metabolized by CYP450 3A4. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of zonisamide should be considered.

MANAGEMENT: Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to notify their physician if they experience symptoms such as severe drowsiness, confusion, loss of coordination, depression, aphasia, decreased sweating, fever, loss of seizure control, or slow pulse.

Buspirone

MONITOR: The combination of buspirone and some macrolide antibiotics may lead to elevated buspirone concentrations and adverse effects. The mechanism may be due to macrolide inhibition of CYP450 3A4 metabolism of buspirone.

MANAGEMENT: Patients should be monitored for adverse buspirone effects, such as increased sedation. A reduction in dosage may be necessary.

Clopidogrel

MONITOR: The concomitant administration of some macrolide antibiotics may reduce the metabolic activation of the prodrug clopidogrel and its antiplatelet effects. The proposed mechanism is inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of clopidogrel to its active metabolite. After coadministration of erythromycin stearate 250 mg four times a day and clopidogrel 75 mg/day to healthy subjects (n=9), the percent platelet aggregation was 42% with clopidogrel alone, 55% with clopidogrel plus erythromycin, and 93% at baseline. After coadministration of single doses of troleandomycin 500 mg and clopidogrel 450 mg, the percent platelet aggregation was 45% with clopidogrel alone, 78% with clopidogrel plus troleandomycin, and 93% at baseline. Clarithromycin also inhibits CYP450 3A4 activity and is also expected to affect clopidogrel metabolism.

MANAGEMENT: Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if a macrolide is coadministered with clopidogrel. Azithromycin and dirithromycin do not inhibit CYP450 3A4 and are theoretically not expected to interact with clopidogrel.

Clozapine

MONITOR: The concomitant administration of some macrolides may result in decreased clearance of clozapine and increased risk of toxicity. The mechanism of this interaction is suspected to be inhibition of the CYP450 hepatic metabolism of clozapine.

MANAGEMENT: While clinical data are limited, clinical and laboratory monitoring may be appropriate whenever a macrolide is added to or withdrawn from therapy. Alternatively, azithromycin and dirithromycin may be considered, as they do not inhibit CYP450 and are not expected to affect clozapine metabolism. Patients should be advised to report symptoms such as somnolence, disorientation, slurred speech, seizures, uncontrolled movements, dizziness, irregular heartbeat, palpitations, fever, or hypersalivation to their physician.

Leflunomide (oral)

MONITOR: The concomitant or sequential use of leflunomide (without the recommended washout period) with agents known to induce hepatotoxicity may potentiate the risk of liver injury. Leflunomide has been associated with hepatotoxicity, including elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis,

MANAGEMENT: Baseline and frequent monitoring of hepatic function is recommended during concurrent use.

Thioguanine

MONITOR: The concomitant or sequential use of thioguanine with agents known to induce hepatotoxicity may potentiate the risk of liver injury. Thioguanine has been associated with hepatotoxicity, including elevated liver transaminases, hyperbilirubinemia, hepatomegaly, portal hypertension, hepatoportal sclerosis, peliosis hepatitis, and fibrosis.

MANAGEMENT: Frequent monitoring of hepatic function is recommended during concurrent use.

Paclitaxel, Paclitaxel protein-bound

MONITOR: Theoretically, coadministration with drugs that are inhibitors of CYP450 2C8 and/or 3A4 may increase the plasma concentrations of paclitaxel, which is metabolized by these isoenzymes.

MANAGEMENT: Clinicians should recognize the potential for interaction with drugs that inhibit CYP450 2C8 and/or 3A4 and monitor for evidence of dose-related toxicities of paclitaxel during coadministration. Patients should be advised to contact their physician if they develop signs and symptoms of myelosuppression (eg., pallor, dizziness, fatigue, lethargy, easy bruising or bleeding, or signs of infection such as fever, chills, or sore throat) or neuropathy (e.g., visual disturbances and burning, tingling, or numbness in the hands and feet).

Chlorpromazine, Azithromycin, Nortriptyline, Desipramine, Amitriptyline, Doxepin, Flecainide, Fluphenazine, Imipramine, Prochlorperazine, Propafenone, Quinine, Tamoxifen, Terbutaline inhalation, Promethazine (oral), Perphenazine, Thiethylperazine, Ondansetron, Trimipramine, Amoxapine, Protriptyline, Clomipramine, Trifluoperazine, Risperidone (oral), Daunorubicin, Doxorubicin, Idarubicin, Vasopressin, Terbutaline (oral), Promethazine (rectal), Promethazine (injection), Ondansetron (injection), Maprotiline, Doxorubicin liposomal, Tizanidine, Daunorubicin liposomal, Epirubicin, Formoterol, Palonosetron, Abarelix, Paliperidone

MONITOR: Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, due to additive arrhythmogenic potential related to their effects on cardiac conduction. The risk of an individual agent or a combination of these agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution and clinical monitoring are recommended if multiple agents associated with QT interval prolongation are prescribed together. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

Mycophenolate mofetil (oral/injection), Mycophenolic acid

MONITOR: Theoretically, drugs that alter the gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid products. Some investigators believe that antimicrobials may interfere with the enterohepatic recirculation of mycophenolic acid by decreasing bacterial hydrolytic enzymes in the gastrointestinal tract that are responsible for regenerating mycophenolic acid from its glucuronide metabolite following first-pass metabolism.

MANAGEMENT: Close clinical and laboratory monitoring for evidence of diminished immunosuppressive effect of mycophenolic acid is recommended during concomitant therapy with anti-infective agents.

Quetiapine

MONITOR: There is some concern that quetiapine may have additive adverse cardiovascular effects in combination with other drugs that are known to prolong the QT interval of the electrocardiogram. Data are conflicting. In clinical trials, there was no statistically significant difference between quetiapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters including QT, QTc, and PR intervals. However, QT prolongation has been reported in quetiapine overdose and with therapeutic use of other atypical antipsychotic agents such as sertindole, ziprasidone, and risperidone. In one case report, torsade de pointes arrhythmia developed in a patient treated with low-dose quetiapine. However, the relationship to quetiapine is uncertain, as there were multiple confounding risk factors such as hypomagnesemia, a history of QT prolongation (possibly prior to initiation of quetiapine), a history of substance abuse, and uncertain medication compliance. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Some clinicians recommend caution when quetiapine is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Vinblastine

MONITOR: Three study patients receiving vinblastine and cyclosporine developed severe vinblastine toxicity when erythromycin was added to their regimens. Symptoms included severe constipation, muscle and back pain, and neutropenia. In one patient, previous courses of vinblastine and cyclosporine only, sometimes at higher doses of each drug, had been well tolerated. Other macrolide antibiotics may interact with vinblastine and cyclosporine in a similar manner.

MANAGEMENT: Until more information is available, patients receiving this combination should be monitored for clinical and laboratory evidence of toxicity.

Phenytoin (oral), Mephenytoin, Ethotoin

One study has suggested that the pharmacokinetic disposition of phenytoin is not significantly altered in patients receiving erythromycin. However, occasional large changes in phenytoin clearance were noted in some patients. The authors have recommended caution if erythromycin and phenytoin must be administered concomitantly. Some other macrolide antibiotics may interact with hydantoins in a similar manner.

Bortezomib

Strong inhibitors or inducers of cytochrome-P450 3A4 may affect the plasma concentrations of bortezomib. In vitro, bortezomib is a substrate of CYP450 3A4, 2D6, 2C19, 2C9, and 1A2 isoenzymes. The clinical significance is unknown. Caution and monitoring for altered safety and efficacy is recommended during concomitant therapy.

Montelukast

The coadministration with drugs that are inhibitors of the CYP450 3A4 and/or 2C9 enzymatic pathways may increase the plasma concentrations of montelukast, which is metabolized by both of these isoenzymes. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of montelukast should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 and/or 2C9 inhibitor is added to or withdrawn from therapy.

Mifepristone

The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of mifepristone, which is metabolized by CYP450 3A4. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of mifepristone should be considered. Patients should be advised to notify their physician if they experience excessive or prolonged bleeding or cramping, or severe nausea, vomiting, diarrhea, headache, or dizziness.

Sibutramine (oral)

The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of sibutramine and its active metabolites, which are metabolized by CYP450 3A4. Inhibitors such as ketoconazole, cimetidine and erythromycin have led to moderate increases in the peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of the active metabolites. The data suggest that although the potential for such interaction exists, the magnitude appears to be small. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to notify their physician if they experience symptoms of possible toxicity, such as high blood pressure (fast or irregular heartbeat, severe headache, blurry vision) or seizures.

Pimecrolimus topical

Theoretically, coadministration with CYP450 3A inhibitors may increase the plasma concentrations of pimecrolimus due to inhibition of its metabolism by CYP450 3A isoenzymes. Although clinically significant drug interactions are not expected due to minimal systemic absorption of topically administered pimecrolimus, the possibility cannot be ruled out. The manufacturer recommends caution in patients with widespread or erythrodermic disease.

Zolpidem

Use of drugs that inhibit the isoenzyme CYP450 3A4 may decrease the metabolism and increase the plasma levels of zolpidem. This can result in increased clinical effectiveness and risk of toxicity associated with zolpidem. Monitoring for signs and symptoms of altered zolpidem effect is recommended. Patients should be advised to notify their physician if they experience nausea, vomiting, diarrhea, confusion, daytime sedation, dizziness, or unconsciousness. A reduction in zolpidem dosage may be necessary.

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