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The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Cisapride, pimozide, astemizole and terfenadine.
Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly.
This may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).
Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias eg, QT prolongation, ventricular tachycardia, ventricular fibrillation and Torsades de pointes (see Contraindications). In 1 study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a 2- to 3-fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergot Alkaloids: Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system (CNS). Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see Contraindications).
Effects of Other Medicinal Products on Clarithromycin: Drugs that are inducers of CYP3A (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.
The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine: Strong inducers of the cytochrome P450 (CYP450) metabolism system eg, efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active.
Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore, alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole: Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18%, respectively. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir: A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every 8 hrs and clarithromycin 500 mg every 12 hrs resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin peak plasma concentration (Cmax) increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with creatinine clearance (CrCl) 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CrCl <30 mL/min, the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin >1 g/day should not be co-administered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir (see Bi-directional Drug Interactions as follows).
Effect of Clarithromycin on Other Medicinal Products: Antiarrhythmics: There have been post-marketed reports of Torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum levels of these medications should be monitored during clarithromycin therapy.
CYP3A-based Interactions: Co-administration of clarithromycin, known to inhibit CYP3A and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (eg, carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.
The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: Alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the CYP450 system include phenytoin, theophylline and valproate.
Omeprazole: Clarithromycin (500 mg every 8 hrs) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and t½ increased by 30%, 89% and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hr gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.
Sildenafil, Tadalafil, and Vardenafil: Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.
Theophylline, Carbamazepine: Results of clinical studies indicate there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin.
Tolterodine: The primary route of metabolism for tolterodine is via the 2D6 isoform of CYP450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors eg, clarithromycin in the CYP2D6 poor metabolizer population.
Triazolobenzodiazepines (eg, Alprazolam, Midazolam, Triazolam): When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after IV administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If midazolam IV is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and CNS effects (eg, somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
Other Drug Interactions: Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are administered together, inhibition of P-gp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine.
Patients should be monitored for clinical symptoms of colchicine toxicity. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function.
Concomitant use of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see Contraindications and Precautions).
Digoxin: Digoxin is thought to be a substrate for the efflux transporter, P-gp. Clarithromycin is known to inhibit P-gp. When clarithromycin and digoxin are administered together, inhibition of P-gp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
Zidovudine: Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine. This interaction does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine.
Phenytoin and Valproate: There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs metabolized by CYP450 isoforms other than CYP3A (eg, phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Bi-Directional Drug Interactions: Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (CrCl 30-60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with CrCl <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin >1,000 mg/day should not be co-administered with protease inhibitors.
Calcium Channel Blockers: Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (eg, verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction.
Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bi-directional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1,200 mg 3 times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the 2 drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see previous text).
Incompatibilities: Not applicable.
