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Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state levels of Cmax, Cmin, and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.
Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receivingconcurrent verapamil, belonging to the calcium channel blockers drug class.
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown toresult in increased plasma concentrations of carbamazepine. Blood level monitoring ofcarbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acidmetabolite of terfenadine were threefold higher, on average, than the values observed whenterfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not significantly affected by coadministration of terfenadine once clarithromycinreached steady-state conditions. Concomitant administration of clarithromycin with terfenadine iscontraindicated. (See CONTRAINDICATIONS.)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily tohealthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax,AUC0-24, and t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration ofclarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administeredalone and 5.7 when coadministered with clarithromycin.
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant.
Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adultpatients may result in decreased steady-state zidovudine concentrations. Because clarithromycinappears to interfere with absorption of simultaneously administered oral zidovudine, this interactioncan be largely avoided by staggering the doses of clarithromycin and zidovudine. This interactiondoes not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension withzidovudine or dideoxyinosine. Similar interaction studies have not been conducted with clarithromycinextended release and zidovudine.
Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patientsresulted in no statistically significant change in didanosine pharmacokinetics.
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21healthy volunteers led to increases in the mean steady-state clarithromycin Cmin and AUC of 33% and18%, respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly affectedby concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Concomitant administration of clarithromycin and ritonavir (n = 22) resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin. Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir. However, for patients with renal impairment, the following dosage adjustments should be considered. For patients with CLCR 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CLCR less than 30 mL/min, the dose of clarithromycin should be decreased by 75%.
Spontaneous reports in the post-marketing period suggest that concomitant administration ofclarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oralanticoagulants simultaneously.
Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin isknown to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp byclarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations inpatients receiving clarithromycin and digoxin concomitantly have also been reported in postmarketingsurveillance. Some patients have shown clinical signs consistent with digoxin toxicity,including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitoredwhile patients are receiving digoxin and clarithromycin simultaneously.
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp).Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin andcolchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead toincreased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicinetoxicity. (See WARNINGS.)
Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized byCYP3A may be associated with elevations in drug concentrations that could increase or prolong boththerapeutic and adverse effects of the concomitant drug.
Clarithromycin should be used with caution in patients receiving treatment with other drugs known tobe CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g.,carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Dosage adjustmentsmay be considered, and when possible, serum concentrations of drugs primarily metabolized byCYP3A should be monitored closely in patients concurrently receiving clarithromycin.
The following are examples of some clinically significant CYP3A based drug interactions. Interactionswith other drugs metabolized by the CYP3A isoform are also possible.
Carbamazepine and Terfenadine
Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine wereobserved in clinical trials with clarithromycin.
Efavirenz, Nevirapine, Rifampicin, Rifabutin and Rifapentine
Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine,rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lowerthe plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite thatis also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impairedduring concomitant administration of clarithromycin and enzyme inducers.
Sildenafil, Tadalafil, and Vardenafil
Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3Amay be inhibited by concomitantly administered clarithromycin.
Coadministration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increasedphosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages shouldbe considered when these drugs are co-administered with clarithromycin.
TolterodineThe primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6).However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is viaCYP3A. In this population subset, inhibition of CYP3A results in significantly higher serumconcentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence ofCYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)
When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolamAUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oraladministration. Concomitant administration of oral midazolam and clarithromycin should be avoided. Ifintravenous midazolam is co-administered with clarithromycin, the patient must be closely monitoredto 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 fortheir elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction withclarithromycin is unlikely. There have been post-marketing reports of drug interactions and centralnervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use ofclarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects issuggested.
Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of abi-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 inexposure 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 necessaryin patients with normal renal function. For patients with moderate renal function (creatinine clearance30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients withcreatinine clearance less than 30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day shouldnot be coadministered with protease inhibitors.
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectionaldrug interaction. Clarithromycin may increase the plasma levels of itraconazole, whileitraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole andclarithromycin concomitantly should be monitored closely for signs or symptoms of increased orprolonged pharmacologic effects.
Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of abi-directional drug interaction. Concomitant administration of clarithromycin (500 mg bid) andsaquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state AUCand Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinaviralone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen withclarithromycin alone. No dose adjustment is required when the two drugs are co-administered for alimited time at the doses/formulations studied. Observations from drug interaction studies using thesoft gelatin capsule formulation may not be representative of the effects seen using the saquinavirhard gelatin capsule. Observations from drug interactions studies performed with saquinavir alonemay not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir isco-administered with ritonavir, consideration should be given to the potential effects of ritonavir onclarithromycin (see PRECAUTIONS – Drug Interactions).
The following CYP3A based drug interactions have been observed with erythromycin products and/orwith clarithromycin in post-marketing experience:
There have been post-marketing reports of torsades de pointes occurring with concurrent use ofclarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTcprolongation during coadministration of clarithromycin with these drugs. Serum concentrations ofthese medications should also be monitored.
Post-marketing reports indicate that coadministration of clarithromycin with ergotamine ordihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm andischemia of the extremities and other tissues including the central nervous system. Concomitantadministration of clarithromycin with ergotamine or dihydroergotamine is contraindicated (seeCONTRAINDICATIONS).
Triazolobenziodidiazepines (Such as Triazolam and Alprazolam) and Related Benzodiazepines (Such as Midazolam)
Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus,may increase the pharmacologic effect of these benzodiazepines. There have been post-marketingreports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitantuse of clarithromycin and triazolam.
HMG-CoA Reductase Inhibitors
As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoAreductase inhibitors (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have beenreported in patients taking these drugs concomitantly.
Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. A similarinteraction may occur with clarithromycin; reduction of sildenafil dosage should be considered. (SeeViagra package insert.)
There have been spontaneous or published reports of CYP3A based interactions of erythromycinand/or clarithromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide,rifabutin, quinidine, methylprednisolone, cilostazol, bromocriptine and vinblastine.
Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, or terfenadine iscontraindicated (see CONTRAINDICATIONS.)
In addition, there have been reports of interactions of erythromycin or clarithromycin with drugs notthought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
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