Zeclar 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%.
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in
increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acid metabolite of
terfenadine were threefold higher, on average, than the values observed when terfenadine was administered alone. The
pharmacokinetics of clarithromycin and the 14-hydroxy-clarithromycin were not significantly affected by
coadministration of terfenadine once clarithromycin reached steady-state conditions. Concomitant administration of
clarithromycin with terfenadine is contraindicated.
Zeclar 500 mg every 8 hours 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 increases of 30%, 89%, and 34%, respectively), by the concomitant
administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole
was administered alone and 5.7 when co-administered with clarithromycin.
Co-administration 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 and zidovudine to HIV-infected adult patients resulted in
decreased steady-state zidovudine concentrations. When 500 mg of clarithromycin were administered twice daily,
steady-state zidovudine AUC was reduced by a mean of 12% (n=4). Individual values ranged from a decrease of 34% to an
increase of 14%. Based on limited data in 24 patients, when clarithromycin was administered two to four hours prior
to oral zidovudine, the steady-state zidovudine Cmax was increased by approximately 2-fold, whereas the AUC was unaffected.
Simultaneous administration of clarithromycin and didanosine to 12 HIV-infected adult patients resulted in no
statistically significant change in didanosine pharmacokinetics.
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 clarithromycin Cmin and AUC of 33% and 18%,
respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly
affected by concomitant administration of fluconazole.
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. Zeclar 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 mg/min, the dose of
clarithromycin should be reduced by 50%. For patients with CLCR < 30 ml/min, the dose of clarithromycin
should be decreased by 75%.
Spontaneous reports in the post-marketing period suggest that concomitant administration of clarithromycin and
oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully
monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously.
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 levels should be carefully monitored while patients
are receiving digoxin and clarithromycin simultaneously.
The following drug interactions, other than increased serum concentrations of carbamazepine and active acid
metabolite of terfenadine, have not been reported in clinical trials with clarithromycin; however, they have been
observed with erythromycin products and/or with clarithromycin in post-marketing experience.
Concurrent use of erythromycin or clarithromycin and ergotamine or dihydroergotamine has been associated in some
patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Erythromycin has been reported to decrease the clearance of triazolam and, thus, may increase the pharmacologic
effect of triazolam. There have been post-marketing reports of drug interactions and CNS effects (e.g.,
somnolence and confusion) with the concomitant use of clarithromycin and triazolam.
There have been reports of an interaction between erythromycin and astemizole resulting in QT prolongation and
torsades de pointes. Concomitant administration of erythromycin and astemizole is contraindicated. Because
clarithromycin is also metabolized by cytochrome P450, concomitant administration of clarithromycin with astemizole
is not recommended.
As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase
inhibitors (e.g., lovastatin and simvastatin), through inhibition of cytochrome P450 metabolism of these
drugs. Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.
The use of erythromycin and clarithromycin in patients concurrently taking drugs metabolized by the cytochrome
P450 system may be associated with elevations in serum levels of these other drugs. There have been reports of
interactions of erythromycin and/or clarithromycin with carbamazepine, cyclosporine, tacrolimus, hexobarbital,
phenytoin, alfentanil, disopyramide, lovastatin, bromocriptine, valproate, terfenadine, cisapride, pimozide,
rifabutin, and astemizole. Serum concentrations of drugs metabolized by the cytochrome P450 system should be
monitored closely in patients concurrently receiving these drugs.