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Biaxin, Biaxin XL
The majority of side effects observed in clinical trials were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections and fewer than 2% of pediatric patients without mycobacterial infections discontinued therapy because of drug-related side effects. Fewer than 2% of adult patients taking BIAXIN XL tablets discontinued therapy because of drug-related side effects.
The most frequently reported events in adults taking BIAXIN tablets (clarithromycin tablets, USP) were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). In pediatric patients, the most frequently reported events were diarrhea (6%), vomiting (6%), abdominal pain (3%), rash (3%), and headache (2%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, only 1% was described as severe.
The most frequently reported events in adults taking BIAXIN XL (Clarithromycin extended-release tablets) were diarrhea (6%), abnormal taste (7%), and nausea (3%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, less than 1% were described as severe.
In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking either BIAXIN tablets or BIAXIN XL tablets; however, patients taking BIAXIN XL tablets reported significantly less severe gastrointestinal symptoms compared to patients taking BIAXIN tablets. In addition, patients taking BIAXIN XL tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events compared to BIAXIN tablets.
In community-acquired pneumonia studies conducted in adults comparing clarithromycin to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs 32%; p < 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of clarithromycin-treated patients.
In two U.S. studies of acute otitis media comparing clarithromycin to amoxicillin/potassium clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21% vs. 40%, p < 0.001). One-third as many clarithromycin-treated patients reported diarrhea as did amoxicillin/potassium clavulanate-treated patients.
Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness. There have been reports of tooth discoloration in patients treated with BIAXIN. Tooth discoloration is usually reversible with professional dental cleaning. There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell including smell loss, usually in conjunction with taste perversion or taste loss, have also been reported.
Transient CNS events including anxiety, behavioral changes, confusional states, convulsions, depersonalization, disorientation, hallucinations, insomnia, depression, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing surveillance. Events usually resolve with discontinuation of the drug.
Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with clarithromycin. (See WARNINGS – Hepatotoxicity).
There have been post-marketing reports of BIAXIN XL tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times.
As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.
There have been reports of interstitial nephritis coincident with clarithromycin use.
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. (See WARNINGS and PRECAUTIONS.)
Changes in Laboratory Values
Changes in laboratory values with possible clinical significance were as follows:
Elevated SGPT (ALT) < 1%; SGOT (AST) < 1%; GGT < 1%; alkaline phosphatase < 1%; LDH < 1%; total bilirubin < 1%
Decreased WBC < 1%; elevated prothrombin time 1%
Elevated BUN 4%; elevated serum creatinine < 1% GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.
Read the Biaxin, Biaxin XL (clarithromycin) Side Effects Center for a complete guide to possible side effects »
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%.
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-OH-clarithromycin were not significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions. Concomitant administration of clarithromycin with terfenadine is contraindicated. (See CONTRAINDICATIONS.)
Clarithromycin 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 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-hydroxyclarithromycin plasma concentrations (31%). These effects are clinically insignificant.
Simultaneous oral administration of BIAXIN tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Following administration of clarithromycin 500 mg tablets twice daily with zidovudine 100 mg every 4 hours, the steady-state zidovudine AUC decreased 12% compared to administration of zidovudine alone (n=4). Individual values ranged from a decrease of 34% to an increase of 14%. When clarithromycin tablets were administered two to four hours prior to zidovudine, the steady-state zidovudine Cmax increased 100% whereas the AUC was unaffected (n=24). Administration of clarithromycin and zidovudine should be separated by at least two hours. The impact of co-administration of clarithromycin extended-release tablets and zidovudine has not been evaluated.
Simultaneous administration of BIAXIN tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.
Following administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin Cmin and AUC increased 33% and 18%, respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole. No dosage adjustment of clarithromycin is necessary when co-administered with 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. Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex (see PRECAUTIONS – Drug Interactions). Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
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.
Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
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 (e.g., 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 are examples of some clinically significant CYP3A based drug interactions. Interactions with 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 were observed in clinical trials with clarithromycin.
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 a single dose of colchicine 0.6 mg was administered with clarithromycin 250 mg BID for 7 days, the colchicine Cmax increased 197% and the AUC0-∞ increased 239% compared to administration of colchicine alone. 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 WARNINGS).
Efavirenz, Nevirapine, Rifampicin, Rifabutin, and Rifapentine
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A.
Sildenafil, Tadalafil, and Vardenafil
Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Coadministration of these phosphodiesterase inhibitors with clarithromycin is not recommended.
The primary route of metabolism for tolterodine is via 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. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)
When a single dose of midazolam was co-administered with clarithromycin tablets (500 mg twice daily for 7 days), midazolam AUC increased 174% after intravenous administration of midazolam and 600% after oral administration. When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated. Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bidirectional drug interaction. Following administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), the clarithromycin AUC increased 94%, the 14-OH clarithromycin AUC decreased 70% and the atazanavir AUC increased 28%. When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50%. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex (see PRECAUTIONS – Drug Interactions). Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bidirectional drug interaction when administered concomitantly. Clarithromycin may increase the plasma concentrations of itraconazole, while itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bidirectional drug interaction. Following administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers, the steady-state saquinavir AUC and Cmax increased 177% and 187% respectively compared to administration of saquinavir alone. Clarithromycin AUC and C max increased 45% and 39% respectively, whereas the 14–OH clarithromycin AUC and Cmax decreased 24% and 34% respectively, compared to administration with clarithromycin alone. No dose adjustment of clarithromycin is necessary when clarithromycin is co-administered with saquinavir in patients with normal renal function. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to interaction between clarithromycin and ritonavir) (see PRECAUTIONS —Drug Interactions).
The following CYP3A based drug interactions have been observed with erythromycin products and/or with clarithromycin in post-marketing experience:
There have been post-marketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs. Serum concentrations of these medications should also be monitored.
Post-marketing reports indicate that coadministration 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. Concomitant administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated (see CONTRAINDICATIONS).
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-marketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam.
HMG-CoA Reductase Inhibitors
As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.
Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. A similar interaction may occur with clarithromycin; reduction of sildenafil dosage should be considered. (See Viagra package insert.)
There have been spontaneous or published reports of CYP3A based interactions of erythromycin and/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 is contraindicated (see CONTRAINDICATIONS.)
In addition, there have been reports of interactions of erythromycin or clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Last reviewed on RxList: 5/17/2012
This monograph has been modified to include the generic and brand name in many instances.
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