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Clarithromycin: Drug-Drug Interactions


Antifungal imidazoles

In three patients with pulmonary MAC and aspergillosis infections, itraconazole was suggested to increase the plasma concentration of clarithromycin as well as the clarithromycin:14-hydroxyclarithromycin ratio. This effect may have been due to inhibition of CYP3A4 by itraconazole.


Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrolides, especially clarithromycin, typically resulting in prolongation of the QT interval and cardiac dysrhythmias (torsade de pointes).


Cisapride can prolong the QT interval, with a risk of ventricular dysrhythmias. Clarithromycin increases serum concentrations of cisapride. This potentially dangerous interaction can result in QT interval prolongation and dysrhythmias such as torsade de pointes.

  • Torsade de pointes occurred in a 77-year-old woman taking cisapride and clarithromycin.

Warnings have been issued by the manufacturers to avoid concomitant administration.


  • Fatal colchicine intoxication occurred in a 67-year-old man who had taken clarithromycin 500 mg bd for 4 days.

Clarithromycin may have inhibited colchicine metabolism and caused a rise in colchicine concentration.


Clarithromycin has been reported to cause digoxin toxicity. Two different mechanisms are involved, inhibition of the renal excretion of digoxin and alteration of intestinal flora, which reduces the presystemic hydrolysis of digoxin.

  • A 70-year-old woman taking digoxin for atrial fibrillation developed nausea, vomiting, and dizziness 2 days after starting to take clarithromycin. Her serum digoxin concentration was 3.9 µg/ml (target range 0.5-2).


Fatal toxic epidermal necrolysis and fulminant hepatitis occurred shortly after the start of treatment with clarithromycin in a 47-year-old man who was taking disulfiram.

  • A 47-year-old man with a history of chronic alcoholism took disulfiram 250 mg/day for 1 month. He then took clarithromycin 500 mg bd and paracetamol 500 mg tds and 1 week later noticed non-pruritic cutaneous macu-lopapular lesions on his legs, extending to the rest of his body, excluding the palms and soles. Previous drug therapy was withdrawn. A skin biopsy showed toxic epidermal necrolysis. During the next several days the skin lesions worsened. Cutaneous blisters became evident, initially covering less than 10% of the body surface, but then extending all over the body. The serum bilirubin concentration was 359 µmol/l (direct bilirubin 213 µmol/l), the partial thromboplastin time longer than 200 seconds, and the prothrombin time 26 seconds. He developed septic shock and, despite supportive measures, died.

Ergot alkaloids

In patients with ergotamine toxicity, vasoconstriction can lead to frank ischemia. Clarithromycin interferes with ergotamine metabolism.

  • A 41-year-old woman developed worsening lower leg pain, pallor, and a sensation of coolness aggravated by exertion; there was severe vasospasm in the legs. She had taken a caffeine + ergotamine formulation for migraine for many years and had recently been given clarithromycin 500 mg bd for flu-like symptoms.

HIV nucleoside reverse transcriptase inhibitors

Clarithromycin reduced the peak concentration and AUC of zidovudine at steady state by about 12%, possibly as a result of reduced zidovudine absorption. However, if the two drugs were taken at least 2 hours apart, the pharmacokinetics of zidovudine were unaffected.

In 12 HIV-positive patients there was no statistically significant difference in concentrations of didanosine when clarithromycin was added.


In an open, randomized, crossover, pharmacokinetic and pharmacodynamic study in 12 healthy volunteers who took clarithromycin 250 mg bd for 5 days, azithromycin 500 mg/day for 3 days, or no pretreatment, followed by a single dose of midazolam (15 mg), clarithromycin increased the AUC of midazolam by over 3.5 times and the mean duration of sleep from 135 to 281 minutes. In contrast, there was no change with azithromycin, suggesting that it is much safer for co-administration with midazolam.


In 21 healthy volunteers, clarithromycin (400 mg bd) for 3 days before omeprazole (20 mg/day) significantly inhibited the metabolism of omeprazole.


Clarithromycin inhibits the metabolism of pimozide, pimozide plasma concentrations increase, and there is an increased risk of cardiotoxicity through prolongation of the QT interval and fatal ventricular dysrhythmias.


Clarithromycin is one of the core drugs for Mycobacterium avium complex infections in both HIV-infected and non-infected patients. For this indication, doses of up to 2000 mg/day are used, typically in combination with other drugs.

The interaction of clarithromycin with the rifamycins is complex. Clarithromycin inhibits CYP3A4, while both rifampicin and rifabutin induce P450 cytochromes, including CYP3A4, resulting in enhanced metabolism of drugs. The changes in serum concentrations of clarithromycin and its metabolite in the presence of the enzyme inducers rifampicin and rifabutin suggest that metabolism of clarithromycin by CYP3A4 is increased.

After the addition of rifampicin, peak serum concentrations of clarithromycin fell markedly, from a mean of 5.8-2.5 µg/ml. At the same time the ratio of the serum concentrations of clarithromycin and its 14-OH metabolite was reversed from 3.3:1 to 1:2.7. There were similar, although less marked, changes after the addition of rifabutin 600 mg/day to a regimen that included clarithromycin 1000 mg/day.

Whether these changes in serum clarithromycin concentrations are relevant to its antimicrobial activity is unknown, since prediction of clinical efficacy based on serum concentrations of clarithromycin is probably not justified, given that the macrolides accumulate to a large degree in tissues and macrophages.

In patients with Mycobacterium avium complex infections taking rifabutin or rifampicin the addition of clarithromycin resulted in rifamycin-related adverse events in 77% of patients. These included uveitis, especially at rifabutin doses of 600 mg/day or more, neutropenia, nausea, vomiting, diarrhea, and abnormal liver enzyme activities. In addition, diffuse polyarthralgia (19%) was observed. Since inhibition of cytochrome P450 by clarithromycin can interfere with rifabutin metabolism, as illustrated by a report of a significant increase in the AUC of rifabutin during treatment with clarithromycin, the authors recommended using rifabutin in a dosage of 300 mg/day in regimens that include a macrolide.

The effects of fluconazole and clarithromycin on the pharmacokinetics of rifabutin and 25-O-desacetylrifabu-tin have been studied in ten HIV-infected patients who were given rifabutin 300 mg qds in addition to fluconazole 200 mg qds and clarithromycin 500 mg qds. There was a 76% increase in the plasma AUC of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together. The authors concluded that patients should be monitored for adverse effects of rifabutin when it is co-administered with fluconazole or clarithromycin.


Severe hypoglycemia occurred in two elderly men with type 2 diabetes mellitus and mild to moderate impaired renal function, who took clarithromycin 1000 mg/day for respiratory infections, in addition to a sulfonylurea (glibenclamide 5 mg/day in one case and glipizide 15 mg/day in the other). Both developed severe hypoglycemia within 48 hours of starting clarithromycin.


Clarithromycin can increase the steady-state concentrations of drugs that depend primarily on CYP3A metabolism.

  • Steady-state tacrolimus concentrations rose in a 32-year-old African-American man who took clarithromycin 500 mg bd for 4 days.
  • In two women aged 37 and 69, acute and reversible tacrolimus nephrotoxicity developed after the addition of clarithromycin for an upper respiratory tract infection.

Theophylline and other xanthines

Inhibition of cytochrome P450 activity by clarithromycin affects the metabolism of theophylline. However, the results of several studies of the effect of clarithromycin on theophylline concentrations are conflicting. While the total body clearance of theophylline fell and plasma theophylline concentrations increased by 18%, mean theophylline concentrations remained within the target range. Based on these data it is wise to monitor serum theophylline concentrations in patients taking high dosages of theophylline or in patients with theophylline concentrations in the upper target range who start to take clarithromycin.


Increases in International Normalized Ratio (INR) have been detected in patients who have previously been stabilized on warfarin when they were simultaneously given clarithromycin. In one case this caused a suprachoroidal hemorrhage.

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Synonyms of Clarithromycin:

CLA, Clarithromycine, Clathromycin

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Therapeutic classes of Clarithromycin:

Anti-Bacterial Agents, Macrolides, Other Macrolides, Protein Synthesis Inhibitors


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