Drug Interaction Report

GENERALLY AVOID: The coadministration of clarithromycin and rifabutin at normally recommended dosages has been reported to have resulted in significantly altered pharmacokinetics for both drugs. In a study of 34 clinically stable subjects with advanced HIV infection (CD4 less than 200 cells/mm3), the addition of rifabutin in patients stabilized on clarithromycin therapy slowly decreased the clarithromycin area under the plasma concentration-time curve (AUC) and C(max) up to an average of 44% and 41%, respectively, at the end of 4 weeks of combination therapy. In patients stabilized on rifabutin therapy, the addition of clarithromycin significantly increased rifabutin AUC and C(max) after the first dose. After 4 weeks, average increases of 99% and 69%, respectively, were reported. This bidirectional interaction is consistent with rifabutin's cumulative inducing effect over time on the CYP450 enzymatic pathway as well as clarithromycin's immediate inhibiting effect on the pathway. In the study, the combination was tolerated by more than 90% of the patients. However, 66% of them experienced gastrointestinal problems including nausea, vomiting and diarrhea. An increased incidence of uveitis has also been reported with this combination. In addition, the combination of clarithromycin and rifampin 600 mg/day (with multiple other drugs) decreased clarithromycin serum levels by approximately 90%. Other macrolide antibiotics may interact in a similar manner with rifamycins.

MANAGEMENT: Some experts recommend that this combination be avoided since it may result in decreased efficacy of the macrolide and increased rifamycin toxicity (e.g, neutropenia, uveitis).

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GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

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Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.

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