Because treatment with rifabutin capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with rifabutin.
Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since rifabutin may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders.
Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with rifabutin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with rifabutin should be made aware of these possibilities.
Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.
Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs metabolized by those enzymes. This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir.
Effect of Other Drugs on Rifabutin Pharmacokinetics
Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Therefore, carefully monitor for rifabutin associated adverse events in those patients also receiving CYP3A inhibitors, which include fluconazole and clarithromycin. In some cases, the dosage of rifabutin may need to be reduced when it is coadministered with CYP3A inhibitors.
Table 2 summarizes the results and magnitude of the pertinent drug interactions assessed with rifabutin. The clinical relevance of these interactions and subsequent dose modifications should be judged in light of the population studied, severity of the disease, patient’s drug profile, and the likely impact on the risk/benefit ratio.
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD-once daily; BID-twice daily; TID – thrice daily
ND -No Data
AUC -Area under the Concentration vs. Time Curve; Cmax -Maximum serum concentration
a compared to rifabutin 300 mg QD alone
b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
c also taking zidovudine 500 mg QD
d compared to rifabutin 150 mg QD alone
e compared to rifabutin 300 mg QD alone
f data from a case report
g compared to voriconazole 200 mg BID alone
|Coadministered drug||Dosing regimen of coadministered drug||Dosing regimen of rifabutin||Study population (n)||Effect on rifabutin||Effect on coadministered drug||Recommendation|
|Amprenavir||1200 mg BID x 10 days||300 mg QD x 10 days||Healthy male subjects (6)||↑ AUC by 193%, ↑ Cmax by 119%||↔||Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.|
|Delavirdine||400 mg TID||300 mg QD||HIV-infected patients (7)||↑ AUC by 230%, ↑ Cmax by 128%||↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17%||CONTRAINDICATED|
|Didanosine||167 or 250 mg BID x 12 days||300 or 600 mg QD x 1||HIV-infected patients (11)||↔||↔|
|Fosamprenavir/ ritonavir||700 mg BID plus ritonavir 100 mg BID x 2 weeks||150 mg every other day x 2 weeks||Healthy subjects (15)||↔ AUCa ↓ Cmax by 15%||↑ AUC by 35%b , ↑ Cmax by 36%, ↑ Cmin by 36%||Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.|
|Indinavir||800 mg TID x 10 days||300 mg QD x 10 days||Healthy subjects (10)||↑ AUC by 173%, ↑ Cmax by 134%||↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by 39%||Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.|
|Lopinavir/ ritonavir||400/100 mg BID x 20 days||150 mg QD x 10 days||Healthy subjects (14)||↑ AUC by 203%c ↓ Cmax by 112%||↔||Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.|
|Saquinavir/ ritonavir||1000/100 mg BID x 14 or 22 days||150 mg every 3 days X 21 to 22 days||Healthy subjects||↑ AUC by 53% d ↑ Cmax by 88% (n=11)||↓ AUC by 13%, ↓ Cmax by 15%, (n=19)||Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.|
|Ritonavir||500 mg BID x 10 days||150 mg QD x 16 days||Healthy subjects (5)||↑ AUC by 300%, ↑ Cmax by 150%||ND||Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.|
|Tipranavir/ ritonavir||500/200 BID X 15 doses||150 mg single dose||Healthy subjects (20)||↑ AUC by 190%, ↑ Cmax by 70%||↔||Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.|
|Nelfinavir||1250 mg BID x 7 to 8 days||150 mg QD x 8 days||HIV-infected patients (11)||↑ AUC by 83%,e ↑ Cmax by 19%||↔||Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID|
|Zidovudine||100 or 200 mg q4h||300 or 450 mg QD||HIV-infected patients (16)||↔||↓ AUC by 32%, ↓ Cmax by 48%||Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.|
|Fluconazole||200 mg QD x 2 weeks||300 mg QD x 2 weeks||HIV-infected patients (12)||↑ AUC by 82%, ↑ Cmax by 88%||↔||Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.|
|Posaconazole||200 mg QD x 10 days||300 mg QD x 17 days||Healthy subjects (8)||↑ AUC by 72%, ↑ Cmax by 31%||↓ AUC by 49%, ↓ Cmax by 43%||If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.|
|Itraconazole||200 mg QD||300 mg QD||HIV-Infected patients (6)||↑f||↓ AUC by 70%, ↓ Cmax by 75%||If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co administration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD).|
|Voriconazole||400 mg BID x 7 days (maintenance dose)||300 mg QD x 7 days||Healthy male subjects (12)||↑ AUC by 331%, ↑ Cmax by 195%||↑ AUC by ~100%, ↑ Cmax by ~100%g||CONTRAINDICATED|
|ANTI-PCP (Pneumocystis carinii pneumonia)|
|Dapsone||50 mg QD||300 mg QD||HIV-infected patients (16)||ND||↓ AUC by 27 to 40%|
|Sulfamethoxazole-Trimethoprim||800/160 mg||300 mg QD||HIV-infected patients (12)||↔||↓ AUC by 15 to 20%|
|ANTI-MAC (Mycobacterium avium intracellulare complex)|
|Azithromycin||500 mg QD x 1 day, then 250 mg QD x 9 days||300 mg QD||Healthy subjects (6)||↔||↔|
|Clarithromycin||500 mg BID||300 mg QD||HIV-infected patients (12)||↑ AUC by 75%||↓ AUC by 50%||Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin|
|Ethambutol||1200 mg||300 mg QD X 7 days||Healthy subjects (10)||ND||↔|
|Isoniazid||300 mg||300 mg QD X 7 days||Healthy subjects (6)||ND||↔|
|Methadone||20 to 100 mg QD||300 mg QD X 13 days||HIV-infected patients (24)||ND||↔|
|Ethinylestradiol (EE)/ Norethindrone (NE)||35 mg EE / 1 mg NE X 21 days||300 mg QD X 10 days||Healthy female subjects (22)||ND||EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46%||Patients should be advised to use additional or alternative methods of contraception.|
|Theophylline||5 mg/kg||300 mg X 14 days||Healthy subjects (11)||ND||↔|
The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although a weaker enzyme inducer than rifampin, rifabutin may be expected to have some effect on those drugs as well.
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