Rifabutin: uses, dosing, side effects & brands

Adverse Reactions from Clinical Trials Rifabutin capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving rifabutin, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of rifabutin were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%). The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with rifabutin in studies 023 and 027. Table 3 Clinical Adverse Experiences Reported in ≥1% of Patients Treated With Rifabutin Adverse event Rifabutin (n = 566) % Placebo (n = 580) % Body as a whole Abdominal pain 4 3 Asthenia 1 1 Chest pain 1 1 Fever 2 1 Headache 3 5 Pain 1 2 Blood and lymphatic system Leucopenia 10 7 Anemia 1 2 Digestive System Anorexia 2 2 Diarrhea 3 3 Dyspepsia 3 1 Eructation 3 1 Flatulence 2 1 Nausea 6 5 Nausea and vomiting 3 2 Vomiting 1 1 Musculoskeletal system Myalgia 2 1 Nervous system Insomnia 1 1 Skin and appendages Rash 11 8 Special senses Taste perversion 3 1 Urogenital system Discolored urine 30 6 CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED RIFABUTIN Considering data from the 023 and 027 pivotal trials, and from other clinical studies, rifabutin appears to be a likely cause of the…

Rifabutin capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins. Rifabutin capsules are contraindicated in patients being treated with cabotegravir/rilpivirine prolonged-release injectable suspension (see PRECAUTIONS-Drug Interactions, Table 2 ).

Effect of Rifabutin on the Pharmacokinetics of Other Drugs 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 co-administered 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. Table 2 Rifabutin Interaction Studies Co-administered drug Dosing regimen of co-administered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on co-administered drug Recommendation ↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change ND - No Data AUC - Area under the Concentration vs. Time Curve; C max - Maximum serum concentration; C min – Minimum serum concentration ANTIRETROVIRALS Amprenavir 1200 mg twice a day for 10 days 300 mg once a day for 10 days Healthy male subjects (6) ↑ AUC by 193%, ↑ C max by 119% ↔ Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. Atazanavir/Ritonavir 300/100 mg once daily 150 mg twice weekly Healthy adult subjects 48% ↑ in AUC, 149% ↑ C max of rifabutin. 990% ↑ in AUC, 677% ↑ C max of 25‑O‑desacetyl-rifabutin. No significant change in pharmacokinetics. A reduction in the dose of rifabutin (to 150 mg every other day or 3 times a week) is recommended. Increased monitoring for adverse reactions is warranted. Bictegravir 75 mg once a day 300 mg once a day (fasted) Healthy subjects ND ↓ AUC 38% ↓ C min 56% ↓ C max 20% Co-administration of rifabutin with Biktarvy (bictegravir/emtricitabine/ tenofovir alafenamide) is not recommended due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in bictegravir. Refer to Biktarvy prescribing information for additional information. Darunavir/Ritonavir 600/100 mg twice a day for 12 days 150 mg every other day for 12 days Healthy HIV- negative adults No significant change in rifabutin pharmacokinetics. 881% ↑ in AUC, 377% ↑ C max of 25‑O‑desacetyl-rifabutin. 57% ↑ in AUC, 42% ↑ C max of darunavir. 66% ↑ in AUC, 68% ↑ C max of ritonavir. A reduction in the dose of rifabutin (to 150 mg every other day or 3 times a week) is recommended. Increased monitoring for adverse reactions is warranted. Delavirdine 400 mg three times a day 300 mg once a day HIV-infected patients (7) ↑ AUC by 230%, ↑ C max by 128% ↓ AUC by 80%, ↓ C max by 75%, ↓ C min by 17% CONTRAINDICATED Didanosine 167 or 250 mg twice a day for 12 days 300 or 600 mg once a day for 12 days HIV-infected patients (11) ↔ ↔ Dolutegravir 50 mg daily for 14 days 300 mg daily for 14 days Healthy adult subjects ND No significant change in dolutegravir pharmacokinetics at steady state. Doravirine 100 mg single dose 300 mg once a day for 16 days Healthy subjects (12) ND ↓ 50% in AUC, ↓ 68% in C 24 ↔ in C max If concomitant use is necessary, increase the doravirine dosage as instructed in doravirine-containing product prescribing information. Elvitegravir/Cobicistat 150/50 mg daily 300 mg daily Or 150 mg every other day Healthy subjects (12) No significant change in rifabutin pharmacokinetics. 6.3-fold ↑ in AUC, 4.8-fold ↑ C max of 25‑O‑desacetyl-rifabutin. No change in elvitegravir except 67% ↓ C trough of elvitegravir. No change in cobicistat exposure. Co-administration of rifabutin with elvitegravir/ cobicistat is not recommended due to an expected decrease in elvitegravir exposure. Etravirine 800 mg twice daily for 21 days 300 mg daily on days 8 to 21 Healthy volunteers (18) No significant change in rifabutin pharmacokinetics. 37% ↓ in AUC, 37% ↓ in C max and 35% ↓ in C min No dose adjustment of rifabutin is required when etravirine is not co-administered with protease inhibitor/ritonavir. Rifabutin should not be co-administered with etravirine and boosted PIs due to potential for decreased effectiveness of etravirine. Fosamprenavir/ritonavir 700 mg twice a day plus ritonavir 100 mg twice a day for 2 weeks 150 mg every other day for 2 weeks Healthy subjects (15) ↔ AUC compared to rifabutin 300 mg once a day alone ↓ C max by 15% ↑ AUC by 35% compared to historical control (fosamprenavir/ritonavir 700/100 mg twice a day) , ↑ C max by 36%, ↑ C min 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 three times a day for 10 days 300 mg once a day for 10 days Healthy subjects (10) ↑ AUC by 173%, ↑ C max by 134% ↓ AUC by 34%, ↓ C max by 25%, ↓ C min by 39% Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg three times a day. Lopinavir/ ritonavir 400/100 mg twice a day for 20 days 150 mg once a day for 10 days Healthy subjects (14) ↑ AUC by 203% also taking zidovudine 500 mg once a day ↓ C max 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 twice a day for 14 or 22 days 150 mg every 3 days for 14 or 22 days Healthy subjects ↑ AUC by 53% compared to rifabutin 150 mg once a day alone ↑ C max by 88% (n=11) ↓ AUC by 13%, ↓ C max 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. Rilpivirine 25 mg once a day 300 mg once a day Healthy subjects (18) ND ↓ AUC by 42% ↓ C min by 48% ↓ C max by 31% Co-administration of rifabutin with Odefsey (rilpivirine/tenofovir alafenamide/emtricitabine) is not recommended, due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in rilpivirine. Refer to Odefsey prescribing information for additional information. Co-administration of rifabutin with cabotegravir/rilpivirine prolonged-release injectable suspension is contraindicated. Ritonavir 500 mg twice a day for 10 days 150 mg once a day for 16 days Healthy subjects (5) ↑ AUC by 300%, ↑ C max 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 twice a day for 15 doses 150 mg single dose Healthy subjects (20) ↑ AUC by 190%, ↑ C max 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 twice a day for 7–8 days 150 mg once a day for 8 days HIV-infected patients (11) ↑ AUC by 83%, compared to rifabutin 300 mg once a day alone ↑ C max by 19% ↔ Reduce rifabutin dose by 50% (to 150 mg once a day) and increase the nelfinavir dose to 1250 mg twice a day. Zidovudine 100 or 200 mg every four hours 300 or 450 mg once a day HIV-infected patients (16) ↔ ↓ AUC by 32%, ↓ C max by 48%, Because zidovudine levels remained within the therapeutic range during co-administration of rifabutin, dosage adjustments are not necessary. ANTI-HCV DRUGS Sofosbuvir 400 mg on day 1 and day 21 300 mg daily on day 10 to day 29 Healthy subjects (20) ND 36% ↓ in C max and 24% ↓ AUC Co-administration of rifabutin with sofosbuvir (alone or in combination) is not recommended. ANTIFUNGALS Fluconazole 200 mg once a day for 2 weeks 300 mg once a day for 2 weeks HIV-infected patients (12) ↑ AUC by 82%, ↑ C max by 88% ↔ Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected. Posaconazole 200 mg once a day for 10 days 300 mg once a day for 17 days Healthy subjects (8) ↑ AUC by 72%, ↑ C max by 31% ↓ AUC by 49%, ↓ C max 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 once a day 300 mg once a day HIV-Infected patients (6) ↑ data from a case report ↓ AUC by 70%, ↓ C max 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 once a day) with itraconazole (600–900 mg once a day). Voriconazole 400 mg twice a day for 7 days (maintenance dose) 300 mg once a day for 7 days Healthy male subjects (12) ↑ AUC by 331%, ↑ C max by 195% ↑ AUC by ~100%, ↑ C max by ~100% compared to voriconazole 200 mg twice a day alone CONTRAINDICATED ANTI-PCP (Pneumocystis carinii pneumonia) Dapsone 50 mg once a day 300 mg once a day HIV-infected patients (16) ND ↓ AUC by 27 – 40% Sulfamethoxazole-Trimethoprim 800/160 mg 300 mg once a day HIV-infected patients (12) ↔ ↓ AUC by 15–20% ANTI-MAC (Mycobacterium avium intracellulare complex) Azithromycin 500 mg once a day for 1 day, then 250 mg once a day for 9 days 300 mg once a day Healthy subjects (6) ↔ ↔ Clarithromycin 500 mg twice a day 300 mg once a day 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 ANTI-TB (Tuberculosis) Ethambutol 1200 mg 300 mg once a day for 7 days Healthy subjects (10) ND ↔ Isoniazid 300 mg 300 mg once a day for 7 days Healthy subjects (6) ND ↔ Bedaquiline 400 mg daily on day 1 and day 29 300 mg daily Healthy subjects (17) ND No change in bedaquiline pharmacokinetics. 1.4-fold ↑ in M2 and approximately 3.0-fold ↑ in M3 metabolites of bedaquiline. Avoid bedaquiline co‑administration with rifabutin due to the adverse reactions associated with increased bedaquiline metabolite concentrations. OTHER Methadone 20 – 100 mg once a day 300 mg once a day for 13 days HIV – infected patients (24) ND ↔ Ethinylestradiol (EE)/ Norethindrone (NE) 35 mg EE / 1 mg NE for 21 days 300 mg once a day for 10 days Healthy female subjects (22) ND EE: ↓ AUC by 35%, ↓ C max by 20% NE: ↓ AUC by 46% Patients should be advised to use additional or alternative methods of contraception. Theophylline 5 mg/kg 300 mg for 14 days Healthy subjects (11) ND ↔ Other drugs 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.