Rifabutin

Mechanism of Action Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli , rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC).

INDICATIONS AND USAGE Rifabutin capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

DOSAGE AND ADMINISTRATION It is recommended that rifabutin capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of rifabutin at doses of 150 mg twice daily taken with food may be useful. Doses of Rifabutin capsules may be administered mixed with foods such as applesauce. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), consider reducing the dose of rifabutin by 50%, if toxicity is suspected. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of rifabutin may also be needed for patients receiving concomitant treatment with certain other drugs (see PRECAUTIONS-Drug Interactions ). Mild hepatic impairment does not require a dose modification. The pharmacokinetics of rifabutin in patients with moderate and severe hepatic impairment is not known.

ADVERSE REACTIONS 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 following adverse events which occurred in less than 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, chest pressure or pain with dyspnea, skin discoloration, thrombocytopenia, pancytopenia and jaundice. The following adverse events have occurred in more than one patient receiving rifabutin, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram. When rifabutin was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when rifabutin was discontinued. Mild to severe, reversible uveitis has been reported less frequently when rifabutin is used at 300 mg as monotherapy in MAC prophylaxis versus rifabutin in combination with clarithromycin for MAC treatment (see also WARNINGS ). Uveitis has been infrequently reported when rifabutin is used at 300 mg/day as monotherapy in MAC prophylaxis of HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibacterials. However, if higher doses of rifabutin are administered in combination with these agents, the incidence of uveitis is higher. Patients who developed uveitis had mild to severe symptoms that resolved after treatment with corticosteroids and/or mydriatic eye drops; in some severe cases, however, resolution of symptoms occurred after several weeks. When uveitis occurs, temporary discontinuance of rifabutin and ophthalmologic evaluation are recommended. In most mild cases, rifabutin may be restarted; however, if signs or symptoms recur, use of rifabutin should be discontinued (Morbidity and Mortality Weekly Report, September 9, 1994). Corneal deposits have been reported during routine ophthalmologic surveillance of some HIV-positive pediatric patients receiving rifabutin as part of a multiple drug regimen for MAC prophylaxis. The deposits are tiny, almost transparent, asymptomatic peripheral and central corneal deposits, and do not impair vision. The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in Studies 023 and 027. Table 4 Percentage of Patients With Laboratory Abnormalities Laboratory abnormalities Rifabutin (n = 566) % Placebo (n = 580) % Includes grades 3 or 4 toxicities as specified: Chemistry Increased alkaline phosphatase All values >450 U/L <1 3 Increased SGOT All values >150 U/L 7 12 Increased SGPT 9 11 Hematology Anemia All hemoglobin values <8.0 g/dL 6 7 Eosinophilia 1 1 Leukopenia All WBC values <1,500/mm 3 17 16 Neutropenia All ANC values <750/mm 3 25 20 Thrombocytopenia All platelet count values <50,000/mm 3 5 4 The incidence of neutropenia in patients treated with rifabutin was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with rifabutin in these trials, rifabutin has been clearly linked to thrombocytopenia in rare cases. One patient in Study 023 developed thrombotic thrombocytopenic purpura, which was attributed to rifabutin. Adverse Reactions from Post-Marketing Experience Adverse reactions identified through post-marketing surveillance by system organ class (SOC) are listed below: Blood and lymphatic system disorders: White blood cell disorders (including agranulocytosis, lymphopenia, granulocytopenia, neutropenia, white blood cell count decreased, neutrophil count decreased), platelet count decreased. Immune system disorders: Hypersensitivity, bro

Drug Interactions 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 e