Rifabutin

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

DOSAGE & 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 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.

WARNINGS Tuberculosis Rifabutin capsules must not be administered for MAC prophylaxis to patients with active tuberculosis. Patients who develop complaints consistent with active tuberculosis while on prophylaxis with rifabutin should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of rifabutin as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to rifabutin and to rifampin. There is no evidence that rifabutin is an effective prophylaxis against M. tuberculosis . Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and rifabutin concurrently. Tuberculosis in HIV-positive patients is common and may present with atypical or extrapulmonary findings. Patients are likely to have a nonreactive purified protein derivative (PPD) despite active disease. In addition to chest X-ray and sputum culture, the following studies may be useful in the diagnosis of tuberculosis in the HIV-positive patient: blood culture, urine culture, or biopsy of a suspicious lymph node. MAC Treatment with Clarithromycin When rifabutin is used concomitantly with clarithromycin for MAC treatment, a decreased dose of rifabutin is recommended due to the increase in plasma concentrations of rifabutin (see PRECAUTIONS-Drug Interactions, Table 2 ). Hypersensitivity and Related Reactions Hypersensitivity reactions may occur in patients receiving rifamycins. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis with the use of rifamycins. Monitor patients receiving rifabutin therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue rifabutin. Uveitis Due to the possible occurrence of uveitis, patients should also be carefully monitored when rifabutin is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds (see PRECAUTIONS-Drug Interactions, Table 2 ). If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with rifabutin should be suspended (see also ADVERSE REACTIONS ). Clostridioides difficile Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including rifabutin capsules and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Severe Cutaneous Adverse Reactions There have been reports of severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction w…

CONTRAINDICATIONS 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 ).

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 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 of25-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 pharmacokinetic s 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 C24 ↔ in Cmax 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 Healt…

PREGNANCY Rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant or breastfeeding women. Reproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (about 6 to 13 times the recommended human daily dose based on body surface area comparisons). No teratogenicity was observed in either species. In rats, given 200 mg/kg/day, (about 6 times the recommended human daily dose based on body surface area comparisons), there was a decrease in fetal viability. In rats, at 40 mg/kg/day (approximately equivalent to the recommended human daily dose based on body surface area comparisons), rifabutin caused an increase in fetal skeletal variants. In rabbits, at 80 mg/kg/day (about 5 times the recommended human daily dose based on body surface area comparisons), rifabutin caused maternotoxicity and increase in fetal skeletal anomalies. Because animal reproduction studies are not always predictive of human response, rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus.

NURSING MOTHERS It is not known whether rifabutin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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) % Chemistry Increased alkaline phosphatase 1 <1 3 Increased SGOT 2 7 12 Increased SGPT 2 9 11 Hematology Anemia 3 6 7 Eosinophilia 1 1 Leukopenia 4 17 16 Neutropenia 5 25 20 Thrombocytopenia 6 5 4 Includes grades 3 or 4 toxicities as specified: 1 All value…