DailyMed Label: Rifabutin

DailyMed Label: rifabutin

2023

DailyMed Prescription

rifabutin

rifabutin

Lupin Pharmaceuticals, Inc.

NDC: 68180-285

NDC: 68180-285

NDC: 68180-285

Rifabutin Capsules USP for oral administration contain 150 mg of the rifamycin antimycobacterial agent rifabutin, USP, per capsule, along with the inactive ingredients crospovidone, gelatin, iron oxide red, magnesium stearate, microcrystalline cellulose, potassium hydroxide, shellac, silicon dioxide, sodium lauryl sulphate, and titanium dioxide. The chemical name for rifabutin is 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxorifamycin XIV (Chemical Abstracts Service, 9th Collective Index) or (9 S , 12 E , 14 S , 15 R , 16 S , 17 R , 18 R , 19 R , 20 S , 21 S , 22 E , 24 Z )-6,16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethyl-spiro [9,4-(epoxypentadeca[1,11,13]trienimino)-2 H- furo[2',3':7,8] naphth[1,2-d]imidazole-2,4'-piperidine]-5,10,26-(3 H ,9 H )-trione-16-acetate. Rifabutin has a molecular formula of C 46 H 62 N 4 O 11 , a molecular weight of 847.02 and the following structure: Rifabutin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n-octanol/water). Chemical Structure

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

It is recommended that rifabutin capsules USP 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. 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.

Rifabutin capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins.

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. 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 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. Table 2: Rifabutin Interaction Studies ↑ 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 a compared to rifabutin 300 mg once a day alone b compared to historical control (fosamprenavir/ritonavir 700/100 mg twice a day) c also taking zidovudine 500 mg once a day d compared to rifabutin 150 mg once a day alone e compared to rifabutin 300 mg once a day alone f data from a case report g compared to voriconazole 200 mg twice a day alone Coadministered drug Dosing regimen of coadministered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on coadministered 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. Bictegravir 75 mg once a day 300 mg once a day (fasted) Healthy subjects ND ↓ AUC by 38, ↓C min by 56%, ↓C max by 20% Co-administration of Rifabutin with Biktarvy (bictegravir/ emtricitabin/ 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 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) ↔ ↔ 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. 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 a ↓ C max by 15% ↑ AUC by 35% b , ↑ 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%, ↑ Cmax 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. 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% c ↓ 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 21 to 22 days Healthy subjects ↑ AUC by 53% d ↑ 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. 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 to 8 days 150 mg once a day for 8 days HIV-infected patients (11) ↑ AUC by 83%, e ↑ 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 coadministration of rifabutin, dosage adjustments are not necessary. 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) ↑ f ↓ 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 to 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% g 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 to 40% Sulfamethoxazole-Trimethoprim 800/160 mg 300 mg once a day HIV-infected patients (12) ↔ ↓ AUC by 15 to 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 ↔ OTHER Methadone 20 to 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 X 21 days 300 mg once a day for  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 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. Long-term carcinogenicity studies were conducted with rifabutin in mice and in rats. Rifabutin was not carcinogenic in mice at doses up to 180 mg/kg/day, or approximately 36 times the recommended human daily dose. Rifabutin was not carcinogenic in the rat at doses up to 60 mg/kg/day, about 12 times the recommended human dose. Rifabutin was not mutagenic in the bacterial mutation assay (Ames Test) using both rifabutin-susceptible and resistant strains. Rifabutin was not mutagenic in Schizosaccharomyces pombe P 1   and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro , or mouse bone marrow cells in vivo . Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human daily dose). 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. 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. Safety and effectiveness of rifabutin for prophylaxis of MAC in children have not been established. Limited safety data are available from treatment use in 22 HIV-positive children with MAC who received rifabutin in combination with at least two other antimycobacterials for periods from 1 to 183 weeks. Mean doses (mg/kg) for these children were: 18.5 (range 15.0 to 25.0) for infants 1 year of age, 8.6 (range 4.4 to 18.8) for children 2 to 10 years of age, and 4.0 (range 2.8 to 5.4) for adolescents 14 to 16 years of age. There is no evidence that doses greater than 5 mg/kg daily are useful. Adverse experiences were similar to those observed in the adult population, and included leukopenia, neutropenia and rash. In addition, corneal deposits have been observed in some patients during routine ophthalmologic surveillance of HIV-positive pediatric patients receiving rifabutin as part of a multiple-drug regimen for MAC prophylaxis. These are tiny, almost transparent, asymptomatic peripheral and central corneal deposits which do not impair vision. Doses of rifabutin may be administered mixed with foods such as applesauce. Clinical studies of rifabutin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see Clinical Pharmacology ).

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 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. Table 2: Rifabutin Interaction Studies ↑ 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 a compared to rifabutin 300 mg once a day alone b compared to historical control (fosamprenavir/ritonavir 700/100 mg twice a day) c also taking zidovudine 500 mg once a day d compared to rifabutin 150 mg once a day alone e compared to rifabutin 300 mg once a day alone f data from a case report g compared to voriconazole 200 mg twice a day alone Coadministered drug Dosing regimen of coadministered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on coadministered 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. Bictegravir 75 mg once a day 300 mg once a day (fasted) Healthy subjects ND ↓ AUC by 38, ↓C min by 56%, ↓C max by 20% Co-administration of Rifabutin with Biktarvy (bictegravir/ emtricitabin/ 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 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) ↔ ↔ 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. 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 a ↓ C max by 15% ↑ AUC by 35% b , ↑ 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%, ↑ Cmax 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. 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% c ↓ 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 21 to 22 days Healthy subjects ↑ AUC by 53% d ↑ 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. 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 to 8 days 150 mg once a day for 8 days HIV-infected patients (11) ↑ AUC by 83%, e ↑ 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 coadministration of rifabutin, dosage adjustments are not necessary. 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) ↑ f ↓ 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 to 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% g 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 to 40% Sulfamethoxazole-Trimethoprim 800/160 mg 300 mg once a day HIV-infected patients (12) ↔ ↓ AUC by 15 to 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 ↔ OTHER Methadone 20 to 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 X 21 days 300 mg once a day for  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 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.

Rifabutin Capsules USP are supplied as size '0' capsules having opaque red-brown cap imprinted with 'LU' in white ink and opaque red-brown body imprinted with 'R01' in white ink, containing red-violet granular powder equivalent to 150 mg of rifabutin USP. Rifabutin Capsules USP are available as follows: Bottles of 60 capsules - NDC 68180-285-07 Bottles of 100 capsules - NDC 68180-285-01 Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Keep tightly closed and dispense in a tight container as defined in the USP. Protect from light and from excessive heat. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States   Manufactured by: Lupin Limited Aurangabad 431 210 INDIA Revised: November 2021                                                                   ID#: 269014

Absorption Following a single oral dose of 300 mg to nine healthy adult volunteers, rifabutin was readily absorbed from the gastrointestinal tract with mean (±SD) peak plasma levels (C max ) of 375 (±267) ng/mL (range: 141 to 1033 ng/mL) attained in 3.3 (±0.9) hours (T max range: 2 to 4 hours). Absolute bioavailability assessed in five HIV-positive patients, who received both oral and intravenous doses, averaged 20%. Total recovery of radioactivity in the urine indicates that at least 53% of the orally administered rifabutin dose is absorbed from the gastrointestinal tract. The bioavailability of rifabutin from the capsule dosage form, relative to an oral solution, was 85% in 12 healthy adult volunteers. High-fat meals slow the rate without influencing the extent of absorption from the capsule dosage form. Plasma concentrations post-C max declined in an apparent biphasic manner. Pharmacokinetic dose-proportionality was established over the 300 mg to 600 mg dose range in nine healthy adult volunteers (crossover design) and in 16 early symptomatic human immunodeficiency virus (HIV)-positive patients over a 300 mg to 900 mg dose range. Distribution Due to its high lipophilicity, rifabutin demonstrates a high propensity for distribution and intracellular tissue uptake. Following intravenous dosing, estimates of apparent steady-state distribution volume (9.3 ± 1.5 L/kg) in five HIV-positive patients exceeded total body water by approximately 15-fold. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. The lung-to-plasma concentration ratio, obtained at 12 hours, was approximately 6.5 in four surgical patients who received an oral dose. Mean rifabutin steady-state trough levels (C p, min ss ; 24-hour post-dose) ranged from 50 to 65 ng/mL in HIV-positive patients and in healthy adult volunteers. About 85% of the drug is bound in a concentration-independent manner to plasma proteins over a concentration range of 0.05 to 1 mcg/mL. Binding does not appear to be influenced by renal or hepatic dysfunction. Rifabutin was slowly eliminated from plasma in seven healthy adult volunteers, presumably because of distribution-limited elimination, with a mean terminal half-life of 45 (± 17) hours (range: 16 to 69 hours). Although the systemic levels of rifabutin following multiple dosing decreased by 38%, its terminal half-life remained unchanged. Metabolism Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite:parent area under the curve ratio of 0.10 and 0.07, respectively. The former has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity. Excretion A mass-balance study in three healthy adult volunteers with 14 C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces. Mean systemic clearance (CL s /F) in healthy adult volunteers following a single oral dose was 0.69 (± 0.32) L/hr/kg (range: 0.46 to 1.34 L/hr/kg). Renal and biliary clearance of unchanged drug each contribute approximately 5% to CL s /F. Geriatric Compared to healthy volunteers, steady-state kinetics of rifabutin are more variable in elderly patients (>70 years). Pediatric The pharmacokinetics of rifabutin have not been studied in subjects under 18 years of age. Renal Impairment The disposition of rifabutin (300 mg) was studied in 18 patients with varying degrees of renal function. Area under plasma concentration time curve (AUC) increased by about 71% in patients with severe renal impairment (creatinine clearance below 30 mL/min) compared to patients with creatinine clearance (Cr cl ) between 61 to 74 mL/min. In patients with mild to moderate renal impairment (Cr cl between 30 to 61 mL/min), the AUC increased by about 41%. In patients with severe renal impairment, carefully monitor for rifabutin associated adverse events. A reduction in the dosage of rifabutin is recommended for patients with Cr cl <30 mL/min if toxicity is suspected (see Dosage and Administration ). Hepatic Impairment Mild hepatic impairment does not require a dose modification. The pharmacokinetics of rifabutin in patients with moderate and severe hepatic impairment is not known. Malabsorption in HIV-Infected Patients Alterations in gastric pH due to progressing HIV disease has been linked with malabsorption of some drugs used in HIV-positive patients (e.g., rifampin, isoniazid). Drug serum concentrations data from AIDS patients with varying disease severity (based on CD4+ counts) suggests that rifabutin absorption is not influenced by progressing HIV disease. Drug-Drug Interactions (see also Precautions - Drug Interactions )   Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutin's predominant metabolite (25-desacetyl rifabutin: LM565), may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce a decrease in plasma concentrations of concomitantly administered drugs that are primarily metabolized by the CYP3A enzymes. Similarly concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin.

Two randomized, double-blind clinical trials (Study 023 and Study 027) compared rifabutin (300 mg/day) to placebo in patients with CDC-defined AIDS and CD4 counts ≤200 cells/µL. These studies accrued patients from 2/90 through 2/92. Study 023 enrolled 590 patients, with a median CD4 cell count at study entry of 42 cells/µL (mean 61). Study 027 enrolled 556 patients with a median CD4 cell count at study entry of 40 cells/µL (mean 58). Endpoints included the following: (1) MAC bacteremia, defined as at least one blood culture positive for Mycobacterium avium complex (MAC) bacteria. (2) Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including one or more of the following: fever, night sweats, rigors, weight loss, worsening anemia, and/or elevations in alkaline phosphatase. (3) Survival. Participants who received rifabutin were one-third to one-half as likely to develop MAC bacteremia as were participants who received placebo. These results were statistically significant (Study 023: p<0.001; Study 027: p = 0.002). In Study 023, the one-year cumulative incidence of MAC bacteremia, on an intent to treat basis, was 9% for patients randomized to rifabutin and 22% for patients randomized to placebo. In Study 027, these rates were 13% and 28% for patients receiving rifabutin and placebo, respectively. Most cases of MAC bacteremia (approximately 90% in these studies) occurred among participants whose CD4 count at study entry was ≤100 cells/µL. The median and mean CD4 counts at onset of MAC bacteremia were 13 cells/µL and 24 cells/µL, respectively. These studies did not investigate the optimal time to begin MAC prophylaxis. In association with the decreased incidence of bacteremia, patients on rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, fatigue, abdominal pain, anemia, and hepatic dysfunction. The one-year survival rates in Study 023 were 77% for the group receiving rifabutin and 77% for the placebo group. In Study 027, the one-year survival rates were 77% for the group receiving rifabutin and 70% for the placebo group. These differences were not statistically significant.

Rifabutin Capsules USP, 150 mg NDC 68180-285-01 A Bottle Label containing 100 capsules package label