f 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.

e. 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 with eosinophilia and systemic symptoms (dress), and acute generalized exanthematous pustulosis (agep) associated with rifabutin (see adverse reactions ). if patients develop a skin rash they should be monitored closely, and rifabutin discontinued if lesions progress. specifically, for dress, a multi-system potential life-threatening scar, time to onset of the first symptoms may be prolonged. dress is a clinical diagnosis, and its clinical presentation remains the basis for decision making. an early withdrawal of rifabutin is essential because of the syndrome's mortality and visceral involvement (e.g., liver, bone marrow or kidney). antiretroviral drug interaction s protease inhibitors act as substrates or inhibitors of cyp3a4 mediated metabolism. therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin, their concomitant use should be based on the overall assessment of the patient and a patient-specific drug profile. the concomitant use of protease inhibitors may require at least a 50% reduction in rifabutin dose, and depending on the protease inhibitor, an adjustment of the antiretroviral drug dose. increased monitoring for adverse events is recommended when using these drug combinations (see precautions - drug interactions ). rifabutin is a cyp3a inducer. co-administration with antiretroviral drugs metabolized by cyp3a, including but not limited to products containing bictegravir, rilpivirine, or doravirine may decrease plasma concentrations of those antiretroviral drugs, which may lead to loss of virologic response and possible development of resistance. therefore, co-administration with antiretroviral drugs metabolized by cyp3a is not recommended or there may be a need to increase the dose of antiretroviral drugs (see precautions-drug interactions). for further recommendations, please refer to the most recent prescribing information of the antiretrovirals or contact the specific manufacturer.

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 includes grades 3 or 4 toxicities as specified: 1 all values >450 u/l 2 all values >150 u/l 3 all hemoglobin values < 8.0 g/dl 4 all wbc values < 1,500/mm 5 all anc values < 750/mm 6 all platelet count values < 50,000/mm 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 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, bronchospasm, rash, and eosinophilia. gastrointestinal disorders clostridioides difficile colitis/ clostridioides difficile associated diarrhea. pyrexia, rash and other hypersensitivity reactions such as eosinophilia and bronchospasm might occur, as has been seen with other antibacterials. a limited occurrence of skin discoloration has been reported. severe cutaneous adverse reactions (scars): rifabutin has been associated with the occurrence of dress as well as other scars such as sjs, ten, and agep (see warnings ). rifamycin hypersensitivity reactions hypersensitivity to rifamycins have been reported including flu-like symptoms, bronchospasm, hypotension, urticaria, angioedema, conjunctivitis, thrombocytopenia or neutropenia. to report suspected adverse reactions, contact lupin pharmaceuticals, inc. at 1-800-399-2561 or fda at 1-800-fda-1088 or www.fda.gov/medwatch . animal toxicology liver abnormalities (increased bilirubin and liver weight) occurred in mice, rats and monkeys at doses (respectively) 0.5, 1, and 3 times the recommended human daily dose based on body surface area comparisons. testicular atrophy occurred in baboons at doses 2 times the recommended human dose based on body surface area comparisons, and in rats at doses 6 times the recommended human daily dose based on body surface area comparisons.

f 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.

alies. 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.

ic peripheral and central corneal deposits which do not impair vision. doses of rifabutin may be administered mixed with foods such as applesauce.

e 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. pharmacokinetics in special populations 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.

e 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.

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. clinically significant disseminated mac disease 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. survival 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.

er having taken the last dose of the antibacterial. if this occurs, patients should contact their physician as soon as possible.