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MYCOBUTIN® (rifabutin) Warnings and Precautions

WARNINGS

Tuberculosis

MYCOBUTIN 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 MYCOBUTIN should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of MYCOBUTIN as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to MYCOBUTIN and to rifampin.

There is no evidence that MYCOBUTIN is an effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN 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 MYCOBUTIN is used concomitantly with clarithromycin for MAC treatment, a decreased dose of MYCOBUTIN is recommended due to the increase in plasma concentrations of MYCOBUTIN (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 MYCOBUTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue MYCOBUTIN.

Uveitis

Due to the possible occurrence of uveitis, patients should also be carefully monitored when MYCOBUTIN 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 MYCOBUTIN should be suspended (see also ADVERSE REACTIONS).

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MYCOBUTIN (rifabutin) Capsules, USP, 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.

Protease Inhibitor Drug Interaction

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 antiviral drug dose. Increased monitoring for adverse events is recommended when using these drug combinations (see PRECAUTIONS-Drug Interactions). For further recommendations, please refer to current, official product monographs of the protease inhibitor or contact the specific manufacturer.


PRECAUTIONS

General

Because treatment with MYCOBUTIN Capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with MYCOBUTIN.

Information for Patients

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 MYCOBUTIN 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 MYCOBUTIN 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.

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 MYCOBUTIN 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
Coadministered drugDosing regimen of coadministered drugDosing regimen of rifabutinStudy population (n)Effect on rifabutinEffect on coadministered drugRecommendation
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD- once daily; BID- twice daily; TID – thrice daily
ND - No Data
AUC - Area under the Concentration vs. Time Curve; Cmax - Maximum serum concentration
*
compared to rifabutin 300 mg QD alone
compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
also taking zidovudine 500 mg QD
§
compared to rifabutin 150 mg QD alone
compared to rifabutin 300 mg QD alone
#
data from a case report
Þ
compared to voriconazole 200 mg BID alone
ANTIVIRALS
Amprenavir1200 mg BID × 10 days300 mg QD × 10 daysHealthy male subjects (6)↑ AUC by 193%,
↑ Cmax by 119%
Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine400 mg TID300 mg QDHIV-infected patients (7)↑ AUC by 230%,
↑ Cmax by 128%
↓ AUC by 80%,
↓ Cmax by 75%,
↓ Cmin by 17%
CONTRAINDICATED
Didanosine167 or 250 mg BID × 12 days300 or 600 mg QD × 1HIV-infected patients (11)
Fosamprenavir/ ritonavir700 mg BID plus ritonavir 100 mg BID × 2 weeks150 mg every other day × 2 weeksHealthy subjects (15)↔ AUC*
↓ Cmax by 15%
↑ AUC by 35%,
↑ Cmax by 36%,
↑ Cmin 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.
Indinavir800 mg TID × 10 days300 mg QD × 10 daysHealthy subjects (10)↑ AUC by 173%,
↑ Cmax by 134%
↓ AUC by 34%,
↓ Cmax by 25%,
↓ Cmin by 39%
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir400/100 mg BID × 20 days150 mg QD × 10 daysHealthy subjects (14)↑ AUC by 203%
↓ Cmax 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/ ritonavir1000/100 mg BID × 14 or 22 days150 mg every 3 days × 21–22 daysHealthy subjects↑ AUC by 53% §
↑ Cmax by 88%
(n=11)
↓ AUC by 13%,
↓ Cmax 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.
Ritonavir500 mg BID × 10 days150 mg QD × 16 daysHealthy subjects (5)↑ AUC by 300%,
↑ Cmax by 150%
NDReduce 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/ ritonavir500/200 BID × 15 doses150 mg single doseHealthy subjects (20)↑ AUC by 190%,
↑ Cmax 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.
Nelfinavir1250 mg BID × 7–8 days150 mg QD × 8 daysHIV-infected patients (11)↑ AUC by 83%,
↑ Cmax by 19%
Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine100 or 200 mg q4h300 or 450 mg QDHIV-infected patients (16)↓ AUC by 32%,
↓ Cmax by 48%,
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole200 mg QD × 2 weeks300 mg QD × 2 weeksHIV-infected patients (12)↑ AUC by 82%,
↑ Cmax by 88%
Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected.
Posaconazole200 mg QD × 10 days300 mg QD × 17 daysHealthy subjects (8)↑ AUC by 72%,
↑ Cmax by 31%
↓ AUC by 49%,
↓ Cmax 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.
Itraconazole200 mg QD300 mg QDHIV-Infected patients (6)#↓ AUC by 70%,
↓ Cmax 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 QD) with itraconazole (600–900 mg QD).
Voriconazole400 mg BID × 7 days (maintenance dose)300 mg QD × 7 daysHealthy male subjects (12)↑ AUC by 331%,
↑ Cmax by 195%
↑ AUC by ~100%,
↑ Cmax by ~100%Þ
CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone50 mg QD300 mg QDHIV-infected patients (16)ND↓ AUC by 27 –40%
Sulfamethoxazole- Trimethoprim800/160 mg300 mg QDHIV-infected patients (12)↓ AUC by 15–20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin500 mg QD × 1 day, then 250 mg QD × 9 days300 mg QDHealthy subjects (6)
Clarithromycin500 mg BID300 mg QDHIV-infected patients (12)↑ AUC by 75%↓ AUC by 50%Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol1200 mg300 mg QD × 7 daysHealthy subjects (10)ND
Isoniazid300 mg300 mg QD × 7 daysHealthy subjects (6)ND
OTHER
Methadone20 – 100 mg QD300 mg QD × 13 daysHIV-infected patients (24)ND
Ethinylestradiol (EE)/Norethindrone (NE)35 mg EE / 1 mg NE × 21 days300 mg QD × 10 daysHealthy female subjects (22)NDEE: ↓ AUC by
35%, ↓ Cmax by 20%
NE: ↓ AUC by 46%
Patients should be advised to use additional or alternative methods of contraception.
Theophylline5 mg/kg300 mg × 14 daysHealthy 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 P1 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).

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.

Pediatric Use

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 MYCOBUTIN 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 MYCOBUTIN 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 MYCOBUTIN may be administered mixed with foods such as applesauce.

Geriatric Use

Clinical studies of MYCOBUTIN 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).

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