Rifabutin (Page 2 of 4)

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.

MICROBIOLOGY

Mechanism of Action

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

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

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

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).

Clostridium difficile Associated Diarrhea

Clostridium 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.

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 rifabutin capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with rifabutin.

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 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.

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 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

QD-once daily; BID-twice daily; TID – thrice daily

ND -No Data

AUC -Area under the Concentration vs. Time Curve; Cmax -Maximum serum concentration

a compared to rifabutin 300 mg QD alone

b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)

c also taking zidovudine 500 mg QD

d compared to rifabutin 150 mg QD alone

e compared to rifabutin 300 mg QD alone

f data from a case report

g compared to voriconazole 200 mg BID alone

Coadministered drug Dosing regimen of coadministered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on coadministered drug Recommendation
ANTIVIRALS
Amprenavir 1200 mg BID x 10 days 300 mg QD x 10 days Healthy male subjects (6) ↑ AUC by 193%, ↑ Cmax by 119% Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine 400 mg TID 300 mg QD HIV-infected patients (7) ↑ AUC by 230%, ↑ Cmax by 128% ↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17% CONTRAINDICATED
Didanosine 167 or 250 mg BID x 12 days 300 or 600 mg QD x 1 HIV-infected patients (11)
Fosamprenavir/ ritonavir 700 mg BID plus ritonavir 100 mg BID x 2 weeks 150 mg every other day x 2 weeks Healthy subjects (15) ↔ AUCa ↓ Cmax by 15% ↑ AUC by 35%b , ↑ 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.
Indinavir 800 mg TID x 10 days 300 mg QD x 10 days Healthy 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/ ritonavir 400/100 mg BID x 20 days 150 mg QD x 10 days Healthy subjects (14) ↑ AUC by 203%c ↓ 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/ ritonavir 1000/100 mg BID x 14 or 22 days 150 mg every 3 days X 21 to 22 days Healthy subjects ↑ AUC by 53% d ↑ 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.
Ritonavir 500 mg BID x 10 days 150 mg QD x 16 days Healthy subjects (5) ↑ AUC by 300%, ↑ Cmax 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 BID X 15 doses 150 mg single dose Healthy 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.
Nelfinavir 1250 mg BID x 7 to 8 days 150 mg QD x 8 days HIV-infected patients (11) ↑ AUC by 83%,e ↑ Cmax by 19% Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine 100 or 200 mg q4h 300 or 450 mg QD HIV-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
Fluconazole 200 mg QD x 2 weeks 300 mg QD x 2 weeks HIV-infected patients (12) ↑ AUC by 82%, ↑ Cmax by 88% Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole 200 mg QD x 10 days 300 mg QD x 17 days Healthy 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.
Itraconazole 200 mg QD 300 mg QD HIV-Infected patients (6) f ↓ 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 to 900 mg QD).
Voriconazole 400 mg BID x 7 days (maintenance dose) 300 mg QD x 7 days Healthy male subjects (12) ↑ AUC by 331%, ↑ Cmax by 195% ↑ AUC by ~100%, ↑ Cmax by ~100%g CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone 50 mg QD 300 mg QD HIV-infected patients (16) ND ↓ AUC by 27 to 40%
Sulfamethoxazole-Trimethoprim 800/160 mg 300 mg QD HIV-infected patients (12) ↓ AUC by 15 to 20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin 500 mg QD x 1 day, then 250 mg QD x 9 days 300 mg QD Healthy subjects (6)
Clarithromycin 500 mg BID 300 mg QD 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 QD X 7 days Healthy subjects (10) ND
Isoniazid 300 mg 300 mg QD X 7 days Healthy subjects (6) ND
OTHER
Methadone 20 to 100 mg QD 300 mg QD X 13 days HIV-infected patients (24) ND
Ethinylestradiol (EE)/ Norethindrone (NE) 35 mg EE / 1 mg NE X 21 days 300 mg QD X 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 X 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.

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