No information is available on accidental overdosage in humans.
TreatmentWhile there is no experience in the treatment of overdose with Macbutin Capsules, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help absorb any remaining drug from the gastrointestinal tract.
Rifabutin is 85% protein bound and distributed extensively into tissues (Vss:8 to 9 L/kg). It is not primarily excreted via the urinary route (less than 10% as unchanged drug); therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifabutin from the body in a patient with an overdose of Macbutin.
Macbutin Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins.
Macbutin Capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving Macbutin, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of Macbutin were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%).
The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with Macbutin in studies 023 and 027.
Table: 3 Clinical Adverse Experiences Reported in ≥ 1% of Patients Treated With Macbutin
| Adverse event | Macbutin (n = 566) % | Placebo (n = 580)% |
| Body as a whole | ||
| Abdominal pain | 4 | 3 |
| Asthenia | 1 | 1 |
| Chest pain | 1 | 1 |
| Fever | 2 | 1 |
| Headache | 3 | 5 |
| Pain | 1 | 2 |
| Blood and lymphatic system | ||
| Leucopenia | 10 | 7 |
| Anemia | 1 | 2 |
| Digestive System | ||
| Anorexia | 2 | 2 |
| Diarrhea | 3 | 3 |
| Dyspepsia | 3 | 1 |
| Eructation | 3 | 1 |
| Flatulence | 2 | 1 |
| Nausea | 6 | 5 |
| Nausea and vomiting | 3 | 2 |
| Vomiting | 1 | 1 |
| Musculoskeletal system | ||
| Myalgia | 2 | 1 |
| Nervous system | ||
| Insomnia | 1 | 1 |
| Skin and appendages | ||
| Rash | 11 | 8 |
| Special senses | ||
| Taste perversion | 3 | 1 |
| Urogenital system | ||
| Discolored urine | 30 | 6 |
Considering data from the 023 and 027 pivotal trials, and from other clinical studies, Macbutin 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 Macbutin, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram.
When Macbutin was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when Macbutin was discontinued.
Mild to severe, reversible uveitis has been reported less frequently when Macbutin is used at 300 mg as monotherapy in MAC prophylaxis versus Macbutin in combination with clarithromycin for MAC treatment (see also WARNINGS).
Uveitis has been infrequently reported when Macbutin is used at 300 mg/day as montherapy in MAC prophylaxis of HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibacterials. However, if higher doses of Macbutin 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 Macbutin and ophthalmologic evaluation are recommended. In most mild cases, Macbutin may be restarted; however, if signs or symptoms recur, use of Macbutin 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 Macbutin as part of a multiple drug regimen for MAC prophylaxis. The deposits are tiny, almost transparent, asymptomatic peripheral and central corneal deposits, and do not impair vision.
The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in Studies 023 and 027.
Table 4 : Percentage of Patients With Laboratory Abnormalities
| Laboratory abnormalities | Macbutin (n = 566)% | PLACEBO (n = 580)% |
| Chemistry | ||
| Increased alkaline phosphatase * | < 1 | 3 |
| Increased SGOT † | 7 | 12 |
| Increased SGPT † | 9 | 11 |
| Hematology | ||
| Anemia ‡ | 6 | 7 |
| Eosinophilia | 1 | 1 |
| Leukopenia § | 17 | 16 |
| Neutropenia ¶ | 25 | 20 |
| Thrombocytopenia # | 5 | 4 |
| Includes grades 3 or 4 toxicities as specified: *All values > 4 50 U/L †All values > 150 U/L ‡All hemoglobin values < 8.0 g/dL §All WBC values < 1,500/mm³ ¶All ANC values < 750/mm³ #All platelet count values < 50,000/mm³ | ||
The incidence of neutropenia in patients treated with Macbutin was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with Macbutin in these trials, Macbutin has been clearly linked to thrombocytopenia in rare cases. One patient in Study 023 developed thrombotic thrombocytopenic purpura, which was attributed to Macbutin.
Adverse Reactions From Post-Marketing ExperienceAdverse 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 : Clostridium difficile colitis/ Clostridium 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 number of skin discoloration have been reported.
Rifamycin hypersensitivity reactions
Hypersensitivity to rifamycins have been reported including flu-like symptoms, bronchospasm, hypotension, urticaria, angioedema, conjunctivitis, thrombocytopenia or neutropenia.
Macbutin Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.
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 Macbutin 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 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 × 2 weeks | 150 mg every other day × 2 weeks | Healthy subjects (15) | ↔A UC* ↓ 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. |
| 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%‡ ↓ 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 e ve ry 3 days x 21-22 days | Healthy 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. |
| 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. |
| Nenniavir | 1250 mg BIDx 7–8 days | 150 mg QD × 8 days | HIV- infected patients (11) | ↑ AUC by 83%,¶ ↑ Cmax by 19% | ↔ | Reduce rifabutin dose by 50% (to 150 mg QD) andincrease 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 | g2 ExJS | HIV- infected patients (12) | ↑ AUC by 82%, ↑ Cmax by 88% | ↔ | Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend Macbutin 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 o f po saco nazo le efficacy. |
| Itraconazole | 200 mg QD | 300 mg QD | HIV-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 coadministration of rifabutin (300 mg QD) with itraconazole (600900 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%Þ | CONTRAINDICATED |
| ANTI-PCP (Pneumocys tis carinii pneumonia) | ||||||
| Dapsone | 50 mg QD | 300 mg QD | HIV- infected patients (16) | ND | ↓ AUC by 27 – 40% | |
| Sulfamethoxazole- Trimethoprim | 800/160 mg | 300 mg QD | HIV- infected patients (12) | ↔ | ↓ AUC by 15– 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 Macbutin 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 - 100 mg QD | 300 mg QD x 13 days | HIV- infected patients (24) | ND | ↔ | |
| Ethinylestradiol (EE)/N orethindrone (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 | ↔ | |
| ↑ 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 Þcompared to voriconazole 200 mg BID alone | ||||||
Macbutin 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 Macbutin should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of Macbutin as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to Macbutin and to rifampin.
There is no evidence that Macbutin is an effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and Macbutin 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 ClarithromycinWhen Macbutin is used concomitantly with clarithromycin for MAC treatment, a decreased dose of Macbutin is recommended due to the increase in plasma concentrations of Macbutin (see DRUG INTERACTIONS, Table 2).
Hypersensitivity And Related ReactionsHypersensitivity 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 Macbutin therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue Macbutin.
UveitisDue to the possible occurrence of uveitis, patients should also be carefully monitored when Macbutin is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds (see DRUG INTERACTIONS, Table 2). If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with Macbutin should be suspended (see also ADVERSE REACTIONS).
Clostridium Difficile Associated DiarrheaClostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Macbutin (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 InteractionProtease 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 DRUG INTERACTIONS). For further recommendations, please refer to current, official product monographs of the protease inhibitor or contact the specific manufacturer.
PRECAUTIONS GeneralBecause treatment with Macbutin Capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with Macbutin.
Carcinogenesis, Mutagenesis, Impairment Of FertilityLong-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).
PregnancyRifabutin 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 MothersIt 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 UseSafety 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 Macbutin 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 Macbutin 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 Macbutin may be administered mixed with foods such as applesauce.
Geriatric UseClinical studies of Macbutin 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).
It is recommended that Macbutin Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of Macbutin 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 Macbutin by 50%, if toxicity is suspected. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of Macbutin may also be needed for patients receiving concomitant treatment with certain other drugs (see 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.
