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Adverse Reactions From Clinical Trials
MYCOBUTIN 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 MYCOBUTIN, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of MYCOBUTIN 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 MYCOBUTIN in studies 023 and 027.
Table: 3 Clinical Adverse Experiences Reported in
≥ 1% of Patients Treated With MYCOBUTIN
(n = 566)%
(n = 580) %
|Body as a whole|
|Blood and lymphatic system|
|Nausea and vomiting||3||2|
|Skin and appendages|
Clinical Adverse Events Reported In < 1% Of Patients Who Received Mycobutin
Considering data from the 023 and 027 pivotal trials, and from other clinical studies, MYCOBUTIN 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 MYCOBUTIN, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and nonspecific T wave changes on electrocardiogram.
When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when MYCOBUTIN was discontinued.
Mild to severe, reversible uveitis has been reported less frequently when MYCOBUTIN is used at 300 mg as monotherapy in MAC prophylaxis versus MYCOBUTIN in combination with clarithromycin for MAC treatment (see also WARNINGS).
Uveitis has been infrequently reported when MYCOBUTIN 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 MYCOBUTIN are administered in combination with these agents, the incidence of uveitis is higher. FDA proposes moving this paragraph from below with some revisions.
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 MYCOBUTIN and ophthalmologic evaluation are recommended. In most mild cases, MYCOBUTIN may be restarted; however, if signs or symptoms recur, use of MYCOBUTIN 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 MYCOBUTIN 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
(n = 566) %
(n = 580) %
|Increased alkaline phosphatase 1||< 1||3|
|Increased SGOT 2||7||12|
|Increased SGPT 2||9||11|
|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 3
5 All ANC values < 750/mm 3
6 All platelet count values < 50,000/mm 3
The incidence of neutropenia in patients treated with MYCOBUTIN was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with MYCOBUTIN in these trials, MYCOBUTIN has been clearly linked to thrombocytopenia in rare cases. One patient in Study 023 developed thrombotic thrombocytopenic purpura, which was attributed to MYCOBUTIN.
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.
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.
Read the Mycobutin (rifabutin) Side Effects Center for a complete guide to possible side effects
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 drug||Dosing regimen of coadministered drug||Dosing regimen of rifabutin||Study population (n)||Effect on rifabutin||Effect on coadminister ed drug||Recommendation|
|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%
|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 21-22 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||500mg 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 7-8 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.|
|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 MYCOBUTIN 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 coadministration of rifabutin (300 mg QD) with itraconazole (600-900 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
|ANTI-PCP (Pneumocystis 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 MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin|
|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||↔|
|Methadone||20 - 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||↔|
|↑ 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
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.
Read the Mycobutin Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 7/20/2015
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