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MYCOBUTIN is a brand name for Rifabutin, supplied as a capsule. The medicine, its uses, side effects and dosage are the same regardless of brand.
Verbatim from this product's HC label. Tap a section to expand.
and 7 WARNING AND PRECAUTIONS). ANTI-TB (Tuberculosis) Ethambutol ND No significant change in AUC or Cmax Isoniazid ND Pharmacokineti cs not affected Pyrazinamide No significant change in AUC or Cmax No significant change in AUC or Cmax No dose adjustment needed Bedaquiline ND No change in bedaquiline kinetics.
0-fold in M3 metabolites of bedaquiline. If the drugs are co-administered, patients should be monitored for adverse events associated with bedaquiline administration. ORAL CONTRACEPTIVES Ethinylestradiol/ Norethindrone ND Ethinylestradiol: 20% ↓ in Cmax, 35% ↓ in AUC.
Norethindrone: 32% ↓ in Cmax, 46% ↓ in AUC. Patients should be advised to use other additional non-hormonal methods of contraception. OTHER Methadone ND No significant effect No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC.
Rifabutin kinetics not evaluated. Ethinylestradiol ND 35%↓ AUC 20%↓ Cmax Patients should be advised to use other methods of contraception. MYCOBUTIN (rifabutin) – Product Monograph Page 20 of 41 Coadministered Drugs Effect on Rifabutin Effect on Coadministered Drug Comments Norethindrone ND 46%↓ AUC Patients should be advised to use other methods of contraception.
Tacrolimus ND ND Authors report that rifabutin decreases tacrolimus trough blood levels. Theophylline ND No significant change in AUC or Cmax compared with baseline.
ND: Not done; AUC:
Area under the Concentration vs.
Time Curve; Cmax:
Maximum serum concentration * A lower dose of ritonavir was used when combined with fosamprenavir, lopinavir or tipranavir than when used alone; the PK effects upon ritonavir used alone or in combination with these antivirals were not studied.
** - Drug plus active metabolite *** - Voriconazole dosed at 400 mg twice daily † Formerly known as Pneumocystis carinii pneumonia MYCOBUTIN has liver enzyme-inducing properties. The related drug rifampin is known to reduce the activity of a number of drugs, including dapsone, narcotics (including methadone), anticoagulants, corticosteroids, cyclosporine, cardiac glycoside preparations, quinidine, oral contraceptives, oral hypoglycemic agents (sulfonylureas), and analgesics.
Rifampin has also been reported to decrease the effects of concurrently administered ketoconazole, barbiturates, diazepam, verapamil, beta-adrenergic blockers, clofibrate, progestins, disopyramide, mexiletine, theopylline, chloramphenicol, and anticonvulsants.
Because of the structural similarity of rifabutin and rifampin, MYCOBUTIN may be expected to have some effect on these drugs as well. However, unlike rifampin, MYCOBUTIN appears not to affect the acetylation of isoniazid. When the effects of rifabutin on hepatic microsomal enzyme activity were compared to those of rifampin in a study with 8 healthy normal volunteers, rifabutin appeared to be a less potent enzyme inducer than rifampin.
). • Rifabutin is a CYP450 3A inducer. 2 Drug Interactions Overview). • For further recommendations, please refer to the most recent Product Monograph of the antiretrovirals or contact the specific manufacturer. • Anaphylactic shock has occurred with other antibiotics of the same class.
MYCOBUTIN (rifabutin) – Product Monograph Page 7 of 41 Cardiovascular In the rat, single intravenous doses of up to 36 mg/kg or oral doses of up to 200 mg/kg daily for four days did not affect blood pressure or heart rate or the responses of these parameters to several autocoids.
There was an increase of about 50% in respiratory rate beginning about 100 minutes following an intraduodenal dose of 50 mg/kg in the anaesthetized dog. There were, however, no other significant changes in cardiovascular or respiratory system parameters.
, rifampin, isoniazid). Drug serum concentration data from AIDS patients with varying disease severity (based on CD4+ counts) suggest that rifabutin absorption is not influenced by progressing HIV disease. However, when stomach pH is increased with drug co-administration, rifabutin absorption may be impaired.
Oral doses of up to 20 mg/kg rifabutin did not affect gastric emptying rate in the rat. Clostridium difficile-associated disease (CDAD) Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including MYCOBUTIN (rifabutin).
CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent.
CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD.
, General). INDICATIONS). 4 Administration The capsule(s) should be swallowed whole with a drink of water. 5 Missed Dose If a dose is missed, the patient should take the dose as soon as remembered. If it is almost time for the next dose, the patient should skip the missed dose and take the next dose at the regularly scheduled time.
Do not double the dose. 5.
OVERDOSAGE Symptoms:
No information is available on accidental overdosage in humans.
Treatment:
While there is no experience in the treatment of overdose with MYCOBUTIN (rifabutin), clinical experience with rifamycins suggest 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.
MYCOBUTIN is 85% protein bound, and distributed extensively into tissues (Vss: 8 to 9 L/kg). As unchanged drug, MYCOBUTIN is not primarily excreted via the urinary route (less than 10%), therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged MYCOBUTIN from the body in a patient with MYCOBUTIN overdose.
6. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING Table 1 – Dosage Forms, Strengths, Composition and Packaging For management of a suspected drug overdose, contact your regional poison control centre. Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients oral 150 mg rifabutin microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink.
MYCOBUTIN (rifabutin) – Product Monograph Page 6 of 41 MYCOBUTIN (rifabutin) is supplied as hard gelatin capsules having an opaque red-brown cap and body, imprinted with PHARMACIA & UPJOHN/ MYCOBUTIN, in white ink, each containing 150 mg rifabutin.
). 5 fold increase in Cmax ND In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased. If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered (see 7 WARNING AND PRECAUTIONS, General).
7-fold ↑ Cmax No significant change in tipranavir kinetics. Therapeutic drug monitoring of rifabutin is recommended. Zidovudine No significant change in kinetics. Approximately 32% in Cmax and AUC A large controlled clinical study has shown that these changes are of no clinical relevance.
ANTI-HCV DRUGS MYCOBUTIN (rifabutin) – Product Monograph Page 17 of 41 Coadministered Drugs Effect on Rifabutin Effect on Coadministered Drug Comments Sofosbuvir ND 36% in Cmax and 24% AUC Co-administration of rifabutin with sofosbuvir (alone or in combination) is not recommended (see 7 WARNING AND PRECAUTIONS, General).
ANTIFUNGALS Fluconazole 82% in AUC No significant change in steady-state plasma concentrations Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored (see 7 WARNING AND PRECAUTIONS, Ophthalmologic) Itraconazole ND 70% to 75% in Cmax and AUC One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole.
Posaconazole 31%↑ Cmax, 72%↑ AUC 43%↓ Cmax, 49%↓ AUC If the drugs are coadministered, patients should be monitored for adverse events associated with rifabutin administration. MYCOBUTIN (rifabutin) – Product Monograph Page 18 of 41 Coadministered Drugs Effect on Rifabutin Effect on Coadministered Drug Comments Voriconazole 195%↑ Cmax, 331%↑ AUC *** Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively.
During co- administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily.
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The significance of this finding for clinical drug interactions is not known. Dosage adjustment of drugs listed above may be necessary if they are given concurrently with MYCOBUTIN. Patients using oral contraceptives should consider changing to nonhormonal methods of birth control.
5 Drug-Food Interactions Interactions with food have not been established. 6 Drug-Herb Interactions Interactions with herbal products have not been established. 7 Drug-Laboratory Test Interactions Interactions with laboratory tests have not been established.
1 Mechanism of Action MYCOBUTIN (rifabutin) is a derivative of rifamycin S, belonging to the class of ansamycins. The rifamycins owe their antimycobacterial efficacy to their ability to penetrate the cell wall and to their ability to complex with and to inhibit DNA-dependent RNA polymerase.
Rifabutin has been found to interact with and to penetrate the outer layers of the mycobacterial envelope. 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 constitutes M. avium complex (MAC).
Rifabutin inhibited incorporation of thymidine into DNA of rifampin-resistant M. tuberculosis suggesting that rifabutin may also inhibit DNA synthesis which may explain its activity against rifampin- resistant organisms. 2 Pharmacodynamics Over a dose range of 300 to 900 mg/day, administration of multiple, daily rifabutin doses did not elicit any serious/unexpected adverse events in 34 HIV positive patients.
Doses higher than 900 mg/day produced chest discomfort, flu-like syndromes, lower back pain, skin discoloration, and gastrointestinal symptoms. However, a steep dose-related increase in the incidence of arthralgia, from 0% at 900 mg/day to 100% at 1200 mg/day, and the occurrence of uveitis at doses higher than 1800 mg/day was seen.
No apparent effects on hematological or hepatic parameters were seen for doses up to 1200 mg/day, except mild leukopenia. Rifabutin in HIV positive patients was well tolerated up to 900 mg/day. The minimum effective dose and the optimal dose of rifabutin for prophylaxis, are not known.
3 Pharmacokinetics Rifabutin pharmacokinetics have been studied using daily doses ranging from 150 mg to 1200 mg (600 mg bid) in the pivotal pharmacokinetics and dose-tolerance studies involving both healthy normal volunteers and HIV positive patients, for periods of up to 28 days.
The pharmacokinetic profile of rifabutin is not significantly modified by age or by hepatic dysfunction, although the inter-individual variability in elderly subjects (71-80 years) was slightly higher. Renal insufficiency was correlated to a decrease in urinary excretion with AUC and Cmax increases most apparent in severe […]
CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy. If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile.
In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases.
Genitourinary Rifabutin, at oral doses of up to 100 mg/kg, did not affect urinary volume, pH or electrolytes in the rat. MYCOBUTIN (rifabutin) – Product Monograph Page 8 of 41 Hepatic/Biliary/Pancreatic The pharmacokinetics of rifabutin were studied in 40 patients with mild (n=30), moderate (n=6) and severe (n=4) hepatic impairment.
Significant variability was noted. Caution should be exercised in treating patients with severe hepatic disease. For patients with severe liver insufficiency a dose reduction should be considered. Mild and moderate hepatic impairment does not require a dose modification.
2 Recommended Dose and Dosage Adjustment). Neurologic Oral doses of 200 mg/kg rifabutin in the mouse and 100 mg/kg in the rat caused CNS depression lasting up to six hours post dose. Rifabutin (50 mg/kg) did not antagonize amphetamine, pentylenetetrazol or reserpine in the mouse.
Rifabutin did not affect neuromuscular coordination (rotorod) or conditioned avoidance response in the rat at 50 mg/kg. There were no consistent effects on body temperature in mice, rats or dogs treated with rifabutin. Ophthalmologic Uveitis is rare when MYCOBUTIN is used as a single agent at 300 mg/day for prophylaxis of MAC in HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibiotics.
However, if higher doses of MYCOBUTIN 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 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. Renal Caution is recommended when treating patients with severe renal insufficiency.
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 insufficiency (creatinine clearance below 30 mL/min) compared to patients with creatinine clearance (CrCl) between 61–74 mL/min.
In patients with mild to moderate renal insufficiency (CrCl between 30–61 mL/min), the AUC increased by […]
7. WARNINGS AND PRECAUTIONS General • MYCOBUTIN (rifabutin) prophylaxis must not be administered to patients with active tuberculosis. Among HIV positive patients, tuberculosis is common and may present with atypical or extrapulmonary findings.
Patients are likely to have a nonreactive purified protein derivative (PPD) test 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.
• Patients who develop signs and symptoms consistent with active tuberculosis while on MYCOBUTIN prophylaxis 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 which is resistant both to MYCOBUTIN and to rifampin. • There is no evidence that MYCOBUTIN provides effective prophylaxis against M.
tuberculosis infections. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN concurrently. • Significant drug-drug interactions between rifabutin and protease inhibitors, among many other drugs, requires careful consideration based upon the overall assessment of the patient and patient’s specific drug profile since drug safety and efficacy can be impacted.
• Patients should be carefully monitored to avoid uveitis. If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with MYCOBUTIN should be suspended (see 7 WARNINGS AND PRECAUTIONS, Ophthalmologic, 9 Drug Interactions and
Concurrent administration of voriconazole and rifabutin is not recommended. ANTI-PCP (Pneumocystis jirovecii pneumonia †) Dapsone ND Approximately 27% to 40% in AUC Study conducted in HIV infected patients (rapid and slow acetylators).
Sulfamethoxazole- Trimethoprim No significant change in Cmax and AUC Approximately 15% to 20% in AUC In another study, only trimethoprim (not sulfamethoxazole) had 14% in AUC and 6% in Cmax but were not considered clinically significant.
MYCOBUTIN (rifabutin) – Product Monograph Page 19 of 41 Coadministered Drugs Effect on Rifabutin Effect on Coadministered Drug Comments ANTI-MAC (Mycobacterium avium intracellulare complex) Azithromycin No PK interaction No PK interaction Clarithromycin Approximately 77% in AUC Approximately 50% in AUC Study conducted in HIV infected patients.
Dose of rifabutin should be adjusted in the presence of clarithromycin (see