Mycobutin

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

Mycobutin is a prescription medication used to prevent Mycobacterium avium complex (MAC) in people with HIV infection. The MAC infection can occur in the lungs, intestines, bone marrow, liver, and spleen.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Mycobacterium avium Complex (MAC) Infections

Primary prevention (primary prophylaxis) of disseminated MAC infection in adults, adolescents, and children† with advanced HIV infection;1 11 17 23 24 46 47 59 60 72 m designated an orphan drug by FDA for this use.17 The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the IDSA (USPHS/IDSA) recommend monotherapy with azithromycin or clarithromycin for primary prevention of MAC in HIV-infected individuals and consider rifabutin (with or without azithromycin) an alternative.72

Prevention of recurrence (secondary prophylaxis) of disseminated MAC infections† in HIV-infected adults, adolescents, and children†;72 f g designated an orphan drug by FDA for this use.17 USPHS/IDSA, CDC, NIH, IDSA, and others recommend clarithromycin (or azithromycin) given with ethambutol (with or without rifabutin) for secondary prophylaxis after the initial infection has been treated.72 f g

Treatment of pulmonary MAC infections† in conjunction with other antimycobacterials.60 For initial treatment of nodular/bronchiectatic pulmonary disease caused by macrolide-susceptible MAC, ATS and IDSA recommend a 3-times weekly regimen of clarithromycin (or azithromycin), ethambutol, and rifampin in most patients.60 For initial treatment of fibrocavitary or severe nodular/bronchiectatic pulmonary disease caused by macrolide-susceptible MAC, ATS and IDSA recommend a daily regimen of clarithromycin (or azithromycin), ethambutol, and rifampin (or rifabutin) and state that consideration can be given to adding amikacin or streptomycin during the first 2–3 months of treatment for extensive (especially fibrocavitary) disease or when previous therapy has failed.60

Treatment of disseminated MAC infections† in conjunction with other antimycobacterials, including infections in HIV-infected adults, adolescents, and children†;60 f g designated an orphan drug by FDA for this use.17 ATS, CDC, NIH, and IDSA recommend a regimen of clarithromycin (or azithromycin) and ethambutol with or without rifabutin.60 f g

Although either rifampin or rifabutin can be used in multiple-drug regimens for treatment of MAC infections, rifampin may be the preferred rifamycin for most patients with pulmonary MAC infections since it may be better tolerated (e.g., in older patients).60 Rifabutin may be the preferred rifamycin for treatment of disseminated MAC disease (especially in HIV-infected individuals) since it appears to be more active in vitro against MAC and is associated with fewer drug interactions.60 (See Specific Drugs under Interactions.)

Treatment of MAC infections is complicated and should be directed by clinicians familiar with mycobacterial diseases; consultation with a specialist is particularly important when the patient cannot tolerate first-line drugs or when the infection has not responded to prior therapy or is caused by macrolide-resistant MAC.60 In addition, specialized references should be consulted for guidance on the use of rifabutin in HIV-infected patients receiving HIV protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs).67 73 82 (See Specific Drugs under Interactions.)

Other Mycobacterial Infections

Treatment of infections caused by M. xenopi† in conjunction with other antimycobacterials.60 Optimum regimens not established; in vivo response may not correlate with in vitro susceptibility.60 ATS and IDSA state that a regimen of clarithromycin, rifampin, and ethambutol has been used, although the rate of relapse is high.60 A regimen of isoniazid, rifampin (or rifabutin), ethambutol, and clarithromycin (with or without streptomycin during initial treatment) also has been suggested.60

Tuberculosis

Treatment of active (clinical) tuberculosis† (TB) in conjunction with other antituberculosis agents.65 66 67 82 f g m o

First-line agent for treatment of all forms of TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug when rifampin cannot be used.82

Usually reserved for patients who cannot receive rifampin because of intolerance or because they are receiving other drugs that have clinically important interactions with rifampin (e.g., HIV patients receiving certain antiretroviral agents).67 82 f g m Used in both the initial intensive treatment phase and continuation treatment phase.82

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months).82 m Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,82 m ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.82 A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.82 m

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.82 f

Latent Tuberculosis Infection

Treatment of latent tuberculosis infection† (LTBI), including in HIV-infected adults and adolescents.67 72 73 o

LTBI is asymptomatic infection with M. tuberculosis; usually defined as a positive tuberculin skin test (TST) or Quantiferon-TB gold test (QFT-G) with no evidence of active (clinical) TB.67 73 m n o p LTBI is treated to decrease the risk of progression to active TB.67 73 o p

Regimen of choice for treatment of LTBI is isoniazid monotherapy, unless the patient has been in contact with an individual with drug-resistant TB.67 72 73 n o Rifampin monotherapy is the preferred alternative and is especially useful in adults, adolescents, or children who have been exposed to isoniazid-resistant M. tuberculosis and those who cannot tolerate isoniazid.67 72 73 n o Rifabutin is used in those who cannot receive rifampin because of intolerance or because they are receiving other drugs that have clinically important interactions with rifampin (e.g., HIV patients receiving certain antiretroviral agents).67 72 73 o

Treatment of LTBI in patients who have been exposed to a source case with drug-resistant TB, including MDR TB or XDR TB, should be managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.73 m n o

Prior to initiating treatment of LTBI, clinical (active) TB must be excluded using appropriate testing (e.g., radiographs).67 72 73 n o

• Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.82

• Importance of completing full course of therapy; importance of not missing any doses.1

• Advise patient of the signs and symptoms of MAC infections and TB; importance of consulting clinician if new symptoms consistent with either disease occur.1

• Possibility of uveitis; importance of consulting clinician if signs or symptoms of an inflammatory ocular condition occur (e.g., eye pain, redness, loss of vision).1

• Possibility of arthralgias or myositis; importance of consulting clinician if signs or symptoms of these disorders occur (e.g., joint stiffness, swelling, tenderness, paresthesia).1

• Advise patient that rifabutin may impart a brown-orange color to urine, feces, saliva, sputum, sweat, tears, and skin.1 23 Soft contact lenses may become permanently stained.1

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Advise that reliability of systemic hormonal contraceptives may be affected; alternative contraceptives should be considered.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

• If you have an allergy to rifabutin or any other part of Mycobutin (rifabutin).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have active TB (tuberculosis).
• If you are taking any of these drugs: Delavirdine or voriconazole.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Mycobutin with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Allergic side effects may rarely happen.
• This medicine may stain contact lenses.
• This medicine may change the color of urine, stools, saliva, sweat, tears, and skin to a brown-orange color. This is normal and not harmful.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom when taking Mycobutin.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use Mycobutin as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• Take with or without food. Take with food if it causes an upset stomach.
• You may swallow whole or mix the contents of the capsule with certain foods like applesauce. Take the mixture right away. Do not store for later use.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Chest pain or pressure.
• Flu-like signs. These include headache, weakness, fever, shakes, aches, pains, and sweating.
• Fever or chills.
• Sore throat.
• Any unexplained bruising or bleeding.
• Feeling very tired or weak.
• Muscle or joint pain.
• Shortness of breath.
• Change in eyesight, eye pain, or very bad eye irritation.
• If bright lights bother your eyes.
• Dizziness or passing out.
• Very upset stomach or throwing up.
• Coughing.
• A heartbeat that does not feel normal.
• It is common to have diarrhea when taking Mycobutin. Rarely, a very bad form of diarrhea called Clostridium difficile (C diff)–associated diarrhea (CDAD) may occur. Sometimes, this has led to a deadly bowel problem (colitis). CDAD may happen while you are taking this medicine or within a few months after you stop taking it. Call your doctor right away if you have stomach pain or cramps, very loose or watery stools, or bloody stools. Do not try to treat loose stools without first checking with your doctor.

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.

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

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.

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.

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).

No information is available on accidental overdosage in humans.

Treatment

While there is no experience in the treatment of overdose with Mycobutin 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 Mycobutin.

Mycobutin (rifabutin) Capsules, USP are supplied as hard gelatin capsules having an opaque red-brown cap and body, imprinted with Mycobutin/PHARMACIA & UPJOHN in white ink, each containing 150 mg of rifabutin, USP.

Mycobutin is available as follows:

NDC 0013-5301-17 Bottles of 100 capsules

Keep tightly closed and dispense in a tight container as defined in the USP. Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

LAB-0217-7.0
August 2016

Rifabutin has been assigned to pregnancy category B by the FDA. Animal studies failed to reveal evidence of teratogenicity, although some studies demonstrated a decrease in fetal viability and an increase in fetal skeletal variants. There are no controlled data in human pregnancy. Rifabutin is only recommended for use during pregnancy when benefit outweighs risk.

Summary of Use during Lactation

The amount of rifabutin in milk is insufficient to treat tuberculosis in the breastfed infant. The Centers for Disease Control and Prevention and other professional organizations state that breastfeeding should not be discouraged in women taking rifabutin.[1][2][3]

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Rifampin

References

1. Blumberg HM, Burman WJ, Chaisson RE et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603-62. PMID: 12588714

2. Anon. Treatment of tuberculosis. MMWR Recomm Rep. 2003;52:1-77. PMID: 12836625

3. Bartlett JG. Guidelines section. Infect Dis Clin Pract. 2002;11:467-71. DOI: doi:10.1097/01.idc.0000086415.30743.15