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  • CLASSES

    Other Agents for Tuberculosis

    DEA CLASS

    Rx

    DESCRIPTION

    Used for mycobacterial infections including tuberculosis and atypical mycobacterial infections. First-line antituberculosis agent in combination with isoniazid, pyrazinamide, rifampin, and/or streptomycin. Appears to be more effective and less toxic than other antitubercular agents.

    COMMON BRAND NAMES

    Myambutol

    HOW SUPPLIED

    Ethambutol/Ethambutol Hydrochloride/Myambutol Oral Tab: 100mg, 400mg

    DOSAGE & INDICATIONS

    For the treatment of tuberculosis infection in combination with other antitubercular agents.
    NOTE: The American Thoracic Society (ATS), Infectious Diseases Society of America (IDSA), and the Centers for Disease Control and Prevention (CDC) recommend short-course regimens (e.g., at least 6 months) for uncomplicated pulmonary tuberculosis and most cases of extrapulmonary tuberculosis in adults. According to the ATS, IDSA, CDC, and American Academy of Pediatrics (AAP), short-course regimens are also suitable in children. Directly observed therapy (DOT) should be used for all regimens administered 2, 3, or 5 times per week and in all pediatric patients. The initial treatment regimen should include 4 drugs unless the likelihood of INH or rifampin resistance is low (i.e., less than 4%), in which case an initial regimen of INH, rifampin, and pyrazinamide may be considered. HIV-positive patients should always receive induction therapy with 4 drugs by DOT. When drug susceptibility results are available, the regimen should be altered as appropriate. For multi-drug resistant tuberculosis (MDR-TB), drug therapy choice should be based on specific resistance patterns. For pediatrics, the CDC recommends treatment for 18 to 24 months after culture conversion in patients with bacteriologic confirmation and for at least 12 months in patients who are culture-negative. The World Health Organization (WHO) recommends at least 8 months of an intensive phase of treatment with a total treatment duration of 20 months in MDR-TB. The WHO also provides an alternative set of international dosing guidelines.
    Oral dosage
    Adults and Adolescents (product label dosing)

    15 mg/kg/dose (Max: 1.5 g) PO once daily in treatment-naive patients and 25 mg/kg/dose (Max: 2.5 g) PO once daily in patients who have previously received therapy. After 60 days, decrease the 25 mg/kg/dose to 15 mg/kg PO once daily. The usual initial treatment regimen is isoniazid plus pyrazinamide, ethambutol, and rifampin once daily or 5 times per week DOT for 2 months; once daily or 5 times per week DOT for 2 weeks then 2 times per week for 6 weeks; or 3 times per week DOT for 2 months. Patients with HIV infection should not be treated with 2 or 3 times per week regimens due to the occurrence of acquired rifamycin resistance. Rifabutin may be used instead of rifampin in patients with HIV. When isoniazid cannot be used or for strains of Mycobacterium tuberculosis due to resistance, administer ethambutol once daily for the first 2 months and then once daily or 2 or 3 times per week in combination with rifampin and pyrazinamide for 6 months or in combination with rifampin for 12 months (preferably with pyrazinamide for the first 2 months). For patients with extensive disease, consider adding a quinolone. Guidelines for HIV patients suggest rifampin (or rifabutin) plus ethambutol, pyrazinamide, and a quinolone (levofloxacin or moxifloxacin) for the first 2 months, then rifampin (or rifabutin) and ethambutol (and potentially a quinolone) for 7 months. Patients unable to take, or with tuberculosis due to strains of Mycobacterium tuberculosis resistant to, pyrazinamide should receive ethambutol once daily or 5 times per week with rifampin and isoniazid for 2 months, then 7 additional months of isoniazid plus rifampin. For patients unable to take, or with strains of Mycobacterium tuberculosis resistant to, the rifamycins, administer pyrazinamide once daily in combination with isoniazid, ethambutol, and a quinolone for 2 months, then isoniazid plus ethambutol and a quinolone for a treatment duration of 12 to 18 months.

    Adults and Adolescents 76 kg or more (Guideline dosing)†

    1.6 g PO once daily or 5 times per week; 2.4 g PO 3 times per week; or 4 g PO 2 times per week. Dosage should be based on lean body weight. Monitor for therapeutic response and consider therapeutic drug monitoring in those more than 90 kg to assure dosing adequacy. The usual initial treatment regimen is isoniazid plus pyrazinamide, ethambutol, and rifampin once daily or 5 times per week DOT for 2 months; once daily or 5 times per week DOT for 2 weeks then 2 times per week for 6 weeks; or 3 times per week DOT for 2 months. Patients with HIV infection should not be treated with 2 or 3 times per week regimens due to the occurrence of acquired rifamycin resistance. Rifabutin may be used instead of rifampin in patients with HIV. When isoniazid cannot be used, or for strains of Mycobacterium tuberculosis resistant to isoniazid, give ethambutol once daily for the first 2 months and then once daily or 2 or 3 times per week with rifampin and pyrazinamide for 6 months or with rifampin alone for 12 months (preferably with pyrazinamide for the first 2 months). For extensive disease, consider adding a quinolone. Guidelines for HIV patients suggest rifampin (or rifabutin) plus ethambutol, pyrazinamide, and a quinolone (levofloxacin/moxifloxacin) for the first 2 months, then rifampin (or rifabutin) and ethambutol (and potentially a quinolone) for 7 months. Patients unable to take, or with tuberculosis due to strains of Mycobacterium tuberculosis resistant to, pyrazinamide, should receive ethambutol once daily or 5 times per week with rifampin and isoniazid for 2 months, then 7 additional months of isoniazid plus rifampin. For patients unable to take, or with strains of Mycobacterium tuberculosis resistant to, rifamycins give pyrazinamide once daily with isoniazid, ethambutol, and a quinolone for 2 months, then isoniazid with ethambutol and a quinolone for a treatment duration of 12 to 18 months.

    Adults and Adolescents 56 to 75 kg (Guideline dosing)†

    1.2 g PO once daily or 5 times per week; 2 g PO 3 times per week; or 2.8 g PO 2 times per week. Dosage should be based on lean body weight. The usual initial treatment regimen is isoniazid plus pyrazinamide, ethambutol, and rifampin once daily or 5 times per week DOT for 2 months; once daily or 5 times per week DOT for 2 weeks then 2 times per week for 6 weeks; or 3 times per week DOT for 2 months. Patients with HIV infection should not be treated with 2 or 3 times per week regimens due to the occurrence of acquired rifamycin resistance. Rifabutin may be used instead of rifampin in patients with HIV. When isoniazid cannot be used, or for strains of Mycobacterium tuberculosis resistant to isoniazid, give ethambutol once daily for the first 2 months and then once daily or 2 or 3 times per week with rifampin and pyrazinamide for 6 months or with rifampin alone for 12 months (preferably with pyrazinamide for the first 2 months). For extensive disease, consider adding a quinolone. Guidelines for HIV patients suggest rifampin (or rifabutin) plus ethambutol, pyrazinamide, and a quinolone (levofloxacin/moxifloxacin) for the first 2 months, then rifampin (or rifabutin) and ethambutol (and potentially a quinolone) for 7 months. Patients unable to take, or with strains of Mycobacterium tuberculosis resistant to, pyrazinamide should receive ethambutol once daily or 5 times per week with rifampin and isoniazid for 2 months, then 7 additional months of isoniazid plus rifampin. For patients unable to take, or with strains of Mycobacterium tuberculosis resistant to, rifamycins give pyrazinamide once daily with isoniazid, ethambutol, and a quinolone for 2 months, then isoniazid with ethambutol and a quinolone for a treatment duration of 12 to 18 months.

    Adults and Adolescents 40 to 55 kg (Guideline dosing)†

    800 mg PO once daily or 5 times per week; 1.2 g PO 3 times per week; or 2 g PO 2 times per week. Dosage should be based on lean body weight. The usual initial treatment regimen is isoniazid plus pyrazinamide, ethambutol, and rifampin once daily or 5 times per week DOT for 2 months; once daily or 5 times per week DOT for 2 weeks then 2 times per week for 6 weeks; or 3 times per week DOT for 2 months. Patients with HIV infection should not be treated with 2 or 3 times per week regimens due to the occurrence of acquired rifamycin resistance. Rifabutin may be used instead of rifampin in patients with HIV. When isoniazid cannot be used, or for strains of Mycobacterium tuberculosis resistant to isoniazid, give ethambutol once daily for the first 2 months and then once daily or 2 or 3 times per week with rifampin and pyrazinamide for 6 months or with rifampin alone for 12 months (preferably with pyrazinamide for the first 2 months). For extensive disease, consider adding a quinolone. Guidelines for HIV patients suggest rifampin (or rifabutin) plus ethambutol, pyrazinamide, and a quinolone (levofloxacin/moxifloxacin) for the first 2 months, then rifampin (or rifabutin) and ethambutol (and potentially a quinolone) for 7 months. Patients unable to take, or with tuberculosis due to strains of Mycobacterium tuberculosis resistant to, pyrazinamide, should receive ethambutol once daily or 5 times per week with rifampin and isoniazid for 2 months, then 7 additional months of isoniazid plus rifampin. For patients unable to take, or with strains of Mycobacterium tuberculosis resistant to, rifamycins give pyrazinamide once daily with isoniazid, ethambutol, and a quinolone for 2 months, then isoniazid with ethambutol and a quinolone for a treatment duration of 12 to 18 months.

    Infants† and Children†

    15 to 25 mg/kg/dose (Max: 1 g) given PO once daily or 5 time per week, OR 50 mg/kg/dose (Max: 2.5 g) given PO 2 times per week is recommended by the ATS, IDSA, CDC, and AAP. The usual initial treatment regimen is isoniazid, rifampin, pyrazinamide, and ethambutol given once daily, 5 times per week, or 2 times per week for the first 2 months. HIV patients should only be given once daily therapy. Ethambutol may be removed from the initial regimen, especially if 4 drugs are not tolerated or visual exams are not possible; however, ethambutol or streptomycin is recommended in HIV patients. If the organism is found to be susceptible to isoniazid, rifampin, and pyrazinamide during the 2-month intensive phase of therapy, ethambutol (or streptomycin) can be discontinued and the intensive phase completed using 3 drugs. Rifabutin may be substituted for rifampin in patients with HIV. When isoniazid cannot be used, or for strains of Mycobacterium tuberculosis resistant to isoniazid, give ethambutol (or ethionamide or streptomycin) with rifampin and pyrazinamide for 9 to 12 months. Patients unable to take, or with tuberculosis due to strains of Mycobacterium tuberculosis resistant to, pyrazinamide, should receive ethambutol once daily or 5 times per week with rifampin and isoniazid for 2 months, then 7 additional months of isoniazid plus rifampin. For patients unable to take, or with strains of Mycobacterium tuberculosis resistant to, the rifamycins, administer pyrazinamide once daily with isoniazid, ethambutol, and a quinolone for 2 months, then isoniazid plus ethambutol and a quinolone for a treatment duration of 12 to 18 months. For patients with meningitis, initiate with 2 months of isoniazid, rifampin, and pyrazinamide with ethambutol, an aminoglycoside, or ethionamide, given once daily.

    For the treatment of Mycobacterium avium complex infection† (MAC) in HIV-infected patients.
    Oral dosage
    Adults

    15 mg/kg/dose PO once daily plus clarithromycin or azithromycin. May consider addition of third or fourth drug (rifabutin, amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Duration of treatment depends on clinical response but should continue for at least 12 months.[34362]

    Adolescents

    15 mg/kg/dose PO once daily plus clarithromycin or azithromycin. May consider addition of third or fourth drug (rifabutin, amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Duration of treatment depends on clinical response but should continue for at least 12 months.[34362]

    Infants and Children

    15 to 25 mg/kg/dose PO once daily (Max: 2.5 g/day) plus clarithromycin or azithromycin. For severe disease, consider adding rifabutin. If rifabutin cannot be administered or if a fourth drug is needed for patients with more severe symptoms or disseminated disease, consider adding ciprofloxacin, levofloxacin, or amikacin. Duration of treatment depends on clinical response but should continue for at least 12 months.[34361]

    For secondary Mycobacterium avium complex (MAC) prophylaxis† in HIV-infected patients with disseminated disease after treatment of the acute illness.
    Oral dosage
    Adults

    15 mg/kg/dose PO once daily plus clarithromycin or azithromycin. May consider addition of third or fourth drug (rifabutin, amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Consider discontinuing secondary prophylaxis in patients who have completed at least 12 months of MAC treatment, have no signs or symptoms of MAC, and have a sustained (more than 6 months) CD4 count more than 100 cells/mm3 in response to ART. Restart secondary prophylaxis if the CD4 count decreases to less than 100 cells/mm3.[34362]

    Adolescents

    15 mg/kg/dose PO once daily plus clarithromycin or azithromycin. May consider addition of third or fourth drug (rifabutin, amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Consider discontinuing secondary prophylaxis in patients who have completed at least 12 months of MAC treatment, have no signs or symptoms of MAC, and have a sustained (more than 6 months) CD4 count more than 100 cells/mm3 in response to ART. Restart secondary prophylaxis if the CD4 count decreases to less than 100 cells/mm3.[34362]

    Infants and Children

    15 to 25 mg/kg/dose PO once daily (Max: 2.5 g/day) plus clarithromycin or azithromycin with rifabutin for children older than 5 years who received rifabutin as part of initial treatment. Do not discontinue secondary prophylaxis for children younger than 2 years. Consider discontinuing secondary prophylaxis in children older than 2 years who have received at least 12 months of MAC treatment, have no signs or symptoms of MAC, have been receiving stable antiretroviral therapy, and have a sustained (more than 6 months) CD4 count more than 200 cells/mm3 for children 2 to 5 years and more than 100 cells/mm3 for children 6 years and older. Restart secondary prophylaxis if the CD4 count falls below these thresholds.[34361]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    25 mg/kg/dose (2.5 g maximum) PO for daily therapy. Doses of 50 mg/kg/dose (4 g maximum) PO for twice weekly therapy and 30 mg/kg/dose (2.4 g maximum) PO for three times weekly therapy have been used off label.

    Elderly

    25 mg/kg/dose ((2.5 g maximum) PO for daily therapy. Doses of 50 mg/kg/dose (4 g maximum) PO for twice weekly therapy and 30 mg/kg/dose (2.4 g maximum) PO for three times weekly therapy have been used off label.

    Adolescents

    25 mg/kg/dose (2.5 g maximum) PO for daily therapy. Doses of 50 mg/kg/dose (4 g maximum) PO for twice weekly therapy and 30 mg/kg/dose (2.4 g maximum) PO for three times weekly therapy have been used off label.

    Children

    Safety and efficacy have not been established. Doses of 25 mg/kg/dose (2.5 g maximum) PO for daily therapy or 50 mg/kg/dose (4 g maximum) PO for twice weekly therapy have been used off-label.

    Infants

    Safety and efficacy have not been established. Doses of 25 mg/kg PO daily (2.5 g maximum) have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. However, ethambutol should be used cautiously in patients with hepatic disease; hepatotoxicity including fatalities have been reported.

    Renal Impairment

    The manufacturer recommends reducing the dose in patients with renal dysfunction based on serum concentrations, but gives no further recommendations. Guidelines recommend that the dosage be adjusted in patients with a CrCl < 70 mL/min; however, dosage recommendations are incomplete: 
    CrCl > 70 mL/min: No dosage adjustment needed.
    CrCl 50?69 mL/min: No recommendations are available; however, one guideline does not make dosage adjustments until the CrCl is < 50 mL/min.
    CrCl 30—50 mL/min: 15—20 mg/kg PO every 24—36 hours.
    CrCl 10—30 mL/min: Some guidelines suggest 15—25 mg/kg PO three times per week. Another guideline recommends 15—20 mg/kg PO every 24—36 hours.
    CrCl < 10 ml/min: Some guidelines suggest 15—25 mg/kg PO three times per week. Another guideline recommends 15—20 mg/kg PO every 48 hours.
    Intermittent hemodialysis
    15—25 mg/kg PO three times per week after hemodialysis.

    ADMINISTRATION

     
    NOTE: Ethambutol should not be given alone, but should be used in combination with other antitubercular agents.

    Oral Administration

    Administer with food to minimize gastric irritation.

    STORAGE

    Myambutol:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Renal impairment

    The primary route of elimination is via the kidneys, so ethambutol should be used with caution in patients with renal impairment. Dosage adjustments may be necessary.

    Cataracts, diabetic retinopathy, ocular disease, optic neuritis

    Ethambutol is contraindicated in patients with known optic neuritis unless clinical judgment determines that it may be used. Ethambutol is also contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision (i.e., young pediatric patients or unconscious patients). Ethambutol has been associated with optic neuritis characterized by central and peripheral scotomas, decreases in visual acuity, and constriction of visual fields. Preexisting ocular disease can be potentiated. All patients should be closely monitored for changes in visual acuity. In certain patients with visual defects (e.g., cataracts, recurrent inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy), evaluation of visual acuity changes is more difficult; care should be taken to determine if the variations in vision are not due to the underlying disease conditions. Since the incidence increases with increasing doses, a pretreatment ophthalmologic exam should be performed, in addition to monthly testing in patients receiving doses greater than 15 mg/kg/day. These visual effects are generally reversible when ethambutol is promptly discontinued. However, irreversible blindness has been reported. Ethambutol should not be used in patients who are unable to appreciate and report visual adverse effects or changes in vision (e.g., unconscious patients).

    Hepatic disease

    Ethambutol should be used cautiously in patients with hepatic disease. Hepatotoxicity including fatalities have been reported. Baseline and periodic hepatic function assessment should be performed. Most combination therapy for active TB disease includes more than 1 agent that may contribute to hepatotoxicity. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.

    Gout

    Ethambutol can cause hyperuricemia. Uric acid levels should be measured periodically in patients with a history of gout.

    Children, infants, neonates

    Ethambutol also contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision (e.g., young children). Neonates, infants and children < 13 years are generally considered too young for accurate assessment and safe and effective use in this age group have not been determined.

    Pregnancy

    Ethambutol is classified in FDA pregnancy risk category B. The drug crosses the placenta and results in fetal plasma concentrations that are approximately 30% of maternal plasma concentrations. Although safe and effective use of ethambutol during pregnancy has not been established, it has been used (in combination with isoniazid or isoniazid plus rifampin) in pregnant women to treat tuberculosis. No fetal adverse effects have been reported.

    Breast-feeding

    Ethambutol is distributed into human breast milk at concentrations similar to maternal serum concentrations and the manufacturer recommends caution with use in breast feeding women. However, ethambutol is considered usually compatible with breast-feeding according to the American Academy of Pediatrics (AAP). Additionally, the American Thoracic Society (ATS), the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) state that breast-feeding should not be discouraged in women taking ethambutol. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / 0-1.0
    optic neuritis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known

    Moderate

    scotomata / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    gout / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known

    Mild

    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    headache / Early / Incidence not known
    dizziness / Early / Incidence not known
    fever / Early / Incidence not known
    malaise / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Aluminum Hydroxide: (Moderate) Aluminum hydroxide can reduce the rate or extent of ethambutol absorption. At least 4 hours should elapse between doses of aluminum hydroxide-containing antacids and ethambutol.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Aluminum hydroxide can reduce the rate or extent of ethambutol absorption. At least 4 hours should elapse between doses of aluminum hydroxide-containing antacids and ethambutol.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Aluminum hydroxide can reduce the rate or extent of ethambutol absorption. At least 4 hours should elapse between doses of aluminum hydroxide-containing antacids and ethambutol.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Aluminum hydroxide can reduce the rate or extent of ethambutol absorption. At least 4 hours should elapse between doses of aluminum hydroxide-containing antacids and ethambutol.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Aluminum hydroxide can reduce the rate or extent of ethambutol absorption. At least 4 hours should elapse between doses of aluminum hydroxide-containing antacids and ethambutol.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of aminosalicylate sodium, aminosalicylic acid and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of ethambutol could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
    Capreomycin: (Moderate) Adverse hepatic effects have been associated with capreomycin, especially with concurrent use of other antituberculosis drugs known to alter hepatic function. Theoretically, coadministration of capreomycin and ethambutol could increase the risk of hepatotoxicity. Monitor patients for changes in liver function if these drugs are coadministered.
    Colchicine; Probenecid: (Moderate) Probenecid has uricosuric actions. Ethambutol can also cause hyperuricemia. Although this effect represents a pharmacodynamic interaction, dosage adjustments of probenecid may be necessary if ethambutol is administered to patients being treated with probenecid.
    Ethionamide: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethambutol and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethambutol and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of pyrazinamide, PZA and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.[. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethambutol and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Probenecid: (Moderate) Probenecid has uricosuric actions. Ethambutol can also cause hyperuricemia. Although this effect represents a pharmacodynamic interaction, dosage adjustments of probenecid may be necessary if ethambutol is administered to patients being treated with probenecid.
    Pyrazinamide, PZA: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of pyrazinamide, PZA and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.[.
    Rifabutin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Sulfinpyrazone: (Minor) Because ethambutol can cause hyperuricemia, it may counteract the uricosuric effects of sulfinpyrazone. Dosage adjustments of sulfinpyrazone may be necessary if these agents are administered concurrently to patients with gout.
    Vigabatrin: (Major) Vigabatrin should not be used with ethambutol, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.

    PREGNANCY AND LACTATION

    Pregnancy

    Ethambutol is classified in FDA pregnancy risk category B. The drug crosses the placenta and results in fetal plasma concentrations that are approximately 30% of maternal plasma concentrations. Although safe and effective use of ethambutol during pregnancy has not been established, it has been used (in combination with isoniazid or isoniazid plus rifampin) in pregnant women to treat tuberculosis. No fetal adverse effects have been reported.

    Ethambutol is distributed into human breast milk at concentrations similar to maternal serum concentrations and the manufacturer recommends caution with use in breast feeding women. However, ethambutol is considered usually compatible with breast-feeding according to the American Academy of Pediatrics (AAP). Additionally, the American Thoracic Society (ATS), the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) state that breast-feeding should not be discouraged in women taking ethambutol. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Ethambutol is primarily bacteriostatic, although in higher doses it also exhibits bactericidal properties. The exact mechanism is not known; however, it appears to inhibit RNA synthesis, resulting in impaired cellular metabolism and multiplication. Ethambutol is effective only against bacilli that are actively dividing. Cross-resistance between ethambutol and other antitubercular agents has not been demonstrated.
     
    In general, the following organisms are susceptible to ethambutol: M. tuberculosis; M. bovis; M. marinum; and some strains of M. kansasii, M. avium, M. fortuitum, and M. intracellulare.

    PHARMACOKINETICS

    Ethambutol is administered orally. Ethambutol is widely distributed, with high concentrations in the kidneys, lungs, and saliva. It penetrates inflamed meninges (10—50%) to reach therapeutic levels in the CSF. The drug crosses the placenta, resulting in plasma fetal concentrations that are 30% of maternal concentrations, and is distributed into breast milk in amounts similar to maternal plasma levels. Ethambutol is partially metabolized in the liver. The parent drug and its metabolites are excreted primarily in the urine (65%), with the remaining 20—25% excreted unchanged in the feces. The elimination half-life is 3.5 hours and can be up to 15 hours in renal disease.

    Oral Route

    Approximately 75—80% of an ethambutol oral dose is absorbed. Peak serum levels are attained within 2—4 hours.