Mycobacterium avium complex disease (off-label use):
Pulmonary disease (nodular/bronchiectatic disease): Oral: 25 mg/kg 3 times weekly as part of an appropriate combination regimen; continue treatment until patient is culture negative on therapy for ≥1 year (ATS/ERS/ESCMID/IDSA [Daley 2020]).
Pulmonary disease (severe nodular/bronchiectatic or cavitary disease): Oral: 15 mg/kg once daily as part of an appropriate combination regimen; continue treatment until patient is culture negative on therapy for ≥1 year (ATS/ERS/ESCMID/IDSA [Daley 2020]).
Disseminated disease in patients with HIV, treatment and chronic maintenance therapy: Oral: 15 mg/kg once daily in combination with a macrolide (azithromycin or clarithromycin); may discontinue when patient has completed ≥12 months of therapy, has no signs/symptoms of M. avium complex disease, and has sustained (>6 months) CD4 count >100 cells/mm3 in response to antiretroviral therapy (ART). Note: Addition of a third or fourth drug should be considered for patients with advanced immunosuppression (CD4 count <50 cells/mm3), high mycobacterial loads (>2 log10 CFU/mL), or in the absence of effective ART (HHS [OI adult 2022]).
Tuberculosis, drug-susceptible:
Note: Always administer in combination with other antitubercular drugs (ATS/CDC/IDSA [Nahid 2016]).
Dosing: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for patients with obesity has not been established):
Once-daily therapy: Note: The preferred frequency of administration is once daily; however, 5-days-per-week administration by directly observed therapy (DOT) is an acceptable alternative (ATS/CDC/IDSA [Nahid 2016]).
40 to 55 kg: Oral: 800 mg (14.5 to 20 mg/kg).
56 to 75 kg: Oral: 1.2 g (16 to 21.4 mg/kg).
76 to 90 kg: Oral: 1.6 g (17.8 to 21.1 mg/kg).
Three-times-weekly DOT (ATS/CDC/IDSA [Nahid 2016]):
40 to 55 kg: Oral: 1.2 g (21.8 to 30 mg/kg).
56 to 75 kg: Oral: 2 g (26.7 to 35.7 mg/kg).
76 to 90 kg: Oral: 2.4 g (26.7 to 31.6 mg/kg).
Twice-weekly DOT (ATS/CDC/IDSA [Nahid 2016]):
40 to 55 kg: Oral: 2 g (36.4 to 50 mg/kg).
56 to 75 kg: Oral: 2.8 g (37.3 to 50 mg/kg).
76 to 90 kg: Oral: 4 g (44.4 to 52.6 mg/kg).
Regimens: Treatment regimens for pulmonary tuberculosis consist of an initial 2-month phase of a 4-drug regimen that includes ethambutol, followed by a continuation phase consisting of a 2-drug regimen (does not include ethambutol) of an additional 4 to 7 months; ethambutol frequency and dosing differs depending on treatment regimen selected; consult current drug-susceptible TB guidelines (ATS/CDC/IDSA [Nahid 2016]).
Tuberculosis, drug resistant (alternative agent): Note: Expert consultation for optimal regimen and duration of treatment is advised (AST/CDC/ERS/IDSA [Nahid 2019]).
Low dose (companion drug): Oral: 15 mg/kg once daily (AST/CDC/ERS/IDSA [Nahid 2019]).
High dose (bacteriostatic drug): Oral: 25 mg/kg once daily (AST/CDC/ERS/IDSA [Nahid 2019]).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Therapeutic drug monitoring should be utilized, when possible, in patients with severe kidney impairment or on renal replacement therapies to avoid drug accumulation and adverse effects, such as optic neuropathy (Alsultan 2014).
Altered kidney function (expert opinion derived from ATS/CDC/IDSA [Nahid 2016]; AST/CDC/ERS/IDSA [Nahid 2019]; HHS [OI Adult 2020]; WHO 2014b):
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: If usual recommended dose is administered once daily, then do not adjust the dose, but only administer 3 times weekly (eg, if usual dose is 15 mg/kg once daily, then administer 15 mg/kg 3 times weekly; if usual dose is 25 mg/kg once daily, then administer 25 mg/kg 3 times weekly). Since there are no clinical or pharmacokinetic data to support a renal dosage adjustment recommendation for dosing strategies other than once daily dosing (eg, the directly observed therapy [DOT] twice-weekly or 3-times–weekly dosing described in patients with normal kidney function) use of these dosing strategies are not recommended.
Hemodialysis, intermittent (thrice weekly): Dialyzable (extent not well characterized) (Chew 2017; Malone 1999): Dose as CrCl <30 mL/minute; administer after hemodialysis on dialysis days (AST/CDC/ERS/IDSA [Nahid 2019]; HHS [OI Adult 2020]; WHO 2014b). Use with caution and close monitoring, as hemodialysis patients may develop optic adverse effects, even with properly adjusted doses (Scoville 2013).
Peritoneal dialysis: Likely dialyzable, but not considered a major route of removal (expert opinion): Dose as for CrCl <30 mL/minute (AST/CDC/ERS/IDSA [Nahid 2019]; Si 2018; expert opinion). Use with caution and close monitoring (Si 2018).
CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse effects (eg, optic neuropathy) due to drug accumulation is important.
Note: Has not been studied in patients undergoing CRRT; some drug removal is expected but relatively large Vd will likely prevent substantial removal (expert opinion).
Dose as for CrCl <30 mL/minute; utilize therapeutic monitoring when possible to guide further dose adjustments (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse effects (eg, optic neuropathy) due to drug accumulation is important.
Note: Limited data available in patients undergoing PIRRT; some drug removal is expected, but relatively large Vd will likely prevent substantial removal (expert opinion). Recommendations assume daily PIRRT sessions.
Dose as for CrCl <30 mL/minute; on PIRRT days, administer after the PIRRT session (expert opinion). Utilize therapeutic monitoring, when possible, to guide further dose adjustments (Strunk 2016; expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
(For additional information see "Ethambutol: Pediatric drug information")
Tuberculosis, active treatment (excluding meningitis): Note: Recommendations often change due to epidemiology (resistance) and emerging information; consult CDC and WHO for current recommendations, as appropriate. Always use as part of a multidrug regimen. Any regimens using less than once daily dosing should administer dosing as directly observed therapy (DOT). Treatment regimens for pulmonary tuberculosis consist of an initial 2-month intensive phase of a 4-drug regimen, followed by a continuation phase of an additional 4 to 7 months of isoniazid and rifampin. Ethambutol frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines for detailed information (ATS/CDC/IDSA [Nahid 2016])
ATS/CDC/IDSA Recommendations (ATS/CDC/IDSA [Nahid 2016]):
Once daily or 5-times-weekly (DOT):
Infants, Children, and Adolescents <15 years, weighing <40 kg: Oral: 20 mg/kg/dose once daily or 5-times-weekly DOT, suggested range: 15 to 25 mg/kg/dose
Children and Adolescents <15 years weighing ≥40 kg or Adolescents ≥15 years: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established): Oral: Weight-band dosing for whole tablets:
40 to 55 kg: 800 mg (14.5 to 20 mg/kg/dose) once daily or 5-times-weekly (DOT)
56 to 75 kg: 1,200 mg (16 to 21.4 mg/kg/dose) once daily or 5-times-weekly (DOT)
76 to 90 kg: 1,600 mg (17.8 to 21.1 mg/kg/dose) once daily or 5-times-weekly (DOT)
Three-times-weekly DOT: Note: Although suggested dosing based on experience with twice-weekly regimen; experts suggest 3-times-weekly regimens are more effective than twice weekly DOT regimens; ethambutol-containing 3-times-weekly DOT may be used as part of an intensive phase; consult guidelines for specific information
Infants, Children, and Adolescents, weighing <40 kg: Oral: 50 mg/kg/dose 3-times-weekly
Children and Adolescents weighing ≥40 kg: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established); Oral: Weight-band dosing for whole tablets:
40 to 55 kg: 1,200 mg (21.8 to 30 mg/kg/dose) 3-times-weekly
56 to 75 kg: 2,000 mg (26.7 to 35.7 mg/kg/dose) 3-times-weekly
76 to 90 kg: 2,400 mg (26.7 to 31.6 mg/kg/dose) 3-times-weekly
Twice weekly DOT: Note: Regimen not generally recommended; do not use in HIV patients or those with smear-positive and/or cavitary disease. This therapy should only be used following completion of a 2-week intensive phase once daily (or 5-times-weekly) regimen. Missed doses result in the equivalent of once-weekly dosing which has been shown to be inferior and is associated with treatment failure, relapse, and development of drug resistance.
Infants, Children, and Adolescents <15 years, weighing <40 kg: Oral: 50 mg/kg/dose twice weekly
Children and Adolescents <15 years weighing ≥40 kg or Adolescents ≥15 years: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established); Oral: Weight-band dosing for whole tablets:
40 to 55 kg: 2,000 mg (36.4 to 50 mg/kg/dose) twice weekly
56 to 75 kg: 2,800 mg (37.3 to 50 mg/kg/dose) twice weekly
76 to 90 kg: 4,000 mg (44.4 to 52.6 mg/kg/dose) twice weekly
Mycobacterium avium complex (MAC) in HIV-exposed/-infected:
Treatment:
Infants and Children: Oral: 15 to 25 mg/kg/dose once daily; maximum dose: 2,500 mg/dose; in combination with clarithromycin (or azithromycin); for severe disease add rifabutin (HHS [pediatric OI 2016])
Adolescents: Oral: 15 mg/kg/dose once daily in combination with clarithromycin (or azithromycin) (HHS [adult OI 2016])
Chronic suppressive therapy : Infants and Children: Oral: 15 to 25 mg/kg/dose once daily; maximum dose: 2,500 mg/dose with clarithromycin (or azithromycin) with or without rifabutin (HHS [pediatric OI 2016])
Nontuberculous mycobacterial infection (eg, m. kansasii): Limited data available: Infants, Children, and Adolescents: 15 to 25 mg/kg/dose once daily; maximum dose: 2,500 mg/dose (Bradley 2016; Red Book [AAP 2015])
There are no dosage recommendations specific for pediatric patients; ethambutol is primarily renally excreted; monitor serum levels to determine adjustments; experience in adult patients suggests dosing adjustment necessary.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Myambutol: 400 mg [scored]
Generic: 100 mg, 400 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Etibi: 100 mg, 400 mg [contains corn starch, fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Oral: Administer with or without food.
Oral: Administer with or without food; if GI upset occurs, administer with food. Tablet may be pulverized and mixed with apple juice or apple sauce. Do not mix with other juices or syrups since they do not mask ethambutol's bitter taste or are not stable. Administer ethambutol at least 4 hours before aluminum hydroxide.
Tuberculosis: Treatment of pulmonary tuberculosis in combination with other antituberculosis agents.
Mycobacterium avium complex disease
Myambutol may be confused with Nembutal
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.
Cardiovascular: Myocarditis, pericarditis
Central nervous system: Confusion, disorientation, dizziness, hallucination, headache, malaise, peripheral neuritis
Dermatologic: Dermatitis, erythema multiforme, exfoliative dermatitis, pruritus, skin rash
Endocrine & metabolic: Acute gout attack, hyperuricemia
Gastrointestinal: Abdominal pain, anorexia, gastric distress, nausea, vomiting
Hematologic & oncologic: Eosinophilia, leukopenia, lymphadenopathy, neutropenia, thrombocytopenia
Hepatic: Abnormal hepatic function tests, hepatitis, hepatotoxicity (possibly related to concurrent therapy)
Hypersensitivity: Anaphylaxis, anaphylactoid reaction, hypersensitivity reaction (syndrome includes cutaneous reactions, eosinophilia, and organ-specific inflammation)
Neuromuscular & skeletal: Arthralgia
Ophthalmic: Color blindness, decreased visual acuity, optic neuritis, scotoma, visual disturbance (usually reversible with discontinuation; irreversible blindness has been described)
Renal: Nephritis
Respiratory: Pneumonitis, pulmonary infiltrates (with or without eosinophilia)
Miscellaneous: Fever
Hypersensitivity to ethambutol or any component of the formulation; optic neuritis (risk vs benefit decision); use in young children, unconscious patients, or any other patient who may be unable to discern and report visual changes.
Concerns related to adverse effects:
• Hepatic toxicity: Has been reported, possibly due to concurrent therapy.
• Optic neuritis: May cause optic neuritis (unilateral or bilateral), resulting in decreased visual acuity or other vision changes. Discontinue promptly in patients with changes in vision, color blindness, or visual defects (effects normally reversible, but reversal may require up to a year). Irreversible blindness has been reported.
Disease-related concerns:
• Ocular disease: Evaluation of visual acuity changes may be more difficult in patients with cataracts, optic neuritis, diabetic retinopathy, and inflammatory conditions of the eye; consideration should be given to whether or not visual changes are related to disease progression or effects of therapy.
• Renal impairment: Use with caution in patients with renal impairment; dosage modification recommended.
Special populations:
• Pediatric: Use only in children whose visual acuity can accurately be determined and monitored (not recommended for use in children <13 years of age unless the benefit outweighs the risk).
Substrate of OCT1, OCT2
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aluminum Hydroxide: May decrease the serum concentration of Ethambutol. Management: Avoid concurrent administration of ethambutol and aluminum hydroxide. If coadministration cannot be avoided administer ethambutol first and then wait at least 4 hours before administering aluminum hydroxide-containing products. Risk D: Consider therapy modification
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Immune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Evaluate pregnancy status prior to treatment of multidrug-resistant tuberculosis in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment for multidrug-resistant tuberculosis (Esmail 2018).
Ethambutol crosses the placenta (Shneerson 1979).
In 1 case report, ethambutol placental concentrations were similar to those in the maternal plasma. Ethambutol was also present in the cord blood and amniotic fluid (Shneerson 1979).
Ophthalmic abnormalities have been reported in infants born to patients receiving ethambutol as a component of antituberculosis therapy. Active tuberculosis infection is also associated with adverse fetal outcomes including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020) as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020).
Due to the risks of untreated tuberculosis, ethambutol is recommended as part of the initial treatment regimen of drug-susceptible active tuberculosis when the probability of maternal disease is moderate to high (ATS/CDC/IDSA [Nahid 2016]).
Ethambutol may also be used to treat multidrug-resistant tuberculosis. The treatment of multidrug-resistant tuberculosis in patients who are pregnant should be individualized; evidence to support a specific regimen is not available (ATS/CDC/ERS/IDSA [Nahid 2019]; WHO 2020).
Pregnancy-induced physiologic changes do not alter the pharmacokinetic properties of ethambutol in a clinically significant way; dose adjustment is not needed in patients who are pregnant (Abdelwahab 2020).
Ethambutol is present in breast milk.
The manufacturer suggests use during breastfeeding only if benefits to the mother outweigh the possible risk to the infant. Breastfeeding is not a contraindication during therapy for drug-susceptible tuberculosis in patients deemed noninfectious who are treated with first-line agents (ie, ethambutol). Exposure to ethambutol via breast milk should not be considered effective treatment for the breastfed infant (ATS/CDC/IDSA [Nahid 2016]). Breastfed infants should be monitored for jaundice (WHO 2002). Patients with multidrug-resistant tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible (Esmail 2018).
Baseline and periodic (monthly) visual testing (Snellen test) and color discrimination tests (each eye individually, as well as both eyes tested together) in patients receiving >15 mg/kg/day; baseline and periodic renal, hepatic, and hematopoietic tests; ethambutol serum concentrations (when clinically indicated).
Ethambutol serum concentrations:
Note: Obtain samples at 2- and 6-hours post dose to detect delayed absorption or malabsorption; in patients on concomitant rifabutin or clarithromycin, 3- and 7-hour postdose samples may be preferred (Alsultan 2014).
If the usual recommended dose is 15 to 25 mg/kg once daily: target Cmax 2 to 6 mcg/mL (Alsultan 2014).
If the usual recommended dose is 50 mg/kg twice weekly: target Cmax 4 to 12 mcg/mL (Alsultan 2014).
Inhibits arabinosyl transferase resulting in impaired mycobacterial cell wall synthesis
Absorption: ~80%
Distribution: Widely throughout body; concentrated in kidneys, lungs, saliva, and red blood cells
CSF:blood level ratio: Normal meninges: 0%; Inflamed meninges: 25%
Protein binding: 20% to 30%
Metabolism: Hepatic (20%) to inactive metabolite
Half-life elimination: 2.5 to 3.6 hours; End-stage renal disease: 7 to 15 hours
Time to peak, serum: 2 to 4 hours
Excretion: Urine (~50% as unchanged drug, 8% to 15% as metabolites); feces (~20% as unchanged drug)
Tablets (Ethambutol HCl Oral)
100 mg (per each): $0.46 - $0.59
400 mg (per each): $0.72 - $1.79
Tablets (Myambutol Oral)
400 mg (per each): $0.98
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