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Ethambutol

Pronunciation

Pronunciation

(e THAM byoo tole)

Index Terms

  • Ethambutol HCl
  • Ethambutol Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as hydrochloride:

Myambutol: 100 mg

Myambutol: 400 mg [scored]

Generic: 100 mg, 400 mg

Brand Names: U.S.

  • Myambutol

Pharmacologic Category

  • Antitubercular Agent

Pharmacology

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%

Metabolism

Hepatic (20%) to inactive metabolite

Excretion

Urine (~50% as unchanged drug, 8% to 15% as metabolites); feces (~20% as unchanged drug)

Time to Peak

Serum: 2-4 hours

Half-Life Elimination

2.5-3.6 hours; End-stage renal disease: 7-15 hours

Protein Binding

20% to 30%

Use: Labeled Indications

Treatment of pulmonary tuberculosis in conjunction with other antituberculosis agents

Off Label Uses

Mycobacterium avium complex disease

Based on the Department of Health and Human Services (HHS) Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, ethambutol, in combination with other appropriate antimycobacterial drugs, is effective and recommended for the treatment and chronic maintenance therapy (secondary prophylaxis) of disseminated MAC disease in HIV-infected patients.

Based on the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) Guideline for the Diagnosis, Treatment, and Prevention of Nontuberculosis Mycobacterial Disease, ethambutol, in combination with other appropriate antimycobacterial drugs, is effective and recommended for the treatment of MAC pulmonary and/or disseminated disease.

Nontuberculous mycobacterial disease (M. kansasii)

Data from a small prospective, single-arm study and a larger retrospective study support the use of ethambutol, in combination with clarithromycin and rifampin, in the treatment of susceptible Mycobacterium kansasii pulmonary disease [Shitrit 2006], [Griffith 2003]. Additional trials may be necessary to further define the role of ethambutol in this condition.

Based on the ATS/IDSA Guideline for the Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases ethambutol, in combination with rifampin and isoniazid, is effective and recommended for the treatment of susceptible M. kansasii pulmonary disease

Tuberculous meningitis (drug-susceptible)

Based on the American Thoracic Society (ATS)/Centers for Disease Control and Prevention (CDC)/Infectious Disease Society of America (IDSA) Treatment of Drug-Susceptible Tuberculosis guidelines, ethambutol, in combination with other antitubercular drugs, is effective and recommended for initial treatment of tuberculous meningitis.

Contraindications

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

Dosing: Adult

Tuberculosis, pulmonary (drug-susceptible): Oral: Note: Always administer in combination with other antitubercular drugs.

ATS/CDC/IDSA drug-susceptible tuberculosis guideline recommendations (Nahid 2016):

Dosing: 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):

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 (Nahid 2016).

40 to 55 kg: 800 mg (14.5 to 20 mg/kg)

56 to 75 kg: 1,200 mg (16 to 21.4 mg/kg)

76 to 90 kg: 1,600 mg (17.8 to 21.1 mg/kg)

Three-times-weekly DOT:

40 to 55 kg: 1,200 mg (21.8 to 30 mg/kg)

56 to 75 kg: 2,000 mg (26.7 to 35.7 mg/kg)

76 to 90 kg: 2,400 mg (26.7 to 31.6 mg/kg)

Twice-weekly DOT:

40 to 55 kg: 2,000 mg (36.4 to 50 mg/kg)

56 to 75 kg: 2,800 mg (37.3 to 50 mg/kg)

76 to 90 kg: 4,000 mg (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-sensitive TB guidelines (Nahid 2016).

Tuberculous meningitis (drug-susceptible) (off-label use): See Tuberculosis, pulmonary for ethambutol dose; use ethambutol as part of a 4-drug initial phase for 2 months; a 2-drug regimen (does not include ethambutol) is continued for an additional 7 to 10 months (optimal duration not defined). Adjunctive corticosteroid therapy (eg, dexamethasone, prednisolone) tapered over 6 to 8 weeks is also recommended.

Mycobacterium avium complex (MAC) disease (off-label use): Oral:

Nodular/bronchiectatic disease: 25 mg/kg 3 times weekly in combination with a 3-times-weekly regimen of a macrolide (azithromycin or clarithromycin) and rifampin; continue treatment until patient is culture negative on therapy for 1 year. Note: Not recommended for severe or previously treated pulmonary disease (ATS/IDSA [Griffith 2007]).

Severe nodular/bronchiectatic or fibrocavitary disease: 15 mg/kg once daily in combination with daily macrolide (azithromycin or clarithromycin) and rifamycin (rifampin or rifabutin) therapy; continue treatment until patient is culture negative on therapy for 1 year. May also consider addition of 3 times weekly amikacin or streptomycin early in therapy. (ATS/IDSA [Griffith 2007]).

Disseminated disease in HIV-infected patients, treatment and chronic maintenance therapy: 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 MAC disease, and has sustained (>6 months) CD4 count >100 cells/mm3 in response to ART. Note: Addition of a third or fourth drug should be considered for patients with advanced immunosuppression, high mycobacterial loads, or in the absence of effective ART (HHS [OI Adult 2017]).

Nontuberculous mycobacterial disease (M. kansasii) (off-label use): Oral: 15 mg/kg/day in combination with rifampin and isoniazid or clarithromycin for a duration to include 12 months of culture-negative sputum (ATS/IDSA [Griffith 2007]; Shitrit 2006).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Mycobacterium avium (MAC), secondary prophylaxis or treatment: HIV-exposed/-infected (off-label use): Oral: Infants and Children: 15 to 25 mg/kg/day once daily (maximum: 2.5 g/day) with clarithromycin (or azithromycin) with or without rifabutin (CDC, 2009)

Tuberculosis, pulmonary (drug-susceptible) (excludes meningitis): Oral: Note: Always administer in combination with other antitubercular drugs.

ATS/CDC/IDSA Drug-susceptible tuberculosis guideline recommendations (Nahid 2016):

Dosing:

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.

Infants, Children, and Adolescents <15 years and ≤40 kg: 15 to 25 mg/kg/dose once daily

Children and Adolescents <15 years and >40 kg and Adolescents ≥15 years: Refer to adult dosing.

Three-times-weekly DOT: Note: Although suggested dosing based on experience with twice-weekly regimen; experts suggest three-times-weekly regimens are more effective than twice-weekly DOT regimens; consult guidelines for specific information.

Infants, Children, and Adolescents <15 years, weighing ≤40 kg: 50 mg/kg/dose administered 3 times weekly.

Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Refer to adult dosing.

Regimens: Refer to adult dosing. Note: As an approach to avoid ethambutol associated ocular toxicity, some clinicians use a 3-drug regimen of isoniazid, rifampin, and pyrazinamide in the initial 2 months of treatment for children who are HIV-uninfected, do not have a history of TB treatment, are living in an area of low prevalence of drug-resistant TB, and have not had exposure to individuals who are from an area of high prevalence of drug-resistant TB; however, the AAP and most experts do include ethambutol as part of the intensive-phase regimen for treatment of TB.

Dosing: Renal Impairment

Manufacturer's labeling: Reduce dosing as determined by serum levels (specific dosing adjustments not provided); primarily renally excreted.

Alternate recommendations:

Treatment of drug-susceptible TB (Nahid 2016): Adults:

CrCl <30 mL/minute: 20 to 25 mg/kg/dose 3 times weekly (do not administer daily dosing)

Hemodialysis: 20 to 25 mg/kg/dose 3 times weekly (do not administer daily dosing); administer after dialysis if given on a dialysis day.

Aronoff 2007:

CrCl 10 to 50 mL/minute: Administer every 24 to 36 hours

CrCl <10 mL/minute: Administer every 48 hours

Hemodialysis: Slightly dialyzable (5% to 20%); Administer dose postdialysis

Peritoneal dialysis: Dose for CrCl <10 mL/minute: Administer every 48 hours

Continuous arteriovenous or venovenous hemofiltration: Dose for CrCl 10 to 50 mL/minute: Administer every 24 to 36 hours

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Dietary Considerations

May be taken with food as absorption is not affected, may cause gastric irritation.

Storage

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F).

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Ethambutol. Consider therapy modification

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. 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. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Adverse Reactions

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

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic toxicity: Has been reported, possibly due to concurrent therapy. Monitor liver function prior to and during treatment.

• 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. Monitor visual acuity prior to and during therapy.

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. Monitor renal function prior to and during treatment.

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).

Monitoring Parameters

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Ophthalmic abnormalities have been reported in infants born to women receiving ethambutol as a component of antituberculous therapy. Due to the risk of untreated tuberculosis to the mother and fetus, treatment is recommended when the probability of maternal disease is moderate to high. Ethambutol is one of the recommended agents to treat tuberculosis in pregnant women (Nahid 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, lack of appetite, loss of strength or energy, dizziness, headache, or abdominal pain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), pharyngitis, chills, confusion, hallucinations, joint pain, joint edema, numbness or tingling of hands or feet, bruising, bleeding, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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