Ethambutol (Myambutol) is a bacteriostatic drug that is used in combination with other medications to treat tuberculosis.

• Indications of Ethambutol:

  • Treatment of pulmonary tuberculosis in addition to other anti-tuberculosis ( ATT) drugs.

• Off Label Use of Ethambutol in Adults:

  • Mycobacterium avium complex disease
  • Nontuberculous mycobacterial disease (M. kansasii)
  • Tuberculous meningitis (drug-susceptible)

Ethambutol Dose in Adults

Ethambutol treatment dosage of Drug-susceptible pulmonary Tuberculosis:

Note: It should always be prescribed in combination with other anti-tuberculous drugs.

• ATS/CDC/ IDSA drug-susceptible tuberculosis guideline recommendations:

  • Dosing: The dose depends 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 recommended frequency of administration is once day, while another option is directly observed therapy (DOT) administered five days per week.

      • 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)

    • Treatment regimen:

      • It comprises  of an initial 8 weeks  phase of a quadruple regime including ethambutol, followed by a continuation phase of a 2-drug regimen (does not include ethambutol) of an additional 4 to 7 months
      • Ethambutol dosage and frequency vary depending on the type of treatment plan being used; refer to the most recent drug-sensitive TB guidelines.

Ethambutol treatment dosage of Drug-susceptible Tuberculous meningitis:

• Ethambutol is used as part of a quadruple regime initially for 2 months;
• a 2-drug regimen (excluding ethambutol) is continued for an additional 7 to 10 months (optimal duration not defined).
• It's also advised to use adjunctive corticosteroid therapy, tapered over 6 to 8 weeks using drugs like dexamethasone and prednisolone.

Ethambutol treatment dosage of Mycobacterium avium complex (MAC) disease (off-label):

• Nodular/ bronchiectatic disease:

  • The oral dosage of 25 mg/kg three times a week together with a three-times-a-week regimen of rifampin and a macrolide (azithromycin or clarithromycin).
  • After receiving therapy for a full year, the patient should still receive treatment.
  • Note: Not recommended for severe or previously treated pulmonary disease.

• Severe nodular/ bronchiectatic or fibrocavitary disease:

  • In addition to daily macrolide (azithromycin or clarithromycin) and rifamycin (rifampin or rifabutin) therapy, the oral dose is 15 mg/kg once every 24 hours.
  • The patient should stay on therapy until they have been culture-negative for 12 months.
  • During the initial phase, it may be advised to add amikacin or streptomycin three times per week.

• For the treatment and chronic maintenance therapy of Disseminated disease in HIV-infected patients:

  • The dosage is combined with a macrolide at 15 mg/kg orally every 24 hours (azithromycin or clarithromycin).
  • After 12 months of therapy, or if the patient is asymptomatic and has maintained (>6 months) a CD4 cell count >100 cells/mm3 in response to ART, treatment may be discontinued.
  • Note: In case of immunosuppression/high bacterial load/absence of effective ART, the addition of a third or fourth drug should be recommended.

Ethambutol treatment dosage of Non-tuberculous mycobacterial disease (M. kansasii) (off-label):

• The dosage is 15 mg/kg orally every 24 hours along with rifampin, isoniazid, or clarithromycin for a time frame that includes a year of sputum that has not undergone a culture.

Ethambutol Dose in Children

Ethambutol treatment dosage of active Tuberculosis (excluding meningitis):

Note: Recommendations are based on epidemiology (resistance) and new information, so CDC and WHO consultation is required. The use of many medications is advised. Any regimen using a dose less than once daily is advised to use directly observed treatment (DOT). A quadruple regimen's initial 8-week intense phase is followed by an additional 4–7 months of isoniazid and rifampin as part of the treatment plan for pulmonary tuberculosis. Ethambutol dosage and frequency vary depending on the type of treatment regimen chosen; for more information, refer to the most recent drug-sensitive TB guidelines.

• ATS/CDC/IDSA Recommendations:

  • Once-daily or 5-times-weekly (Directly observed therapy):

    • Infants/Children/ Adolescents <15 years, weighing <40 kg:

      • Oral dose of 20 mg/kg once every 24 hours or 5 times per week directly observed therapy.
      •  suggested range: 15 to 25 mg per kg per dose

    • Children and Adolescents <15 years weighing ≥40 kg or Adolescents ≥15 years:

    • Note: Doses vary according to  lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established):

      • Oral weight-dependent dosing for whole tablets:

      • 40 to 55 kg:

        • 800 mg (14.5 to 20 mg/kg/dose) one time daily or 5-times every week(DOT)

      • 56 to 75 kg:

        • 1,200 mg (16 to 21.4 mg/kg/dose) one time daily or 5-times every week (DOT)

      • 76 to 90 kg:

        • 1,600 mg (17.8 to 21.1 mg/kg/dose) one time daily or 5-times every week (DOT)

    • Three-times per week  directly observed therapy

    • Note: Three-times-per-week regimens are supposedly more efficient than twice-weekly DOT regimens.
      • Ethambutol containing 3-times weekly directly observed therapy can be considered as part of an intensive phase.
      • Consult guidelines for specific information.

      • Infants/Children/Adolescents, weighing <40 kg:

      • Oral dose of 50 mg/kg 3 times every week

      • Children and Adolescents weighing ≥40 kg:

    • Note: Doses vary according to  lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established)

      • Oral: Weight dependent dosing for whole tablets:

        • 40 to 55 kg:

          • 1,200 mg (21.8 to 30 mg/kg/dose) 3-times every week

        • 56 to 75 kg:

          • 2,000 mg (26.7 to 35.7 mg/kg/dose) 3-times every week

        • 76 to 90 kg:

          • 2,400 mg (26.7 to 31.6 mg/kg/dose) 3-times every week

    • Twice weekly directly observed therapy:

      • Note: This regimen is not usually recommended.
      • It is contraindicated in HIV patients or those with smear-positive and/or cavitary disease.
      • This therapy is recommended following completion of a 2-week intensive phase once every 24 hours (or 5 times per week) regimen.
      • Missed doses result in the equivalent of once-weekly dosing which has been shown to be inferior and it can result in treatment failure, relapse, and drug resistance.

        • Infants/Children/Adolescents <15 years, weighing <40 kg:

          • Oral dose of 50 mg/kg twice weekly

        • Children and Adolescents <15 years weighing ≥40 kg or Adolescents ≥15 years:

        • Note: Doses vary according to lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established)

          • Oral: Weight dependent  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

Ethambutol treatment dosage of Mycobacterium avium complex (MAC) in HIV-exposed/positive:

• Treatment:

  • Infants and Children:

    • Oral dose of 15 to 25 mg/kg once every 24 hours in addition to clarithromycin (or azithromycin). For severe disease add rifabutin.
    • The maximum dose is 2,500 mg/dose.

  • Adolescents:

    • Oral dose of 15 mg/kg once every 24 hours in combination with clarithromycin (or azithromycin).

• Chronic suppressive therapy :

  • Infants and Children:

    • Oral dose of 15 to 25 mg per kg one time every 24 hours.
    • maximum dose: 2,500 mg/dose with clarithromycin (or azithromycin) with or without rifabutin.

Ethambutol treatment dosage of Non-tuberculous mycobacterial infection (eg, m. kansasii):

Limited data available:

• Infants, Children, and Adolescents:

  • Oral dose of 15 to 25 mg per kg one time every 24 hours
  • The maximum dose is 2,500 mg/dose.

Pregnancy Risk Factor: C

• Studies on animal reproduction have shown that there are adverse events.
• Ophthalmic abnormalities have been reported in infants of women who received ethambutol as part of anti-tuberculous treatment.
• Treatment is recommended when there is a high probability of developing tuberculosis in the mother or fetus.
• Ethambutol can be safely used in combination therapy for pregnant women.

Use of Ethambutol while breastfeeding

• Breast milk contains Ethambutol.
• Breastfeeding infants with tuberculosis is difficult because of the low concentration of drugs in breast milk.
• Even though newborn exposure is low and does not cause toxicity, some sources suggest monitoring breastfeeding infants for signs such as rash, malaise or nausea.
• Manufacturer recommends breastfeeding only if the benefits to the mother are greater than the potential risk to the infant.
• Breastfeeding women who have not been infected and are being treated with first-line agents (ethambutol) are not considered contraindicated when ethambutol's treatment is used to treat drug-susceptible tuberculosis.

Ethambutol dose in renal impairment:

• As per the Manufacturer's labeling:

  • Dosing is reduced according to serum levels (However, specific dosing adjustments are not provided).
  • It is primarily excreted via the kidneys.

• Alternate dosing for the treatment of drug-susceptible TB:

  • Creatinine clearance less than 30 mL/minute:

    • 20 to 25 mg per kg 3 times per week (daily dosing not recommended).

  • Hemodialysis:

    • 20 to 25 mg/kg/dose 3 times per week (daily dosing not recommended).
    • administer after dialysis if given on a dialysis day.

• Aronoff 2007:

  • Creatinine clearance 10 to 50 mL/minute:

    • Administer every 24 to 36 hours

  • Creatinine clearance <10 mL/minute:

    • Administer every 48 hours

  • Hemodialysis:

    • Slightly dialyzable (5% to 20%).
    • Administer dose after dialysis

  • Peritoneal dialysis:

    • Dose for Creatinine clearance <10 mL/minute: Administer every 48 hours

  • Continuous arteriovenous or venovenous hemofiltration:

    • Dose for Creatinine clearance 10 to 50 mL/minute:
      • Administer every 24 to 36 hours

Ethambutol dosage in liver disease:

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

Side effects of ethambutol:

• 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

Contraindications to Ethambutol:

• Hypersensitivity to ethambutol and any component of the formulation
• Take care:
  • Optic neuritis (risk-benefit decision)
  • use in young children,
  • unconsciousness,
  • Patients who are unable to report visual changes.

Warnings and precautions

• Hepatic toxicities

  • It has been mostly reported due to combination therapy.
  • Before and after treatment, monitor liver function.

• Optic neuritis:

  • May result in optic neuritis (unilateral/bilateral), causing decreased visual acuity or other vision changes.
  • The drug should be immediately stopped in the event of any visual changes, color blindness or other visual defects. These effects are usually reversible but may take up to one year.
  • It is possible to experience irreversible blindness.
  • Monitor your visual acuity during and before therapy.

• Ocular disease:

  • Visual acuity evaluations may be more difficult in patients with cataracts or optic neuritis, diabetic retinalopathy, or inflammatory conditions.
  • You should consider whether the visual changes you see are due to disease progression, therapy effects or any other cause.

• Renal impairment

  • Patients with impaired renal function should be cautious.
  • Modifications to dosage would be necessary.
  • Before and after treatment, test your renal function.

Ethambutol: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameter:

• Baseline and monthly visual testing (Snellen test) and color discrimination tests (each eye individually, as well as both eyes tested together) is recommended  in patients receiving doses greater than 15 mg/kg/day.
• Baseline and monthly renal, hepatic, and hematopoietic tests should be carried out.

How to administer Ethambutol?

It is administered with or without food. 

Mechanism of action of Ethambutol:

Ethambutol inhibits arabinosyltransferase, resulting in impaired synthesis mycobacterial cell walls.

Absorption

The success rate of the medication is reportedly 80%. Distribution: The body as a whole has a very even distribution. concentrated in the red blood cells, saliva, liver, and lungs. Blood to CSF ratio: 0% for normal meninges; 25% for inflamed meninges binding of proteins 20–30% Hepatic and inactive metabolites make up 20% of metabolism. Half-life removal 3 to 2.5 hours. 7–15 hours for end-stage renal disease Peak serum concentration should be reached within 2 to 4 hours.

Excretion:

• Urine (50% unchanged drug, 8%- 15% as metabolites), and feces (20% unchanged drug).

Ethambutol Brand Names (International):

• Myambutol
• Etibi
• Ambutol
• Amiobutols
• Arbutol
• Clobutol
• Combutol
• Dexambutol
• E-Butol
• Ebutol
• Ecox
• EMB
• EMB-Fatol
• Etambutol
• Etambutol Northia
• Etambutol Richet
• Etambutol Richmond
• Etapiam
• ETH Ciba 400
• Etham
• Ethambin-PIN
• Ethambutol
• Ethbutol
• Etibi
• Eubotol
• Inbutol
• Interbutol
• Lambutol
• Litamol
• Manzida
• Myambutol
• Mycobac
• Mycobutol
• Oributol
• Purderal
• Riotol
• Servambutol
• Stambutol
• Sural
• Tambutol
• Thamtol
• Thural
• Tibigon
• Tibitol
• Tibutol
• Tobutol
• Winbutol

Ethambutol brands in Pakistan: