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ETHAMBUTOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ethambutol is an antituberculosis agent derived from butanol. It is the congener of N, N(1)-diisopropyl-ethylenediamine and the dextrorotatory isomer of 2,2'-(ethylenediimino)-di-1-butanol dihydrochloride.

Specific Substances

    1) Molecular Formula: C10-H24-N2-O2-2HCl (ethambutol hydrochloride)
    2) CAS 74-55-5 (ethambutol)
    3) CAS 1070-11-7 (ethambutol hydrochloride)

Available Forms Sources

    A) FORMS
    1) Ethambutol is available as 100 mg and 400 mg tablets (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    B) USES
    1) Ethambutol is indicated for the treatment of pulmonary TB in conjunction with at least one other antitubercular agent (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    2) Ethambutol is recommended first-line, in combination with other antimycobacterial drugs, for secondary prophylaxis and treatment of disseminated Mycobacterium avium complex disease in adults and children with HIV (Centers for Disease Control and Prevention et al, 2009; Centers for Disease Control and Prevention et al, 2009a).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ethambutol is indicated for the treatment of pulmonary tuberculosis in conjunction with at least one other antitubercular agent. It is also recommended as first-line, in combination with other antimycobacterial drugs, for secondary prophylaxis and treatment of disseminated Mycobacterium avium complex disease in adults and children with HIV.
    B) PHARMACOLOGY: Ethambutol hydrochloride is an antibacterial agent which specifically targets Mycobacteria tuberculosis. It inhibits the synthesis of metabolites, subsequently impairing cell metabolism and cell multiplication eventually leading to cell death.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, optic neuritis, irreversible blindness, scotoma, color blindness, rash, pruritus, hyperuricemia, thrombocytopenia, leukopenia, neutropenia, hepatotoxicities (including fatalities), hypersensitivity reactions (including anaphylactic/anaphylactoid reaction), joint pain, confusion, malaise, headache, dizziness, disorientation, peripheral neuropathy, numbness and tingling of the extremities, persecutory delusions, auditory and visual hallucinations, pulmonary infiltrates (with or without eosinophilia), and fever.
    E) WITH POISONING/EXPOSURE
    1) Acute overdose effects may include abdominal pain, fever, mental confusion, nausea, visual hallucinations, and optic neuropathy. Reported overdoses often occur with the concomitant use of other anti-tuberculosis agents such as isoniazid or rifampin. Acute overdose involving both ethambutol and isoniazid may result in synergistic neurotoxicity.
    0.2.20) REPRODUCTIVE
    A) Ethambutol is classified as FDA pregnancy category C. Two pregnant patients were treated with ethambutol in therapeutic doses. In one, the child born was normal, in the other the aborted fetus was normal.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, CBC with differential, liver enzymes, and mental status following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    E) Monitor for visual disturbances; optic neuritis and various disturbances in color vision have occurred at high therapeutic doses and after overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Vitamin B 12 has been used with some success to treat optic neuritis. Optic neuritis and visual disturbances have also been treated with prednisolone and hydroxycobalamin for 10 to 28 days. There has been mixed success using these agents.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Thrombocytopenia, leukopenia, and neutropenia have been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress or severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis and peritoneal dialysis may reduce the concentration of ethambutol in the blood.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the treating physician should be cognizant of the possibility of multi-drug involvement.
    I) PHARMACOKINETICS
    1) Tmax: 2 to 4 hours. Absorption: Oral: Approximately 80% absorbed. Protein binding: 6% to 30% protein bound. Vd: 30% of body weight, as 3.89 L/kg (mean steady state), and as 56 L (steady state). Excretion: Renal: About 50% of an oral dose is excreted in the urine unchanged during the first 24 hours. Metabolites make up an additional 8% to 15% during this period. Feces: 20% to 22% of an initial dose. Elimination half-life: Oral dosing: 250 minutes; IV dosing: 150 minutes.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause neurotoxicity, ocular toxicity, or hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: No specific toxic dose has been established. Therapeutic doses of greater than 15 mg/kg/day have been associated with visual disturbances. Some sources report that overdoses of 10 grams or more, acutely, may cause optic neuritis, while other case reports state that over 20 grams have been ingested without visual disturbances.
    B) THERAPEUTIC DOSE: ADULT AND CHILDREN 13-YEAR-OLD AND OLDER: 15 to 25 mg/kg as a single oral dose, administered once every 24 hours (MAX daily dose: 2500 mg).

Clinical Effects

Summary Of Exposure

    A) USES: Ethambutol is indicated for the treatment of pulmonary tuberculosis in conjunction with at least one other antitubercular agent. It is also recommended as first-line, in combination with other antimycobacterial drugs, for secondary prophylaxis and treatment of disseminated Mycobacterium avium complex disease in adults and children with HIV.
    B) PHARMACOLOGY: Ethambutol hydrochloride is an antibacterial agent which specifically targets Mycobacteria tuberculosis. It inhibits the synthesis of metabolites, subsequently impairing cell metabolism and cell multiplication eventually leading to cell death.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, optic neuritis, irreversible blindness, scotoma, color blindness, rash, pruritus, hyperuricemia, thrombocytopenia, leukopenia, neutropenia, hepatotoxicities (including fatalities), hypersensitivity reactions (including anaphylactic/anaphylactoid reaction), joint pain, confusion, malaise, headache, dizziness, disorientation, peripheral neuropathy, numbness and tingling of the extremities, persecutory delusions, auditory and visual hallucinations, pulmonary infiltrates (with or without eosinophilia), and fever.
    E) WITH POISONING/EXPOSURE
    1) Acute overdose effects may include abdominal pain, fever, mental confusion, nausea, visual hallucinations, and optic neuropathy. Reported overdoses often occur with the concomitant use of other anti-tuberculosis agents such as isoniazid or rifampin. Acute overdose involving both ethambutol and isoniazid may result in synergistic neurotoxicity.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: Fever has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    B) WITH POISONING/EXPOSURE
    1) FEVER: Fever has been reported in overdose (Ducobu et al, 1982).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLINDNESS
    a) CASE REPORT: Irreversible blindness has been reported in a patient who was taking ethambutol at a dose of 15 mg/kg for 6 days (Chatterjee et al, 1986).
    2) OPTIC NEURITIS
    a) Optic neuritis is the principle side effect of ethambutol therapy, but usually manifests at doses in excess of 15 mg/kg (Sivakumaran et al, 1998; Mathur & Sankhla, 1976; Boman & Calissendorff, 1974). Patients may develop decreases in visual acuity, including irreversible blindness, scotoma, color blindness, and/or visual defect (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    b) Optic neuritis is usually dose-related and often reversible (Barron et al, 1974; Roberts, 1974; Schild & Fox, 1991). Following chronic ethambutol therapy, optic neuropathy is not always reversible, particularly in the elderly population. Permanent visual disability may result (Tsai & Lee, 1997).
    c) CASE SERIES: In 4 cases of optic neuritis, symptoms developed after 2.5, 7.5, 8, and 12 months after therapy. Three cases had irreversible neuritis with one patient developing permanent visual impairment (Sivakumaran et al, 1998).
    d) CASE SERIES: In 10 consecutive patients with severe ethambutol ocular toxicity, only 5 patients had improvement in visual acuity during a follow-up period of 1 to 3 years. The other 5 patients recovered visual acuity slowly, with improvement noted 4 to 11 months after withdrawal of ethambutol. All patients had received ethambutol doses ranging from 13 to 23 mg/kg/day in addition to isoniazid, rifampin, and vitamin B6 (Tsai & Lee, 1997).
    e) Two types of retrobulbar neuritis have been identified. In one, there is involvement of the central fibers of the optic nerve, blurred vision, and diminished visual acuity, a central scotoma, and difficulty with color vision (reds is seen as pink and green is seen as white or gray). The second and less common type involves the peripheral fibers of the optic nerve and does not result in reduced visual acuity or color vision changes. There is instead a constriction of peripheral visual fields (Chatterjee et al, 1986; Schild & Fox, 1991).
    f) Doses of 35 mg/kg or greater has caused optic neuritis in at least 15% of patients treated with ethambutol (Leibold, 1966; Citron & Thomas, 1986).
    g) OPTIC NEURITIS is often manifest by disturbances of color vision. Changes in color vision along the protan or deuteran axis are among the first changes seen in ethambutol toxicity. The color discrimination changes may be subclinical in many cases (Joubert et al, 1986).
    1) One study showed early changes in blue-yellow perception, with red-green changes or tritanomalous defects occurring as well in later stages of toxicity (Polak et al, 1985).
    h) In a study of 27 patients with ethambutol-induced optic neuropathy, 25 patients had normal electroretinograms despite poor visual acuity. However, only 12 of these patients had normal electro-oculograms in both eyes. Based on these findings, it is suggested that a supranormal electro-oculogram may be indicative of an early toxic state during ethambutol therapy and that ethambutol may cause dysfunction of the retinal pigment epithelium (Yen et al, 2000).
    B) WITH POISONING/EXPOSURE
    1) OPTIC NEURITIS
    a) CASE REPORT: Optic neuritis has been reported in acute overdose of over 10 grams (Ducobu et al, 1982).
    2) VISUAL HALLUCINATIONS
    a) Visual hallucinations may be seen in acute overdose (Ducobu et al, 1982).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Pulmonary infiltrates, with or without eosinophilia, has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    b) CASE REPORT: One study reported ethambutol-induced pneumonitis and eosinophilia in a patient receiving ethambutol, isoniazid, and rifampin for treatment of tuberculosis. Symptoms resolved after discontinuation of the regimen. Reintroduction of isoniazid and rifampin produced no recurrence of lung disease (Takami et al, 1997).
    c) CASE REPORT: Pulmonary infiltrates were reported in a 55-year-old man receiving therapy with isoniazid, rifampin, ethambutol, and pyrazinamide that resolved after discontinuation of ethambutol and recurred upon rechallenge (Chien et al, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Mental confusion has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Mental confusion may occur in acute overdose (Ducobu et al, 1982).
    B) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Peripheral neuropathy was seen in a patient taking 1200 to 1400 mg/day of ethambutol for 22 months. Symptoms included ataxia, and numbness of the legs and later the arms (Nair et al, 1980).
    C) MALAISE
    1) WITH THERAPEUTIC USE
    a) Malaise has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    F) DISORIENTATED
    1) WITH THERAPEUTIC USE
    a) Disorientation has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    G) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Numbness and tingling of the extremities due to peripheral neuritis has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Abdominal pain has been reported in cases of acute overdose (Ducobu et al, 1982).
    B) NAUSEA
    1) WITH POISONING/EXPOSURE
    a) Nausea has been reported in cases of acute overdose (Ducobu et al, 1982).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    D) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    E) GASTROINTESTINAL IRRITATION
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal upset has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicities, including fatalities, have been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    B) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Cholestatic jaundice is a rare side effect of therapy (Gulliford et al, 1986).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    b) CASE REPORT: Thrombocytopenia was reported as a side effect in a 71-year-old woman who was taking 15 mg/kg/day for four days. She was also taking rifampin. When the ethambutol was discontinued, the platelet count gradually increased from 5,000 to 90,000 over the next few days. Tests for macrophage inhibition factor have been positive for ethambutol and negative for isoniazid (Rabinovitz et al, 1982).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia has been reported as an idiosyncratic reaction to ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012; Jenkins et al, 1973).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Various types of dermatitis have been reported with the therapeutic use of ethambutol. This includes rashes and pruritus, hair loss, urticaria, erythema multiforme, hyperhidrosis, skin striae, exfoliative dermatitis, epidermal necrolysis, and lichenoid eruption. The overall incidence of skin reactions is about 0.5%. All reactions except for the general dermatitis and pruritus are rare (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012; Holdiness, 1985; Frentz et al, 1981; Pegram et al, 1981; Holdiness, 1986).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Joint pain has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERURICEMIA
    1) WITH THERAPEUTIC USE
    a) Elevated serum uric acid concentration has been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    b) CASE SERIES: In one case series, 66% of 71 patients taking ethambutol in doses of 20 mg/kg/day reported increased uric acid levels in the first 2 to 3 months of therapy. These patients were also on streptomycin and isoniazid, but a control study using streptomycin and isoniazid did not show increases in uric acid levels (Khanna & Gupta, 1984).
    c) Gouty arthritis has been reported after therapeutic administration of ethambutol (Khanna, 1980; Narang et al, 1983; Khanna & Gupta, 1984).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions, including anaphylactic/anaphylactoid reaction, have been reported in patients taking ethambutol (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Ethambutol is classified as FDA pregnancy category C. Two pregnant patients were treated with ethambutol in therapeutic doses. In one, the child born was normal, in the other the aborted fetus was normal.
    3.20.2) TERATOGENICITY
    A) TERATOGENICITY
    1) High-dose ethambutol therapy resulted in slightly increased fetal mortality in pregnant mice and rabbits (p greater than 0.05) and slightly decreased fertility and litter size in female mice (p greater than 0.05) (Prod Info MYAMBUTOL(R) oral tablets, 2004).
    B) CONGENITAL ANOMALY
    1) High-dose ethambutol therapy resulted in a low incidence of minor cervical vertebra abnormalities (rats), monophthalmia (rabbits), and cleft palate, exencephaly, and vertebral column abnormalities (mice) among offspring (Prod Info MYAMBUTOL(R) oral tablets, 2004).
    2) When tested in animal models, ethambutol produced a number of malformations including cleft palate, anophthalmia, limb deformities, abnormal vertebral column, and exencephaly. However, the rate of occurrence of these abnormalities did not appear to be greater than that of the normal population (Holdiness, 1987).
    C) LACK OF EFFECT
    1) Ethambutol has been given to women during pregnancy without detectable effects on the fetus, but data as to long-term ocular effects is lacking (Brock & Roach, 1981; Wall, 1980; Snider et al, 1980).
    2) Two pregnant patients were treated with ethambutol in therapeutic doses. In one, the child born was normal, in the other the aborted fetus was normal.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) ETHAMBUTOL is classified as FDA pregnancy category C (Prod Info MYAMBUTOL(R) oral tablets, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Breastfed infants could ingest 3.4% to 5.7% of a usual therapeutic dose (15 mg/kg), but the authors suggest that ethambutol can probably be administered safely to mothers desiring to breast feed, with minimal risk to the nursing infant (Snider & Powell, 1984).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, CBC with differential, liver enzymes, and mental status following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    E) Monitor for visual disturbances; optic neuritis and various disturbances in color vision have occurred at high therapeutic doses and after overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, CBC with differential, liver enzymes, and mental status following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    E) Monitor for visual disturbances; optic neuritis and various disturbances in color vision have occurred at high therapeutic doses and after overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Vitamin B 12 has been used with some success to treat optic neuritis. Optic neuritis and visual disturbances have also been treated with prednisolone and hydroxycobalamin for 10 to 28 days. There has been mixed success using these agents.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Thrombocytopenia, leukopenia, and neutropenia have been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs, CBC with differential, liver enzymes, and mental status following significant overdose.
    3) Monitor serum electrolytes in patients with significant vomiting.
    4) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    5) Monitor for visual disturbances; optic neuritis and various disturbances in color vision have occurred at high therapeutic doses and after overdose.
    C) OPTIC NEURITIS
    1) PREDNISOLONE/B12: Chatterjee et al (1986) treated one case with prednisolone 40 mg/day orally and large doses (unspecified) of intramuscular hydroxycobalamin. The patient's vision improved transiently but after 16 days continued to deteriorate (Chatterjee et al, 1986).
    2) B12: Patients with optic neuritis who were treated with parenteral hydroxycobalamin 40 mg/day for 10 to 28 weeks followed by a reduced dose of 20 mg/day had a gradual improvement in visual acuity (Guerra & Casu, 1981).
    D) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    E) MYELOSUPPRESSION
    1) Thrombocytopenia, leukopenia, and neutropenia have been reported (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    3) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis and peritoneal dialysis may reduce the concentration of ethambutol in the blood (JEF Reynolds , 2000).

Abstracts

Case Reports

    A) ADVERSE EFFECTS
    1) Spalding & Buss (1986) reported a mixed ingestion of isoniazid (7.5 grams), rifampicin (15 grams) and ethambutol (20 grams). The ingestion produced life threatening neurological and metabolic symptoms that were similar to the symptoms expected of isoniazid alone. No ocular toxicity or hepatotoxicity were seen (Spalding & Buss, 1986).
    2) Ducobu et al (1982) present data on the intentional overdose of a 40-year-old depressed man who ingested 6 grams isoniazid, 20 grams ethambutol, and 9 grams rifampicin. He was admitted to the hospital 2 hours postingestion. The only complications included mild lactic acidosis and eosinophilia. Since overdose with single agents has been associated with a variety of symptoms, it is possible that complications did not develop due to prompt hemodialysis. Four hours postingestion, a 3 hour hemodialysis session was initiated, and the patient later received 10 grams of pyridoxine within a 12 hour period. Serum was not analyzed for drug concentrations before or after therapy. Confirmation of overdose was based on family history (Ducobu et al, 1982a).

Range Of Toxicity

Summary

    A) TOXICITY: No specific toxic dose has been established. Therapeutic doses of greater than 15 mg/kg/day have been associated with visual disturbances. Some sources report that overdoses of 10 grams or more, acutely, may cause optic neuritis, while other case reports state that over 20 grams have been ingested without visual disturbances.
    B) THERAPEUTIC DOSE: ADULT AND CHILDREN 13-YEAR-OLD AND OLDER: 15 to 25 mg/kg as a single oral dose, administered once every 24 hours (MAX daily dose: 2500 mg).

Therapeutic Dose

    7.2.1) ADULT
    A) TREATMENT-NAIVE PATIENTS
    1) In patients who have never gone through antituberculosis therapy, the normal adult dose is 15 mg/kg (7 mg/lb) of body weight, administered orally once every 24 hours (MAX daily dose: 1500 mg) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    B) TREATMENT-EXPERIENCED PATIENTS
    1) In patients who have gone through antituberculosis therapy, the normal adult dose is 25 mg/kg (11 mg/lb) of body weight, administered orally once every 24 hours (MAX daily dose: 2500 mg) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    2) Concomitantly administer at least 1 other antituberculosis drug to which organisms will be susceptible (based on in vitro tests) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    3) After 60 days of therapy, decrease the dose to 15 mg/kg (7 mg/lb) of body weight, administered orally once every 24 hours (MAX daily dose: 1500 mg) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    7.2.2) PEDIATRIC
    A) TREATMENT-NAIVE PATIENTS
    1) In children 13 years of age and older who have never gone through antituberculosis therapy, the normal dose is 15 mg/kg (7 mg/lb) of body weight, administered orally once every 24 hours (MAX daily dose: 1500 mg) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    B) TREATMENT-EXPERIENCED PATIENTS
    1) In children 13 years of age and older who have gone through antituberculosis therapy, the normal dose is 25 mg/kg (11 mg/lb) of body weight, administered orally once every 24 hours (MAX daily dose: 2500 mg) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    2) Concomitantly administer at least 1 other antituberculosis drug to which organisms will be susceptible (based on in vitro tests) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).
    3) After 60 days of therapy, decrease the dose to 15 mg/kg (7 mg/lb) of body weight, administered orally once every 24 hours (MAX daily dose: 1500 mg) (Prod Info ETHAMBUTOL HYDROCHLORIDE oral film-coated tablets, 2012).

Maximum Tolerated Exposure

    A) ACUTE
    1) Eye defects occurred in 1.6% percent of those patients on 15 mg/kg/day, 2.84 percent of those on 25 mg/kg/day (Roberts, 1974) and in 15% of patients taking 35 mg/kg/day or higher (Leibold, 1966; Citron & Thomas, 1986).
    2) Doses of up to 20 grams have been taken acutely without liver or eye injury being noted (Spalding & Buss, 1986).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ethambutol hydrochloride is an antibacterial agent which specifically targets Mycobacteria tuberculosis. It inhibits the synthesis of metabolites, subsequently impairing cell metabolism and cell multiplication eventually leading to cell death (Prod Info ethambutol HCl oral film coated tablets, 2011).

Toxicologic Mechanism

    A) Toxic optic neuritis may have a direct effect on the retina related to an abnormality in zinc metabolism, in that ethambutol chelates the zinc (Lessell, 1976).
    B) Factors which may increase the potential for ethambutol toxicity include impaired renal function, diabetes, and optic neuritis due to alcohol or tobacco (Murray, 1967). The elderly also seem to be predisposed to ocular toxicity with ethambutol (Fledelius et al, 1987).
    C) Although ethambutol was first synthesized in both the d and l forms, it was found that the slow metabolism of the l forms contributed significantly to the ocular toxicity. Most products now only contain the dextrorotary forms which are less harmful (Chatterjee et al, 1986).

Physicochemical

Physical Characteristics

    A) This compound is white, odorless or nearly odorless, and possesses a bitter taste (JEF Reynolds , 2000).

Molecular Weight

    A) 277.2 (JEF Reynolds , 2000)

References

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