Ethambutol

Patient administered digitoxin (0.1 mg/day orally) while taking ethambutol (20-25 mg/kg/day) had markedly decreased serum levels of digitoxin compared to controls (16.6 versus 35 ng/mL). Binding of digitoxin by blood proteins was same in both groups. Its metabolism was probably increased.

Concurrent administration of ethambutol with other neurotoxic medications may increase the potential for neurotoxicity, such as optic and peripheral neuritis.

Aluminum salts may delay and reduce the absorption of ethambutol.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of ethambutol was evaluated in ten healthy volunteers. The subjects received a single oral administration of 1200 mg ethambutol on days 1 and 10 and a single daily oral dose of 300 mg rifabutin from days 3 to 9. No statistically significant difference was found in plasma pharmacokinetics (C(max), t(max), AUC, half-life and MRT) and in the renal clearance, whereas a significant decrease in the amount of unchanged ethambutol excreted in urine was observed. The decrease observed in ethambutol urinary excretion may be accounted for by taking into consideration the variability of the urinary excretion of ethambutol reported in the literature. However, a slight, likely not clinically relevant, induction or activation of kidney alcohol and/or aldehyde dehydrogenase isoenzymes by rifabutin cannot be ruled out at present. Evidence exists in the present study for autoinduction of rifabutin metabolism; this is shown by the lower plasma concentrations obtained 24 hr after the seventh dose as compared to the theoretical concentrations.

Because ethambutol is almost always used in combination with isoniazid, rifampin or other antituberculosis agents, the frequency of serum aminotransferase elevations attributable to ethambutol alone cannot be estimated with any confidence. The addition of ethambutol to isoniazid, rifampin or pyrazinamide does not appear to increase the rate of transient ALT elevations during therapy. In addition, ethambutol is a rare cause of acute, symptomatic liver injury. Despite 50 years of use, ethambutol has been linked to clinically apparent liver injury in only a few case reports. In the best described instance (Case 1), the onset of symptoms was 2 months after starting combination antituberculosis therapy and, in contrast to liver injury due to isoniazid or pyrazinamide, the pattern of serum enzymes was distinctly cholestatic. The recurrence of liver injury upon rechallenge with ethambutol but not isoniazid made the attribution convincing. Other case reports have described liver injury occurring in the context of DRESS syndrome, arising within 2 to 6 weeks of starting antituberculosis therapy with fever, rash, eosinophilia and other organ involvement such as liver, kidney and lung. Several published instances have described recurrence of injury after rechallenge with ethambutol.

IDENTIFICATION: Ethambutol is used to treat tuberculosis. Ethambutol is an odorless crystalline hygroscopic powder. It is soluble in water, alcohol, chloroform, methyl alcohol, and very slightly soluble in ether. HUMAN EXPOSURE: Summary: Main risks and target organs: During chronic treatment ethambutol may produce visual and neurological disturbances, allergic reactions, gastrointestinal symptoms, psychiatric symptoms and transient impairment of liver function. This last event has a very low incidence. Increased serum uric acid levels and acute gouty arthritis have been reported. Summary of clinical effects: Acute overdosage may cause gastrointestinal symptoms, hallucinations and optic neuritis. Acute overdosage symptoms include nausea, abdominal pain, fever, mental confusion, visual hallucinations, and optic neuropathy (retrobulbar neuritis) with doses over 10 g. The effects of overdosage are not well established. During chronic treatment the following have been reported: Visual disturbances: Ethambutol may produce a reduction of visual acuity which appear to be due to optic neuritis. Central scotoma and green-red colour blindness may also occur. Allergic reactions: Rash, anaphylactoid reactions, dermatitis and pruritus. Gastrointestinal symptoms: Abdominal pain, anorexia, nausea, vomiting. Neurological disturbances and psychiatric symptoms: Headache, peripheral neuritis, dizziness, mental confusion, disorientation and hallucinations. Other side effects: Jaundice, transient impairment of liver function, fever, increase of serum uric acid levels, joint pain, acute gouty arthritis, malaise. Ethambutol may diffuse into milk. Ethambutol is a synthetic oral antibiotic derivative of ethylenediamine. Contraindications: Ethambutol hydrochloride is contraindicated in patients who are known to be hypersensitive to this drug. Renal impairment, old age and optic neuritis are relative contraindications. Routes of entry: Oral: Ethambutol is only available for oral use. Absorption by route of exposure: About 80% of an oral dose of ethambutol is absorbed from the gastro-intestinal tract, and the remainder appears in the feces unchanged. Absorption is not significantly impaired by food. Distribution by route of exposure: Ethambutol diffuses readily into red blood cells and into the cerebrospinal fluid when the meninges are inflamed. The concentration in erythrocytes at steady state is approximately twice the plasma concentration. It has been reported to cross the placenta and is excreted in breast milk. Biological half-life by route of exposure: The serum half-life in therapeutic doses is 3 hours, increasing in renal failure, as 80% is excreted renally. Metabolism: The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. Elimination by route of exposure: During the 24 hour period following oral administration of ethambutol, approximately 50% of the initial dose is excreted unchanged in the urine, while an additional 8% to 15% appears in the form of metabolites. From 20 to 22% of the initial dose is excreted in the feces as unchanged drug. Mode of action: Toxicodynamics: The underlying cause of visual alterations appears to be a disturbance of metabolism due to depletion of copper and zinc which serve as prosthetic groups for many enzymes. The eye normally contains a considerable store of zinc. Much of the zinc is in the pigmented cells of the outer zone of the retina, where it serves as a metal prosthetic group for retinol (alcohol) dehydrogenase. Pharmacodynamics: Ethambutol is an oral chemotherapeutic agent which is specifically effective against actively growing microorganisms of the genus Mycobacterium, including M. tuberculosis. Ethambutol is bacteriostatic and appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated. Ethambutol has been shown to be effective against strains of mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Ethambutol is also active against some atypical mycobacteria including M. kansasii. Primary resistance to ethambutol is uncommon in developed countries but resistant strains of M. tuberculosis are readily produced if the drug is used alone. Human data: Adults: Subclinical impairment of colour discrimination was reported to be relatively common in patients receiving ethambutol daily as part of antituberculous chemotherapy when compared with 50 patients receiving other antituberculous agents. Peripheral neuropathy has been reported in tubercular patients who had received ethambutol among other drugs. Interactions: Results of a crossover study involving 13 tuberculous patients suggest that concomitant administration of aluminium hydroxide may delay and reduce absorption of ethambutol in some patients. Untoward effects may be enhanced when ethambutol is combined with isoniazid or rifampicin. Main adverse effects: Ethambutol may produce decreased visual acuity which appear to be due to optic neuritis and to be related to dose and duration of treatment. The effects are generally reversible when administration of the drug is discontinued promptly. Ethambutol may produce constriction of visual field, central and peripheral scotoma, and green-red color blindness which may be associated with retrobulbar neuritis. Renal clearance of urate may be reduced in about 50% of patients receiving ethambutol and acute gout has been precipitated in patients with gout or impaired renal function. Cholestatic jaundice has been reported. ANIMAL/PLANT STUDIES: Relevant animal data: Toxicological studies in dogs on high prolonged doses, produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of the eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These correlated with specific serum levels of ethambutol hydrochloride and with definite neuro-anatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period.

/HUMAN EXPOSURE STUDIES/ The aim of the present study was to describe the side effects related to combined Pyrazinamide (PZA) and ethambutol (EMB) treatment given for LTBI, in contacts previously exposed to MDR-TB. In total, 12 consecutive contacts, all of African origin and aged 38+/-5 yrs, were treated with daily PZA (23+/-4 mg.kg(-1)) and EMB (17+/-4 mg.kg(-1)) at Geneva University Hospital outpatient clinic (Switzerland), as a result of contact-tracing procedures for two patients with contagious MDR-TB. Clinical status and liver function tests (aspartate aminotransferase (ALAT) and alanine aminotransferase (ASAT)) were monitored monthly. In seven cases (58%) treatment was discontinued after a median of 119 days, due to hepatic toxicity in six cases (ALAT or ASAT elevation more than four times the upper normal limit), and gastrointestinal symptoms in one case.

/HUMAN EXPOSURE STUDIES/ Seventy patients with pulmonary tuberculosis and 12 healthy controls were included in a study to observe the effect of ethambutol on serum uric acid level. In ethambutol-treated cases a statistically significant increase in mean serum uric acid levels was observed in the second, third and fourth week of treatment. This increase was independent of dosage of ethambutol. However, 22 of the 52 (42%) ethambutol-treated cases showed no increase. ... Hyperuricemia due to ethambutol was reversed with probenecid but not by salicylates. No patient developed acute gouty arthritis although two developed arthralgia.

/EPIDEMIOLOGY STUDIES/ A retrospective observational case series from a single neuro-ophthalmology practice. 8 patients with a history of ethambutol-induced optic neuropathy were examined within 3 months after stopping ethambutol treatment. All patients underwent a neuro-ophthalmologic examination, including visual acuity, color vision, visual fields and funduscopy. Optical coherence tomography (OCT) was performed on both eyes of each patient using the retinal nerve fibre layer analysis protocol. The interval between cessation of ethambutol treatment and the initial visit ranged from 1 week to 3 months. All patients had visual deficits characteristic of ethambutol-induced optic neuropathy at their initial visit, and the follow-up examination was performed within 12 months. Compared with the initial retinal nerve fibre layer thickness (RNFLT), there was a statistically significant decrease in the mean RNFLT of the temporal, superior and nasal quadrants (p = 0.009, 0.019 and 0.025, respectively), with the greatest decrease in the temporal quadrant (mean decrease 26.5 mum). A decrease in RNFLT is observed in all quadrants in patients with ethambutol-induced optic neuropathy who have recently discontinued the medication. This decrease is most pronounced in the temporal quadrant of the optic disc.

/HUMAN EXPOSURE STUDIES/ From January 1984-December 1987, 1783 patients received combination therapy of isoniazid, rifampin, and ethambutol for the control of tuberculosis. Forty-two developed symptomatic hepatitis during the period of treatment. Fifteen were hepatitis B virus carriers, and the remaining 27 were noncarriers. The peak serum transaminase and bilirubin levels were higher in carriers. Seven carriers died of fulminant or subacute hepatic failure, and only 1 noncarrier died. Eleven carriers had detectable serum hepatitis B virus deoxyribonucleic acid during the acute stage of hepatitis.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

ethambutol

Myambutol

Antimycobacterials

8

most-DILI-concern

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Intramuscular administration of 25 & 250 mg ethambutol-2HCl/kg to rats & cocks produced alterations of seminiferous epithelium with consequent blocking of spermatogenesis in both animals at 250 mg.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in mice given high doses have shown that ethambutol causes a low incidence of cleft palate, exencephaly, and vertebral column abnormalities. In addition, studies in rats given high doses have shown that ethambutol causes minor abnormalities of the cervical vertebrae. Studies in rabbits given high doses have shown that ethambutol may cause monophthalmia, limb reduction defects, hare lip, and cleft palate.

While data specific to ethambutol were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antibacterial agents/

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. ... /Antibacterial agents/

Enhanced elimination: Most antibiotics are excreted unchanged in the urine, so maintenance of adequate urine flow is important. The role of forced diuresis in unclear. Hemodialysis is not usually indicated, except perhaps in patients with renal dysfunction and a high level of a toxic agent. /Antibacterial agents/

LD50 Mouse oral 2800 mg/kg /Mixture with isoniazid methane sulfonate/

LD50 Mouse ip 2210 mg/kg /Mixture with isoniazid methane sulfonate/