Ethionamide (Systemic)

VA CLASSIFICATION
Primary: AM500

Commonly used brand name(s): Trecator-SC.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antibacterial (antimycobacterial; antileprosy agent)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Tuberculosis (treatment)—Ethionamide is indicated in combination with other antituberculosis medications in the treatment of tuberculosis, including tuberculous meningitis, after failure with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) or when these cannot be used because of toxicity or development of resistant tubercle bacilli. Ethionamide is effective only against mycobacteria. ^{{05} {17}}

[Leprosy (treatment)]—Ethionamide is used in combination with other antileprosy agents in the treatment of Hansen's disease. ^{{09} {16} {18}}

[Mycobacterial infections, atypical (treatment)]—Ethionamide is used in the treatment of atypical mycobacterial infections, such as Mycobacterium avium complex (MAC). ^{{01} {08} {11}}

—Not all species or strains of a particular organism may be susceptible to ethionamide.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    166.24 ^{07}

Mechanism of action/Effect:

Ethionamide's mechanism of action is not known, but it appears to inhibit peptide synthesis. Ethionamide is bacteriostatic against Mycobacterium tuberculosis . ^{{05} {17}}

Absorption:

Rapidly absorbed from the gastrointestinal tract following oral administration. Bioavailability approximately 100%. ^{11}

Distribution:

Widely distributed to most tissues and fluids, including liver, kidneys, and spleen. Concentrations in various organs and cerebrospinal fluid (CSF) are approximately equal to plasma concentrations. Readily crosses the placenta, also. ^{11}

Vol _D=Approximately 2.8 L/kg. ^{11}

Protein binding:

Low (10%).

Biotransformation:

Probably hepatic ^{01}; metabolized to sulfoxide, which is active, and to inactive metabolites.

Half-life:

Approximately 2 to 3 hours. ^{{01} {11}}

Time to peak concentration:

Approximately 1.8 hours. ^{11}

Peak serum concentration:

Approximately 2.2 mcg/mL after a single oral 500-mg dose. ^{11}

Elimination:
    Renal; 1% excreted unchanged ^{01}; up to 5% excreted as active metabolite; the remainder excreted as inactive metabolites.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to isoniazid, pyrazinamide, niacin (nicotinic acid), or other chemically related medications may be sensitive to this medication also.

Pregnancy/Reproduction

Pregnancy—
Ethionamide crosses the placenta.

Ethionamide has been shown to be teratogenic in rabbits and rats given doses greater than the usual human dose. ^{{05} {17}}

Breast-feeding

It is not known whether ethionamide is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of ethionamide have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date. ^{04}


Geriatrics


No information is available on the relationship of age to the effects of ethionamide in geriatric patients.


Dental

Ethionamide may cause a metallic taste and stomatitis (sore mouth). ^{{05} {17}}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Cycloserine^{05}{17}    (concurrent use may result in increased incidence of central nervous system [CNS] effects, especially seizures; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity)


Neurotoxic medications, other (See Appendix II )    (concurrent administration of ethionamide with other neurotoxic medications may increase the potential for neurotoxicity, such as optic and peripheral neuritis)

^{02}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])    (serum values may be increased)

^{05}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Diabetes mellitus^{{02}{03}{17}{18}}    (management of diabetes mellitus may be more difficult in patients taking ethionamide)


» Hepatic function impairment, severe^{05}    (may increase risk of hepatotoxicity)


» Hypersensitivity to ethionamide

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hepatic function determinations^{05}{17}    (AST [SGOT] and ALT [SGPT] concentrations may increase during therapy; however, elevated serum enzyme values may not be predictive of clinical hepatitis and may return to normal despite continued treatment; patients with impaired hepatic function may require a reduction in dose)


Ophthalmologic examinations^{05}{17}    (if loss of vision and other symptoms of optic neuritis occur during treatment, ophthalmologic examinations should be performed immediately and periodically thereafter)




Side/Adverse Effects

Note: Peripheral neuritis may be alleviated by administering pyridoxine. ^{02}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent ^{{01} {05} {17}}
    
Hepatitis or jaundice (yellow eyes or skin)
    
peripheral neuritis (clumsiness or unsteadiness; numbness, tingling, burning, or pain in hands and feet)
    
psychiatric disturbances (mental depression, confusion, mood or other mental changes)

Incidence rare
    
Goiter or hypothyroidism (changes in menstrual periods; coldness; decreased sexual ability—males; dry, puffy skin; swelling of front part of neck; weight gain)
^{10}    
hypoglycemia (difficulty in concentrating, faster heartbeat, increased hunger, nervousness, shakiness)^{16}
    
optic neuritis (blurred vision or loss of vision, with or without eye pain)^{05}
    
skin rash^{05}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent ^{{01} {05} {17}}
    
Gastrointestinal disturbances (loss of appetite, metallic taste, nausea or vomiting, sore mouth)
    
orthostatic hypotension (dizziness, especially when getting up from a lying or sitting position)

Incidence less frequent or rare ^{05}
    
gynecomastia (enlargement of the breasts in males)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ethionamide (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to ethionamide

Pregnancy—Ethionamide crosses the placenta





Dental—Ethionamide may cause a metallic taste and stomatitis
Other medications, especially cycloserine
Other medical problems, especially diabetes mellitus or hepatic function impairment

Proper use of this medication
Taking with or after meals if gastrointestinal irritation occurs

» Compliance with full course of therapy, which may take months or years

» Taking pyridoxine concurrently to prevent or minimize signs of peripheral neuritis

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within 2 or 3 weeks

» Regular visits to physician to check progress, as well as ophthalmologic examinations if signs of optic neuritis occur

» Caution if blurred vision or loss of vision occurs

» Need to report promptly to physician signs of optic neuritis and prodromal signs of peripheral neuritis


Side/adverse effects
Signs of potential side effects, especially hepatitis or jaundice, peripheral neuritis, psychiatric disturbances, goiter or hypothyroidism, hypoglycemia, optic neuritis, and skin rash


General Dosing Information
Ethionamide may be given with or after meals if gastrointestinal irritation occurs.

Ethionamide has been given as a single daily dose after the evening meal or at bedtime. Serum concentrations are higher and effectiveness may be greater than with divided doses. However, gastrointestinal irritation may also be increased. ^{02}

Ethionamide has also been given rectally as suppositories, resulting in fewer side effects. However, serum concentrations may be inadequate. ^{11}

Ethionamide should generally be given in the maximum daily dose that the patient can tolerate. However, approximately one-third of the patients taking ethionamide are unable to tolerate therapeutic doses and the dose must be reduced by 1/3 to 1/2 or the medication must be discontinued. ^{12}

Since bacterial resistance may develop rapidly when ethionamide is administered alone in the treatment of tuberculosis, it should only be administered concurrently with other antituberculars. ^{17}

Therapy may have to be continued for 1 to 2 years, and may even be required for up to several years or indefinitely, although in some patients shorter treatment regimens may be effective. ^{17}

For treatment of adverse effects
Recommended treatment consists of the following:

   • Administration of pyridoxine concurrently with ethionamide to help prevent or minimize the symptoms of peripheral neuritis, especially in patients with prior isoniazid-induced peripheral neuritis.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ETHIONAMIDE TABLETS USP

Usual adult and adolescent dose
Tuberculosis; or

[Mycobacterial infections, atypical]—In combination with other antituberculosis medications: Oral, 250 mg every eight to twelve hours, as tolerated. ^{{02} {05}}

[Leprosy]—In combination with other antileprosy agents: Oral, 250 mg every eight to twelve hours. ^{14}

Usual adult prescribing limits
Up to a maximum of 1 gram daily. ^{05}

Usual pediatric dose
Tuberculosis—In combination with other antituberculosis medications: Oral, 4 to 5 mg per kg of body weight every eight hours, as tolerated. ^{{02} {15}}

Note: Some children have received up to 20 mg per kg of body weight per day. However, the maximum daily dose should not exceed 750 mg. ^{15}


Strength(s) usually available
U.S.—


250 mg (Rx) [Trecator-SC]^{05}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Continue medicine for full time of treatment.

Revised: 06/22/1994

References

1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 1154-5.
   

2. Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990: 355, 454-5.
   

3. Trecator-SC (Wyeth). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 2310.
   

4. American Academy of Pedatrics. Report of the committee of infectious diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics, 1991: 502.
   

5. Trecator-SC (Wyeth). In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 2375.
   

6. Personal communication, Wyeth Canada, 6/16/89.
   

7. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993.
   

8. Peloquin CA. Controversies in the management of Mycobacterium avium complex infection in AIDS patients. Ann Pharmacother 1993; 27: 928-37.
   

9. Peters JH, et al. Mutagenic activity of antileprosy drugs and their derivatives. Int J Lepr 1983; 51(1): 45-52.
   

10. Drucker D, et al. Ethionamide-induced goitrous hypothyroidism. Ann Intern Med 1984; 100(6): 837-9.
    

11. Peloquin CA, et al. Pharmacokinetic evaluation of ethionamide suppositories. Pharmacotherapy 1991; 11(5): 359-63.
    

12. AMA Drug evaluations. 6th ed. Chicago: American Medical Association, September 1986: 1541.
    

13. USP Requirements, USP DI 1989: IV/36.
    

14. Panel comment, 11/14/86.
    

15. Shirkey HC. Pediatric drug handbook. Philadelphia: W.B. Saunders Company, 1977: 63.
    

16. Venkatesan K. Clinical pharmacokinetic considerations in the treatment of patients with leprosy. Clin Pharmacokinet 1989; 16: 365-86.
    

17. Trecator-SC package insert (Wyeth—US), Rev 10/90, Rec 6/91.
    

18. Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990: 1911.