Professional Drug Information > Seromycin

Cycloserine (Systemic)

VA CLASSIFICATION
Primary: AM500^{05}

Commonly used brand name(s): Seromycin.

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)—

Indications

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

Accepted

Tuberculosis (treatment)—Cycloserine is indicated in combination with other antituberculars in the treatment of tuberculosis after failure of the primary medications (pyrazinamide ^{04}, streptomycin, isoniazid, rifampin, and ethambutol). ^{{06} {17}}

[Mycobacterial infections, atypical (treatment)]—Cycloserine is used in the treatment of atypical mycobacterial infections, such as Mycobacterium avium complex. ^{{01} {04}}

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

Unaccepted
Although cycloserine has been used for the treatment of urinary tract infections, it has been superseded by newer, safer, and/or more effective agents (e.g., aminoglycosides, beta-lactams, quinolones, trimethoprim). ^{04}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    102.09 ^{07}

Mechanism of action/Effect:

Cycloserine, a broad-spectrum antibiotic, may be bactericidal or bacteriostatic, depending on its concentration at the site of infection and the susceptibility of the organism. ^{10}

Cycloserine is an analog of the amino acid D-alanine. It interferes with an early step in bacterial cell wall synthesis in the cytoplasm by competitive inhibition of 2 enzymes, L-alanine racemase, which forms D-alanine from L-alanine, and D-alanine- D-alanine synthetase, which incorporates D-alanine into the pentapeptide necessary for peptidoglycan formation and bacterial cell wall synthesis. ^{11}

Absorption:

Rapidly and almost completely (70 to 90%) absorbed from the gastrointestinal tract following oral administration. ^{{06} {10}}

Distribution:

Wide, to most body fluids and tissues, including cerebrospinal fluid (CSF), breast milk, bile, sputum, lymph tissue, lungs, and ascitic, pleural, and synovial fluids; crosses the placenta. ^{{06} {15}}

CSF concentrations of cycloserine approach those found in the serum. ^{{15} {17}}


Urine concentrations:

—High, 55 to 340 mcg per mL. ^{15}


Protein binding:

None. ^{10}

Biotransformation:

Up to 35%. ^{06}

Half-life:
^{10}





Normal renal function:

10 hours.



Impaired renal function:

Prolonged.


Time to peak serum concentration

3 to 4 hours. ^{{06} {10}}

Peak serum concentration

25 to 30 mcg/mL after a dose of 250 mg every 12 hours. ^{17}

Elimination:
    Renal, by glomerular filtration; 50% excreted unchanged within 12 hours; 65 to 70% excreted unchanged within 24 to 72 hours ^{06}; accumulates in patients with impaired renal function.
    Fecal, small amounts. ^{17}


Dialysis—
        Cycloserine is removed by hemodialysis. ^{{06} {17}}



Precautions to Consider

Carcinogenicity/Mutagenicity

Studies have not been performed to determine the carcinogenic potential of cycloserine. The Ames test and unscheduled DNA repair test were negative. ^{17}

Pregnancy/Reproduction
Fertility—
A study in 2 generations of rats showed no impairment of fertility relative to controls for the first mating, but somewhat lower fertility for the second mating. ^{17}

Pregnancy—
Cycloserine crosses the placenta ^{10}; fetal serum concentrations may approach maternal serum concentrations.

A study in 2 generations of rats given doses up to 100 mg per kg of body weight per day demonstrated no teratogenic effect in the offspring. ^{17}

FDA Pregnancy Category C.

Breast-feeding

Cycloserine is distributed into breast milk ^{10}; concentrations may approach or exceed maternal serum concentrations. ^{15}

Pediatrics

Appropriate studies on the relationship of age to the effects of cycloserine have not been performed in the pediatric population. ^{17} However, no pediatrics-specific problems have been documented to date.


Geriatrics


No information is available on the relationship of age to the effects of cycloserine in geriatric patients. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of dosage in patients receiving cycloserine.

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.

» Alcohol^{06}    (may increase the risk of seizures, especially in chronic alcohol abuse; patients should be advised to avoid concurrent use)


» Ethionamide^{06}    (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)


Isoniazid^{06}    (concurrent use may result in increased incidence of CNS effects such as dizziness or drowsiness; dosage adjustments may be necessary, and patients should be monitored closely for signs of CNS toxicity)


Pyridoxine^{12}    (cycloserine may cause anemia or peripheral neuritis by acting as a pyridoxine antagonist or increasing renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving cycloserine)



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])    (concentrations may be increased—especially in patients with pre-existing liver disease ^{{06} {16} {17}})


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
» Alcoholism, active or in remission^{03}{16}{17}    (cycloserine may increase the risk of seizures in alcoholics)


Anxiety, severe or
Mental depression or
Psychosis^{16}{17}    (cycloserine may cause anxiety, mental depression, and psychosis, especially at higher doses)


» Hypersensitivity to cycloserine^{16}{17}
» Renal function impairment^{16}{17}    (because cycloserine is renally excreted, cycloserine may accumulate in patients with renal function impairment, leading to an increased risk of side effects; the medication should not be given to patients with renal function impairment [creatinine clearance of <50 mL per minute (0.83 mL per second)])


» Seizure disorders, history of^{16}{17}    (cycloserine may increase the risk of seizures in patients with a seizure disorder)



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):

Blood urea nitrogen (BUN) concentrations and
Creatinine concentrations, serum^{16}    (may be required periodically since patients with impaired renal function require a reduction in dose or discontinuation of the medication)


Cycloserine concentrations, serum^{06}{16}{17}    (may be required at least weekly in patients with slightly impaired, but stable, renal function, in patients receiving more than 500 mg daily, or in patients showing signs and symptoms of toxicity; concentrations above 30 mcg/mL should be avoided)


Hemoglobin concentration^{16}{17}    (may be required periodically since administration of cycloserine and other antituberculars has been associated in a few instances with vitamin B ₁₂ and/or folic acid deficiency, megaloblastic anemia, and sideroblastic anemia)






Side/Adverse Effects

Note: The side effects of cycloserine, particularly CNS toxicity, may be dose-related and more commonly seen with daily doses greater than 500 mg. Acute toxicity may occur if more than 1 gram is ingested by an adult, and chronic toxicity may occur with ingestion of more than 500 mg daily. The ratio of toxic dose to effective dose is small. ^{{16} {17}}
Administraton of 200 to 300 mg of pyridoxine daily may help to prevent cycloserine-related neurotoxicity. ^{17}

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 more frequent ^{{06} {17}}
    
CNS toxicity (anxiety ; confusion; dizziness; drowsiness; increased irritability; increased restlessness; mental depression; muscle twitching or trembling; nervousness; nightmares; other mood or mental changes; speech problems; thoughts of suicide)

Incidence less frequent ^{{06} {17}}
    
Hypersensitivity (skin rash)
    
peripheral neuropathy (numbnesstinglingburning painor weakness in the hands or feet)
    
seizures



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache^{06}{17}





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

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

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Cycloserine crosses the placenta and fetal serum concentrations may approach maternal serum concentrations





Breast-feeding—Cycloserine is distributed into breast milk. Concentrations may approach or exceed maternal serum concentrations
Other medications, especially alcohol and ethionamide
Other medical problems, especially alcoholism (active or in remission), a history of seizure disorders, or renal function impairment

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

» Compliance with full course of therapy; in tuberculosis, therapy may take months or years

» Importance of not missing doses and taking at evenly spaced times

» 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
Regular visits to physician to check progress

Checking with physician if no improvement within 2 to 3 weeks

» Checking with physician immediately if thoughts of suicide occur

» Caution if dizziness or drowsiness occurs

» Avoiding alcoholic beverages while taking this medication


Side/adverse effects
Signs of potential side effects, especially CNS toxicity, hypersensitivity reactions, peripheral neuropathy, and seizures


General Dosing Information
Cycloserine may be taken after meals if gastrointestinal irritation occurs.

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

Patients receiving more than 500 mg of cycloserine daily should be closely observed for symptoms of CNS toxicity. ^{{06} {17}}

In the treatment of tuberculosis, 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 also be effective.

Serum concentrations should be monitored where possible. Concentrations should be maintained at approximately 25 to 30 mcg/mL in the treatment of tuberculosis. Concentrations above 30 mcg/mL should be avoided since toxicity is closely related to excessive serum concentrations ^{{06} {17}}. In addition, the ratio of toxic dose to effective dose is small.

Patients with severe renal function impairment (creatinine clearance of <50 mL per minute [0.83 mL per second]) should not receive cycloserine because of the increased risk of neurotoxicity. ^{{17} {18}}

For treatment of adverse effects
Recommended treatment consists of the following: ^{17}

   • Inducing emesis and/or use of gastric lavage.
   • Administering activated charcoal and cathartic every 4 hours until clinically stable.
   • Providing supportive therapy.
   • Using anticonvulsants to control seizures.
   • Administering 200 to 300 mg of pyridoxine daily to treat neurotoxicity.


Oral Dosage Forms

CYCLOSERINE CAPSULES USP

Usual adult and adolescent dose
Tuberculosis
In combination with other antituberculars: Oral, 250 mg every twelve hours for the first two weeks, then cautiously increased as necessary and tolerated, up to 250 mg every six to eight hours and monitored by serum determinations. ^{{06} {17}}


Usual adult prescribing limits
Up to a maximum of 1 gram daily. ^{{06} {17}}

Note: Doses up to 1.5 grams daily have been used.


Usual pediatric dose
Tuberculosis
In combination with other antituberculars: Doses of 10 to 20 mg per kg of body weight per day in divided doses have been used. ^{{08} {14} {15}}


Strength(s) usually available
U.S.—


250 mg (Rx) [Seromycin]^{06}{17}

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. ^{06}

Stability:
Cycloserine maintains its potency in alkaline solutions, but is rapidly destroyed at neutral or acid pH. ^{06}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness, or dizziness.
   • Continue medicine for full time of treatment.

Revised: 05/02/1994

References

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

2. Seromycin (Lilly). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 1069.
   

3. Seromycin (Lilly). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 1212.
   

4. Panel comments, Cycloserine (Systemic), 8/1/88.
   

5. USP DI 1989, VA Medication Classification System: 2472.
   

6. Seromycin package insert (Lilly—US), Rev 11/88, Rec 2/89.
   

7. Fleeger CA, editor. USAN 1989. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1989: 157.
   

8. Benitz WE, Tatro DS. The pediatric drug handbook. 2nd ed. Chicago: Year Book Medical Publishers, Inc., 1988: 610-1.
   

9. Personal communication, Lilly (Canada), 6/1/89.
   

10. McEvoy GK, editor. AHFS Drug information 88. Bethesda, MD: American Society of Hospital Pharmacists, 1988: 157.
    

11. Gilman AG, Goodman LS, Rall TW, Murad F, editors. Goodman and Gilman's the pharmocological basis of therapeutics. 7th ed. New York: Macmillan, 1985: 1209.
    

12. Wyngaarden JB, Smith LH, editors. Cecil textbook of medicine. Philadelphia: W.B. Saunders Company, 1990: 1233.
    

13. Kucers A, Bennett NM, editors. The use of antibiotics. 3rd ed. New York: Lippincott, 1979: 459.
    

14. Taketomo CK, Hodding JH, Kraus DM. Pediatric dosage handbook. Hudson, Ohio: Lexi-Comp, Inc., 1992: 131-2.
    

15. Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990: 354-5, 452-3.
    

16. Seromycin package insert (Lilly—US), Rev 3/89, Rec 5/89.
    

17. Seromycin package insert (Lilly—US), Rev 5/90, Rec 8/90; Rev 10/93, Rec 12/93.
    

18. Bennett WM. Guide to drug dosage in renal failure. Clin Pharmacokinet 1988; 15: 326-54.
    

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