CycloSERINE

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Generic: 250 mg

Pharmacology

Mechanism of Action

Inhibits bacterial cell wall synthesis by competing with amino acid (D-alanine) for incorporation into the bacterial cell wall; bacteriostatic or bactericidal

Pharmacokinetics/Pharmacodynamics

Absorption

~70% to 90% from GI tract (WHO 2008)

Distribution

Widely to most body fluids and tissues including CSF, bile, sputum, lymph tissue, lungs, and ascitic, pleural, and synovial fluids (WHO 2008)

Metabolism

Hepatic

Excretion

Urine (~65% as unchanged drug) within 72 hours; Feces (small amounts); remainder metabolized

Time to Peak

Serum: 4 to 8 hours

Half-Life Elimination

Normal renal function: 12 hours

Protein Binding

Not plasma protein bound

Use: Labeled Indications

Tuberculosis: Treatment of active pulmonary or extrapulmonary tuberculosis, in combination with other agents, when treatment with primary tuberculosis therapy has proved inadequate

Urinary tract infections: May be effective in treatment of acute urinary tract infections caused by susceptible strains of gram-positive and gram-negative bacteria, especially Enterobacter spp. and Escherichia coli. Note: Should be considered only when more conventional therapy has failed and when the organism has been demonstrated to be susceptible to the drug.

Contraindications

Hypersensitivity to cycloserine or any component of the formulation; epilepsy; depression, severe anxiety, or psychosis; severe renal insufficiency; excessive concurrent use of alcohol

Dosage and Administration

Dosing: Adult

Tuberculosis, active (alternative agent): Oral:

10 to 15 mg/kg/day (maximum: 1,000 mg/day), usually 250 to 500 mg once or twice daily (ATS/CDC/IDSA [Nahid 2016]). Note: Experienced clinicians indicate most patients are unable to tolerate the 500 mg twice daily dose and recommend the following 2-week dose titration: 250 mg once daily for 3 to 4 days, 250 mg every 12 hours for 3 to 4 days, then 250 mg in the morning and 500 mg in the evening (Curry International Tuberculosis Center 2016; Drew 2017). Peak (2 hours post-dose) serum concentrations targeted at 20 to 35 mcg/mL are often useful in determining the optimal dose (ATS 2003; Curry International Tuberculosis Center 2016).

Note: Some neurotoxic effects may be treated or prevented by concomitant administration of 200 to 300 mg of pyridoxine daily or 50 mg of pyridoxine per 250 mg of cycloserine (Curry International Tuberculosis Center 2016; WHO 2008).

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Initial: 250 mg every 12 hours for 14 days, then administer 500 to 1,000 mg/day in 2 divided doses (maximum: 1,000 mg/day)

Urinary tract infections: Oral: There is no dosage provided in the prescribing information. Note: Should be considered only when more conventional therapy has failed and when the organism has been demonstrated to be susceptible to the drug.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Active tuberculosis infection (excluding meningitis); treatment (second-line therapy): Limited data available: Note: Recommendations often change due to epidemiology (resistance) and emerging information; consult CDC and WHO for current recommendations for detailed information. Always use as part of a multidrug regimen (ATS/CDC/IDSA [Nahid 2016]). Concomitant pyridoxine is recommended to prevent cycloserine-induced neuropathy (WHO 2009).

Infants, Children, and Adolescents <15 years; weighing ≤40 kg: Oral: 15 to 20 mg/kg/day divided every 12 to 24 hours (if tolerability issues, may divide into 2 doses); maximum daily dose: 1,000 mg/day (ATS/CDC/IDSA 2016; HHS [pediatric 2013]; Seddon 2012). Note: Some patients may be unable to tolerate recommended doses; experts suggest beginning with a low once daily dose and gradually increasing as tolerated; serum concentrations targeted at 25 to 30 mcg/mL have been suggested to minimize toxicity (ATS/CDC/IDSA [Nahid 2016]; HHS [pediatric 2013]).

Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral: 10 to 15 mg/kg/day divided every 12 to 24 hours; usual dose 250 to 500 mg; maximum daily dose: 1,000 mg/day Note: Patients are often unable to tolerate the maximum dose divided twice daily (eg, in adults, 500 mg twice daily); therefore, experts suggest beginning with a low once daily dose and gradually increasing as tolerated; may consider therapeutic drug monitoring; serum concentrations targeted at 25 to 30 mcg/mL have been suggested to minimize toxicity (ATS/CDC/IDSA [Nahid 2016]; HHS [pediatric 2013]).

Administration

Administer orally in divided doses with or without food.

Dietary Considerations

May be taken with food; may increase vitamin B₁₂ and folic acid dietary requirements.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): May enhance the neurotoxic effect of CycloSERINE. Specifically, the risk for seizures may be increased. Avoid combination

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Avoid combination

Ethionamide: May enhance the adverse/toxic effect of CycloSERINE. Monitor therapy

Isoniazid: May enhance the adverse/toxic effect of CycloSERINE. Specifically, CNS toxicity may be enhanced. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Prothionamide: May enhance the adverse/toxic effect of CycloSERINE. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Terizidone: May enhance the adverse/toxic effect of CycloSERINE. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Cardiac arrhythmia, cardiac failure

Central nervous system: Coma, confusion, dizziness, drowsiness, dysarthria, headache, hyperreflexia, paresis, paresthesia, psychosis, restlessness, seizure, vertigo

Dermatologic: Skin rash

Endocrine & metabolic: Cyanocobalamin deficiency, folate deficiency

Hepatic: Increased liver enzymes

Hypersensitivity: Hypersensitivity reaction

Neuromuscular & skeletal: Tremor

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Has been associated with dose-related CNS toxicity, including seizures, psychosis, depression, and confusion; decrease dosage or discontinue use if occurs. Pyridoxine may be coadministered to prevent/treat CNS effects.
• Skin reactions: Allergic dermatitis may occur; reduce dose or discontinue use if allergic dermatitis develops.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Alcoholism: Use with caution in patients with a history of chronic alcoholism; increased risk of seizures.
• Mental illness: Use with caution in patients with depression, severe anxiety, and/or psychosis.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be necessary. Use is contraindicated in severe renal insufficiency.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Patients with potential for vitamin deficiency: Use with caution in patients with potential vitamin B₁₂ and/or folate deficiency (malnourished, chronic anticonvulsant therapy, or elderly).

Monitoring Parameters

Periodic renal, hepatic, hematological tests, and plasma cycloserine concentrations; assess neuropsychiatric status at monthly intervals and more frequently if symptoms occur (ATS 2003).

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Cycloserine crosses the placenta and can be detected in the fetal blood and amniotic fluid. The American Thoracic Society recommends use in pregnant women only if there are no alternatives (CDC 2003).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Have patient report immediately to prescriber signs of depression (thoughts of suicide, anxiety, emotional instability, or confusion), behavioral changes, mood changes, fatigue, headache, confusion, trouble with memory, dizziness, passing out, seizures, muscle weakness, shortness of breath, excessive weight gain, swelling of arms or legs, severe loss of strength and energy, change in speech, tremors, or burning or numbness feeling (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer:Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.