Cycloserine (Monograph)

Brand name: Seromycin
Drug class: Antituberculosis Agents
- Antimycobacterial Agents
VA class: AM500
CAS number: 68-41-7

Introduction

Antituberculosis agent;¹⁰⁰ structural analog of the amino acid d-alanine.^a

Uses for Cycloserine

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.^{100 101 102}

Second-line agent used in treatment of drug-resistant TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to cycloserine.^{100 101 102}

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months).^{100 101} Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,^{100 101} ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.¹⁰⁰ A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.^{100 101}

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.¹⁰⁰

Urinary Tract Infections (UTIs)

Has been used for treatment of acute UTIs caused by susceptible gram-positive or -negative bacteria, especially Enterobacter or Escherichia coli.¹⁰² No longer recommended;¹⁰³ generally less effective than other antibacterials available for treatment of UTIs.¹⁰²

Should be used for treatment of UTIs only when other more effective and less toxic alternatives are contraindicated and susceptibility to cycloserine has been demonstrated.¹⁰²

Cycloserine Dosage and Administration

Administration

Oral Administration

Administer orally.¹⁰²

Dosage

Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.^{100 101 102}

Data not available to date to support use of cycloserine in intermittent (e.g., 1-3 times weekly) multiple-drug TB regimens.¹⁰⁰

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

Children <15 years of age or weighing ≤40 kg^{† [off-label]}: 10–20 mg/kg daily (up to 1 g daily) given in 2 divided doses recommended by ATS, CDC, IDSA, and AAP.^{100 101}

Children ≥15 years of age^{† [off-label]}: 10–15 mg/kg daily (up to 1 g daily) given in 2 divided doses recommended by ATS, CDC, and IDSA.¹⁰⁰ Usual dosage is 500–750 mg daily given in 2 divided doses; toxicity is more common with dosages >500 mg daily.¹⁰⁰ These experts suggest optimum dosage usually can be determined by maintaining peak cycloserine serum concentrations at 20–35 mcg/mL.¹⁰⁰

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

10–15 mg/kg daily (up to 1 g daily) given in 2 divided doses recommended by ATS, CDC, and IDSA.¹⁰⁰ Usual dosage is 500–750 mg daily given in 2 divided doses; toxicity is more common with dosages >500 mg daily.¹⁰⁰ These experts suggest optimum dosage usually can be determined by maintaining peak cycloserine serum concentrations at 20–35 mcg/mL.¹⁰⁰

Manufacturer states usual initial dosage is 250 mg every 12 hours for the first 2 weeks.¹⁰² Usual dosage is 0.5–1 g daily given in divided doses with serum concentration monitoring.¹⁰² Manufacturer recommends dosage be adjusted to maintain serum concentrations <30 mcg/mL.¹⁰²

Urinary Tract Infections (UTIs)

Acute UTIs

Oral

250 mg every 12 hours for 2 weeks.^a

Prescribing Limits

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

Maximum 1 g daily.^{100 101}

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

Maximum 1 g daily.^{100 102}

Special Populations

Renal Impairment

Contraindicated in severe renal insufficiency.¹⁰² In other patients, adjust dosage according to degree of renal impairment and monitor serum cycloserine concentrations.^{100 103} Maintain serum cycloserine concentrations <30 mcg/mL.¹⁰² (See Renal Impairment under Cautions.)

ATS, CDC, and IDSA state the drug should not be used in patients with Cl_cr <50 mL/minute unless they are undergoing hemodialysis.¹⁰⁰ For those being treated for TB who are undergoing hemodialysis, these experts suggest a dosage of 500 mg 3 times weekly or 250 mg once daily (with close monitoring of serum cycloserine concentrations).¹⁰⁰

Cautions for Cycloserine

Contraindications

• Hypersensitivity to cycloserine.¹⁰²

• History of epilepsy, depression, severe anxiety, or psychosis.¹⁰²

• Severe renal insufficiency.¹⁰² (See Renal Impairment under Cautions.)

• Excessive concurrent use of alcohol.¹⁰² (See CNS Effects under Cautions.)

Warnings/Precautions

Warnings

CNS Effects

CNS effects are the most frequent adverse effects.^a Drowsiness, somnolence, dizziness, headache, lethargy, depression, tremor, dysarthria, hyperreflexia, paresthesia, nervousness, anxiety, vertigo, confusion and disorientation (with loss of memory), paresis, major and minor clonic seizures, seizures, and coma have been reported.^a Psychosis (possibly with suicidal tendencies), personality changes, hyperirritability, and aggression have also occurred.^a

Increased risk of seizures in chronic alcoholics.¹⁰² (See Interactions.)

Adverse CNS effects appear to be dose related and occur within the first 2 weeks of therapy in about 30% of those receiving 500 mg daily.^a Determine plasma concentrations at least once weekly in patients receiving >500 mg daily, in patients with reduced renal function, and in those with signs or symptoms of toxicity.^a Adverse nervous system effects are minimized when plasma cycloserine concentrations are <30 mcg/mL.^{103 a}

Some experts recommend that neuropsychiatric status be assessed at least once monthly and more frequently if symptoms develop.¹⁰⁰ Patients with renal impairment should be closely monitored for evidence of neurotoxicity.¹⁰⁰

If symptoms of CNS toxicity (e.g., seizures, psychosis, somnolence, depression, confusion, hyperreflexia, headache, tremor, vertigo, paresis, dysarthria) occur, reduce dosage or discontinue cycloserine.¹⁰² Symptoms generally disappear when the drug is discontinued.^a

Sedatives may be effective in controlling anxiety or tremor; anticonvulsants may control seizures.^{102 a} (See Interactions.)

Value of pyridoxine in preventing cycloserine-associated CNS toxicity has not been proven.¹⁰² Neurotoxic effects may be relieved or prevented by concomitant administration of pyridoxine hydrochloride (100–300 mg daily).^{100 102}

Sensitivity Reactions

Rash and allergic reactions reported.¹⁰² Photosensitivity has occurred.^a

If allergic dermatitis occurs, reduce dosage or discontinue cycloserine.¹⁰²

General Precautions

Precautions Related to Treatment of Tuberculosis

Should not be used alone for treatment of active (clinical) TB; must be given in conjunction with other antituberculosis agents.^{100 101 102}

Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response.^{100 102} The antituberculosis regimen should be modified as needed.¹⁰⁰ Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).¹⁰⁰ Cycloserine in vitro susceptibility testing may be technically difficult.¹⁰⁰

If cycloserine is added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant TB, at least 2 (preferably 3) new drugs known or expected to be active against the resistant strain should be added at the same time.¹⁰⁰

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.¹⁰⁰ Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.¹⁰⁰

To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active TB whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.^{100 101}

Hematologic Effects

Vitamin B₁₂ and/or folic acid deficiency, megaloblastic anemia, and sideroblastic anemia have been reported in patients receiving cycloserine in conjunction with other antituberculosis agents.¹⁰²

If anemia occurs, initiate appropriate studies and therapy.¹⁰²

Laboratory Monitoring

Monitor renal, hepatic, and hematologic function.¹⁰²

Monitor cycloserine concentrations; measure concentrations at least once weekly in those with reduced renal function, in those receiving >500 mg daily, and in those showing signs and symptoms that suggest toxicity.¹⁰² Adjust dosage to maintain serum concentrations <30 mcg/mL.¹⁰²

Specific Populations

Pregnancy

Category C.¹⁰²

Because cycloserine crosses the placenta and data are limited regarding safety of the drug in pregnant women, ATS, CDC, and IDSA state the drug should be used for treatment of TB during pregnancy only when there are no suitable alternatives.¹⁰⁰

Lactation

Distributed into milk.¹⁰² Discontinue nursing or the drug.¹⁰²

Pediatric Use

Safety and efficacy not established in children.¹⁰²

ATS, CDC, IDSA, and AAP consider cycloserine one of several second-line antituberculosis agents that can be used in children^{† [off-label]}.^{100 101}

Hepatic Impairment

Caution in patients with alcohol-related hepatitis.¹⁰⁰ (See Interactions.)

Renal Impairment

Use caution in patients with renal impairment;^{100 103} contraindicated in those with severe renal insufficiency.¹⁰²

Symptoms of acute toxicity may occur if usual dosage is used in patients with renal impairment.^a Adjust dosage according to the degree of renal impairment and serum cycloserine concentrations.^{100 102 103} Closely monitor patients with renal impairment for evidence of neurotoxicity.¹⁰⁰

Determine serum cycloserine concentrations at least once weekly in patients with reduced renal function; adjust dosage to maintain concentrations <30 mcg/mL.¹⁰² (See CNS Effects under Cautions.)

Common Adverse Effects

CNS effects (seizures, drowsiness, somnolence, dizziness, headache, tremor, dysarthria, hyperreflexia, paresthesia, nervousness, anxiety, vertigo, confusion, disorientation with loss of memory, paresis, coma); hypersensitivity reactions.^{102 a}

Drug Interactions

Specific Drugs

Cycloserine Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from GI tract.¹⁰² About 65–90% of an oral dose absorbed;^{102 a} peak plasma concentrations attained within 3–8 hours.^{102 a}

Plasma Concentrations

Plasma concentrations of 25–30 mcg/mL generally are maintained with a dosage of 250 mg twice daily, but relationship between plasma concentrations and dosage not always consistent.¹⁰²

Some drug accumulation may occur in patients with normal renal function during the first 3 days of cycloserine therapy.^a

Distribution

Extent

Widely distributed into body tissues and fluids including the lungs,¹⁰² ascitic fluid,¹⁰² pleural fluid,¹⁰² lymph tissue,¹⁰² and synovial fluid in concentrations approximately equal to plasma concentrations of the drug.^a Also distributed into bile,¹⁰² sputum,¹⁰² and lymph tissue.¹⁰²

CSF concentrations are 50–80% of concurrent plasma concentrations in patients with uninflamed meninges and 80–100% of concurrent plasma concentrations in patients with inflamed meninges.^a

Readily crosses the placenta and is distributed into amniotic fluid.¹⁰²

Distributed into milk in concentrations similar to maternal plasma concentrations.¹⁰²

Plasma Protein Binding

Not bound to plasma proteins.^a

Elimination

Metabolism

About 35% of a dose appears to be metabolized to unidentified metabolites.¹⁰²

Elimination Route

60–70% of an oral dose excreted unchanged in urine by glomerular filtration within 72 hours.^{102 103 a} The maximum excretion rate occurs during the first 2–6 hours; approximately 50% of the dose is eliminated within 12 hours.¹⁰² Negligible amounts excreted in feces.¹⁰³

Removed by hemodialysis.^{100 104}

Half-life

Approximately 10 hours in patients with normal renal function.^a

Special Populations

Half-life prolonged in patients with impaired renal function.^a

Stability

Storage

Oral

Capsules

20–25°C in tight container.^{102 a}

Destroyed at neutral or acidic pH;¹⁰² deteriorates upon absorbing water.^a

Actions and Spectrum

• May be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism.^a

• Inhibits cell wall synthesis in susceptible organisms by competing with d-alanine for incorporation into the bacterial cell wall.^{102 103 a} In vitro, antibacterial activity may be inhibited by d-alanine.^{103 a}

• Spectrum of activity includes mycobacteria and some gram-positive and -negative bacteria.^{102 103}

• Mycobacteria: Active against M. tuberculosis,^{103 a} M. bovis,^a and some strains of M. kansasii,^{103 105 a} M. marinum,^a M. ulcerans,^a M. avium complex (MAC),^{103 a} M. smegmatis,^a and M. intracellulare.^a

• Gram-positive and gram-negative bacteria: Active against Staphylococcus aureus, Enterobacter, and Escherichia coli.^{103 a}

• Natural and acquired resistance to cycloserine demonstrated in vitro and in vivo in strains of M. tuberculosis.^a No evidence of cross-resistance between cycloserine and other antituberculosis agents available in the US.^a

Advice to Patients

• Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.¹⁰⁰

• Importance of avoiding excessive concurrent use of alcohol.¹⁰²

• Importance of notifying clinicians if allergic dermatitis or symptoms of CNS toxicity (seizures, psychosis, somnolence, depression, confusion, hyperreflexia, headache, tremor, vertigo, paresis, dysarthria) occur.¹⁰²

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹⁰²

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹⁰²

• Importance of informing patients of other important precautionary information.¹⁰² (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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