Cycloserine (Seromycin) Package Insert

DESCRIPTION

D -Cycloserine, (R)-4-amino-3-isoxazolidinone,

is a broad-spectrum antibiotic that is produced

by a strain of Streptomyces orchidaceus and has

also been synthesized. Cycloserine is a white

to off-white powder that is soluble in water and

stable in alkaline solution. It is rapidly destroyed

at a neutral or acid pH.

Cycloserine has a pH between 5.5 and 6.5 in a

solution containing 100 mg/mL. The molecular

weight of cycloserine is 102.09, and it has an

empirical formula of C 3H6N2O 2 . The structural

formula of cycloserine is as follows:

Each capsule contains cycloserine, 250 mg

(2.45 mmol); D & C Yellow No. 10, F D & C Blue

No. 1, F D & C Red No. 3, F D & C Yellow No.

6, gelatin, iron oxide, talc, and titanium dioxide.

CLINICAL PHARMACOLOGY

After oral administration, cycloserine is

readily absorbed from the gastrointestinal

tract, with peak blood levels occurring in 4

to 8 hours. Blood levels of 25 to 30 mcg/mL

can generally be maintained with the usual

dosage of 250 mg twice a day, although the

relationship of plasma levels to dosage is

not always consistent. Concentrations in the

cerebrospinal fluid, pleural fluid, fetal blood,

and mother’s milk approach those found in

the serum. Detectable amounts are found

in ascitic fluid, file, sputum, amniotic fluid,

and lung and lymph tissues. Approximately

65% of a single dose of cycloserine can

be recovered in the urine within 72 hours

after oral administration. The remaining

35% is apparently metabolized to unknown

substances. The maximum excretion rate

occurs 2 to 6 hours after administration, with

50% of the drug eliminated in 12 hours.

Mechanism of Action: The antibacterial activity

of Cycloserine results from inhibition of cell-wall

synthesis in susceptible strains of gram-positive

and gram-negative bacteria.

Antibacterial Activity: Cycloserine has been

shown to be active against most isolates of the

following microorganism, both in vitro and in

clinical infections [see Indications and Usage]:

Mycobacterium tuberculosis.

INDICATIONS AND USAGE

Cycloserine is indicated in the treatment

of active pulmonary and extrapulmonary

tuberculosis (including renal disease) when

the causative organisms are susceptible to

this drug and when treatment with the primary

medications (streptomycin, isoniazid, rifampin,

and ethambutol) has proved inadequate. Like

all antituberculosis drugs, cycloserine should be

administered in conjunction with other effective

chemotherapy and not as the sole therapeutic

agent.

Cycloserine may be effective in the treatment

of acute urinary tract infections caused by

susceptible strains of gram-positive and gram-

negative bacteria. Use of cycloserine in these

infections should be considered only when

more conventional therapy has failed and when

the organism has been demonstrated to be

susceptible to the drug

CONTRAINDICATIONS

Administration is contraindicated in patients with

any of the following:

• Hypersensitivity to cycloserine
• Epilepsy
• Depression, severe anxiety, or psychosis
• Severe renal insufficiency
• Excessive concurrent use of alcoho

WARNINGS

Administration of cycloserine should be

discontinued or the dosage reduced if

the patient develops allergic dermatitis or

symptoms of CNS toxicity, such as convulsions,

psychosis, somnolence, depression, confusion,

hyperreflexia, headache, tremor, vertigo

paresis, or dysarthria.

The toxicity of cycloserine is closely related to

excessive blood levels (above 30 mcg/mL), as

determined by high dosage or inadequate renal

clearance. The ratio of toxic dose to effective

dose in tuberculosis is small.

The risk of convulsions is increased in chronic

alcoholics.

Patients should be monitored by hematologic,

renal excretion, blood level, and liver function

studies.

PRECAUTIONS

General: Before treatment with cycloserine

is initiated, cultures should be taken and the

organism’s susceptibility to the drug should

be established. In tuberculous infections,

the organism’s susceptibility to the other

antituberculosis agents in the regimen should

also be demonstrated.

Anticonvulsant drugs or sedatives may be

effective in controlling symptoms of CNS

toxicity, such as convulsions, anxiety, and

tremor. Patients receiving more than 500 mg

of cycloserine daily should be closely observed

for such symptoms. The value of pyridoxine in

preventing CNS toxicity from cycloserine has

not been proved.

Administration of cycloserine and other

antituberculosis drugs has been associated in

a few instances with vitamin B 12 and/or folic-

acid deficiency, megaloblastic anemia, and

sideroblastic anemia. If evidence of anemia

develops during treatment, appropriate studies

and therapy should be instituted.

Laboratory Tests: Blood levels should be

determined at least weekly for patients with

reduced renal function, for individuals receiving

a daily dosage of more than 500 mg, and for

those showing signs and symptoms suggestive

of toxicity. The dosage should be adjusted to

keep the blood level below 30 mcg/mL.

Drug Interactions: Concurrent administration

of ethionamide has been reported to potentiate

neurotoxic side effects.

Alcohol and cycloserine are incompatible,

especially during a regimen calling for large

doses of the latter. Alcohol increases the

possibility and risk of epileptic episodes.

Concurrent administration of isoniazid 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.

Carcinogenesis, Mutagenicity, and

Impairment of Fertility: Studies have not

been performed to determine potential for

carcinogenicity. The Ames test and unscheduled

DNA repair test were negative. A study in 2

generations of rats showed no impairment of

fertility relative to controls for the first mating but

somewhat lower fertility in the second mating.

Pregnancy Category C: There are no

adequate and well-controlled studies with

the use of Cycloserine in pregnant women.

A study in 2 generations of rats given doses

up to 100 mg/kg/day (approximately equivalent

to the maximum recommended human dose

on a body surface area basis) demonstrated

no teratogenic effect in offspring. Cycloserine

should be used during pregnancy only if the

potential benefit justifies the potential risk to the

fetus.

Nursing Mothers: Because of the potential

for serious adverse reactions in nursing infants

from cycloserine, a decision should be made

whether to discontinue nursing or to discontinue

the drug, taking into account the importance of

the drug to the mother.

Usage in Pediatric Patients: Safety and

effectiveness in pediatric patients have not been

established.

Geriatric Use: Clinical studies of cycloserine

did not include sufficient numbers of subjects

aged 65 and over to determine whether they

responded differently from younger subjects.

Other reported clinical experience has not

identified differences in responses between

the elderly and younger patients. In general,

dose selection for an elderly patient should be

cautious, usually starting at the low end of the

dosing range, reflecting the greater frequency

of decreased hepatic, renal, or cardiac function,

and of concomitant disease or other drug

therapy.

This drug is known to be substantially excreted

by the kidney, and the risk of toxic reactions

to this drug may be greater in patients with

impaired renal function. Because elderly

patients are more likely to have decreased renal

function, care should be taken in dose selection,

and it may be useful to monitor renal function.

The toxicity of cycloserine is closely related

to excessive blood levels (above 30 mcg/mL)

as determined by high dosage or inadequate

renal clearance (see WARNINGS). Blood

levels should be determined at least weekly

for patients with reduced renal function, for

individuals receiving a daily dosage of more

than 500 mg, and for those showing signs

and symptoms suggestive of toxicity. The

dosage should be adjusted to keep the blood

level below 30 mcg/mL (see PRECAUTIONS,

Laboratory Tests).

ADVERSE REACTIONS

Most adverse reactions occurring during therapy

with cycloserine involve the nervous system or

are manifestations of drug hypersensitivity. The

following side effects have been observed in

patients receiving cycloserine:

Nervous system symptoms (which appear to

be related to higher dosages of the drug, i.e.,

more than 500 mg daily)

• Convulsions
• Drowsiness and somnolence
• Headache
• Tremor
• Dysarthria
• Vertigo
• Confusion and disorientation with loss of

memory

• Psychoses, possibly with suicidal tendencies
• Character changes
• Hyperirritability
• Aggression
• Paresis
• Hyperreflexia
• Paresthesia
• Major & minor (localized) clonic seizures
• Coma

Cardiovascular: Sudden development of

congestive heart failure in patients receiving

1 to 1.5 g of cycloserine daily has been

reported.

Allergy (apparently not related to dosage)

Skin rash

Miscellaneous: Elevated serum transaminase,

especially in patients with preexisting liver

disease

To report SUSPECTED ADVERSE REACTIONS, contact Cerovene, Inc. at 1-833-304-9569 or FDA at 1‑800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

Signs and Symptoms: Acute toxicity from

cycloserine can occur if more than 1 g is

ingested by an adult. Chronic toxicity from

cycloserine is dose related and can occur if

more than 500 mg is administered daily. The

central nervous system is the most common

organ system involved with toxicity. Toxic effects

may include headache, vertigo, confusion,

drowsiness, hyperirritability, paresthesias,

dysarthria, psychosis paresis, convulsions, and

coma.

Treatment: In adults, many of the neurotoxic

effects of cycloserine can be both treated and

prevented with the administration of 200 to 300 mg

of pyridoxine daily.

Hemodialysis has been shown to remove

cycloserine from the bloodstream. This

procedure should be reserved for patients with

life threatening toxicity that is unresponsive to

less invasive therapy.

DOSAGE AND ADMINISTRATION

Cycloserine is effective orally and is currently

administered only by this route. The usual

dosage is 500 mg to 1 g daily in divided doses

monitored by blood levels.¹ The initial adult

dosage most frequently given is 250 mg twice

daily at 12-hour intervals for the first 2 weeks.

A daily dosage of 1 g should not be exceeded.

HOW SUPPLIED

Cycloserine is available as a 250 mg capsule

with an opaque red cap and opaque gray body

imprinted with “PGC” and “F04” in edible black

ink on both the cap and the body.

Cycloserine Capsules, USP are supplied in cartons of 3 cards. Each card is a ten-capsules blister card as follows:

NDC 43598-235-31: carton with 3 cards.

NDC 43598-235-10 (ten 250mg capsules per card).

Store at controlled room temperature,

20° to 25°C (68° to 77°F) [see USP Controlled

Room Temperature].

REFERENCES

1. 1. Jones LR: Colorimetric determination of

cycloserine, a new antibiotic. Anal Chem

1956;28:39.

Distributed By:

Dr. Reddy’s Laboratories, Inc.

Princeton, NJ 08540

Rev 02/23