MICROBIOLOGY SECTION.


MICROBIOLOGY SECTION Cycloserine inhibits cellwall synthesis in susceptible strains of grampositive and gramnegative bacteria and in Mycobacterium tuberculosis. Susceptibility Tests Cycloserine clinical laboratory standard powder is available for both direct and indirect methods1 of determining the susceptibility of strains of mycobacteria. Cycloserine MICsfor susceptible strains are 25g/mL or lower.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL PRINCIPAL DISPLAY PANEL SEROMYCIN cycloSERINE Capsules, USP 250mg THE CHAO CENTER NDC 13845-1200-3 40 capsules Rx only Usual Initial Adult Dose: One capsule (250 mg) twice a day at 12 hour intervals. See accompanying literature. Dispense in a tight container. WARNING: Potent drug. May cause serious reactions in some individuals. Use in patients under close medical supervision. Read accompanying literature before using. 13845-1200-3 LM000250.00 Keep tightly closed. Store at controlled room temperature, 20 degrees to 25 degrees C (68 degrees to 77 degrees F). [see USP] Maunfacture The Chao center for Industrial Pharmacy and Contract Manufacturing, West Lafayette, IN 47906, USA Expiration Date Batch No.

PREGNANCY SECTION.


PREGNANCY SECTION Pregnancy Category C A study in 2generations of rats given doses up to 100mg/kg/day demonstrated no teratogenic effect in offspring. It is not known whether cycloserine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Seromycin should be given to a pregnant woman only if clearly needed.

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS SECTION Most adverse reactions occurring during therapy with Seromycin involve the nervous system or are manifestations of drug hypersensitivity. The following side effects have been observed in patients receiving Seromycin: Nervous system symptoms (which appear to be related to higher dosages of the drug, i.e.,more than 500mg 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 and minor (localized) clonic seizures Coma Cardiovascular Sudden development of congestive heart failure in patients receiving 1to 1.5 g of Seromycin daily has been reported Allergy (apparently not related to dosage) Skin rash Miscellaneous Elevated serum transaminase, especially in patients with preexisting liver disease

INDICATIONS & USAGE SECTION.


INDICATIONS & USAGE SECTION Seromycin 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, Seromycin should be administered in conjunction with other effective chemotherapy and not as the sole therapeutic agent. Seromycin may be effective in the treatment of acute urinary tract infections caused by susceptible strains of grampositive and gramnegative bacteria, especially Enterobacterspp. and Escherichia coli. It is generally no more and is usually less effective than other antimicrobial agents in the treatment of urinary tract infections caused by bacteria other than mycobacteria. Use of Seromycin 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.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE & ADMINISTRATION SECTION Seromycin is effective orally and is currently administered only by this route. The usual dosage is 500mg to 1g daily in divided doses monitored by blood levels.2 The initial adult dosage most frequently given is 250mg twice daily at 12hour intervals for the first2 weeks. A daily dosage of 1g should not be exceeded.

HOW SUPPLIED SECTION.


HOW SUPPLIED SECTION Seromycin is available as a 250 mg capsule with an opaque red cap and opaque gray body imprinted with CHAO andF04 in edible black ink on both the cap and the body. Bottlesof40 NDC 13845-1200-3 Store at controlled room temperature, 20to25C (68to77F) [seeUSP].

DESCRIPTION SECTION.


DESCRIPTION SECTION Seromycin (Cycloserine Capsules, USP), 3-isoxazolidinone, 4-amino , (R) is a broadspectrum antibiotic that is produced by a strain of Streptomyces orchidaceus and has also been synthesized. Cycloserine is a white to offwhite 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 C3H6N2O2.

OVERDOSAGE SECTION.


OVERDOSAGE SECTION Acute toxicity from cycloserine can occur if more than 1g is ingested by an adult. Chronic toxicity from cycloserine is dose related and can occur if more than 500mg is administered daily. Patients with renal impairment will accumulate cycloserine and may develop toxicity if the dosing regimen is not modified. Patients with severe renal impairment should not receive the drug. The central nervous system is the most common organ system involved with toxicity. Toxic effects may include headache, vertigo, confusion, drowsiness, hyperirritability, paresthesias, dysarthria, and psychosis. Following larger ingestions, paresis, convulsions, and coma often occur. Ethyl alcohol may increase the risk of seizures in patients receiving cycloserine. The oral median lethal dose in mice is 5290mg/kg.Treatment To obtain uptodate information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians Desk Reference(PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Overdoses of cycloserine have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered. Protect the patients airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patients vital signs, blood gases, serum electrolytes,etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patients airway when employing gastric emptying or charcoal. In adults, many of the neurotoxic effects of cycloserine can be both treated and prevented with the administration of 200to 300mg of pyridoxine daily. The use of 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.

PRECAUTIONS SECTION.


PRECAUTIONS SECTION Before treatment with Seromycin is initiated, cultures should be taken and the organisms susceptibility to the drug should be established. In tuberculous infections, the organisms susceptibility to the other antituberculosis agents in the regimen should also be demonstrated. Anticonvulsant drugs or sedatives may be effective in controlling symptoms of CNStoxicity, such as convulsions, anxiety, and tremor. Patients receiving more than 500mg of Seromycin daily should be closely observed for such symptoms. The value of pyridoxine in preventing CNStoxicity from Seromycin has not been proved. Administration of Seromycin and other antituberculosis drugs has been associated in a few instances with vitaminB12 and/or folicacid deficiency, megaloblastic anemia, and sideroblastic anemia. If evidence of anemia develops during treatment, appropriate studies and therapy should be instituted.

PEDIATRIC USE SECTION.


PEDIATRIC USE SECTION Safety and effectiveness in pediatric patients have not been established.

NURSING MOTHERS SECTION.


NURSING MOTHERS SECTION Because of the potential for serious adverse reactions in nursing infants from Seromycin, 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.

DRUG INTERACTIONS SECTION.


DRUG INTERACTIONS SECTION Concurrent administration of ethionamide has been reported to potentiate neurotoxic side effects. Alcohol and Seromycin 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 CNSeffects, such as dizziness or drowsiness. Dosage adjustments may be necessary and patients should be monitored closely for signs of CNStoxicity. Carcinogenesis, Mutagenicity, and Impairment of Fertility Studies have not been performed to determine potential for carcinogenicity. The Ames test and unscheduled DNArepair test were negative. A study in 2generations of rats showed no impairment of fertility relative to controls for the first mating but somewhat lower fertility in the second mating.

REFERENCES SECTION.


REFERENCES SECTION 1. Kubica GP, Dye WE: Laboratory methods for clinical and public health - mycobacteriology, US Department of Health, Education, and Welfare, Public Health Services, 1967, pp47-55, 66-70. 2. Jones LR: Colorimetric determination of cycloserine, a new antibiotic. Anal Chem 1956; 28:39. The Chao Center for Industrial Pharmacy and Contact Manufacturing West Lafayette, IN, 47906, USA Literature revised 14 JANUARY 2009 LM000251.00 PRINTED IN USA

LABORATORY TESTS SECTION.


LABORATORY TESTS SECTION Blood levels should be determined at least weekly for patients with reduced renal function, for individuals receiving a daily dosage of more than 500mg, and for those showing signs and symptoms suggestive of toxicity. The dosage should be adjusted to keep the blood level below 30g/mL.

INACTIVE INGREDIENT SECTION.


INACTIVE INGREDIENT SECTION Each capsule contains cycloserine, 250mg (2.45mmol); D and CYellow No.10, FD and CBlue No.1, FD and CRed No.3, FD and CYellow No.6, gelatin, iron oxide, talc, titanium dioxide, and other inactive ingredients.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY SECTION After oral administration, cycloserine is readily absorbed from the gastrointestinal tract, with peak blood levels occurring in 4to 8hours. Blood levels of 25to 30g/mL can generally be maintained with the usual dosage of 250mg 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 mothers milk approach those found in the serum. Detectable amounts are found in ascitic fluid, bile, sputum, amniotic fluid, and lung and lymph tissues. Approximately 65 percent of a single dose of cycloserine can be recovered in the urine within 72hours after oral administration. The remaining 35 percent is apparently metabolized to unknown substances. The maximum excretion rate occurs 2to 6hours after administration, with 50 percent of the drug eliminated in 12hours.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS SECTION 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 alcohol

WARNINGS SECTION.


WARNINGS SECTION Administration of Seromycin should be discontinued or the dosage reduced if the patient develops allergic dermatitis or symptoms of CNStoxicity, such as convulsions, psychosis, somnolence, depression, confusion, hyperreflexia, headache, tremor, vertigo, paresis, or dysarthria. The toxicity of Seromycin is closely related to excessive blood levels(above 30g/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.