Cefoperazone

Pregnancy Category B.

Reproduction studies have been performed in mice, rats, and monkeys at doses up to 10 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefoperazone. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Only low concentrations of cefoperazone are excreted in human milk. Although cefoperazone passes poorly into breast milk of nursing mothers, caution should be exercised when cefoperazone is administered to a nursing woman.

Long term studies in animals have not been performed to evaluate carcinogenic potential. The maximum duration of cefoperazone animal toxicity studies is six months. In none of the in vivo or in vitro genetic toxicology studies did cefoperazone show any mutagenic potential at either the chromosomal or subchromosomal level.

Cefoperazone produced no impairment of fertility and had no effects on general reproductive performance or fetal development when administered subcutaneously at daily doses up to 500 to 1000 mg/kg prior to and during mating, and to pregnant female rats during gestation. These doses are 10 to 20 times the estimated usual single clinical dose.

Cefoperazone had adverse effects on the testes of prepubertal rats at all doses tested. Subcutaneous administration of 1000 mg/kg per day (approximately 16 times the average adult human dose) resulted in reduced testicular weight, arrested spermatogenesis, reduced germinal cell population and vacuolation of Sertoli cell cytoplasm. The severity of lesions was dose dependent in the 100 to 1000 mg/kg per day range; the low dose caused a minor decrease in spermatocytes. This effect has not been observed in adult rats. Histologically the lesions were reversible at all but the highest dosage levels. However, these studies did not evaluate subsequent development of reproductive function in the rats. The relationship of these findings to humans is unknown.

Clinical Trials Experience

In clinical studies the following adverse effects were observed and were considered to be related to cefoperazone therapy or of uncertain etiology:

Hypersensitivity: As with all cephalosporins, hypersensitivity manifested by skin reactions (1 patient in 45), drug fever (1 in 260), or a change in Coombs' test (1 in 60) has been reported. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin.

Hematology: As with other beta-lactam antibacterial drugs, reversible neutropenia may occur with prolonged administration. Slight decreases in neutrophil count (1 patient in 50) have been reported. Decreased hemoglobins (1 in 20) or hematocrits (1 in 20) have been reported, which is consistent with published literature on other cephalosporins. Transient eosinophilia has occurred in 1 patient in 10.

Hepatic: Of 1285 patients treated with cefoperazone in clinical trials, one patient with a history of liver disease developed significantly elevated liver function enzymes during cefoperazone therapy. Clinical signs and symptoms of nonspecific hepatitis accompanied these increases. After cefoperazone therapy was discontinued, the patient’s enzymes returned to pre-treatment levels and the symptomatology resolved. As with other antibacterial drugs that achieve high bile levels, mild transient elevations of liver function enzymes have been observed in 5–10% of the patients receiving cefoperazone therapy. The relevance of these findings, which were not accompanied by overt signs or symptoms of hepatic dysfunction, has not been established.

Gastrointestinal: Diarrhea or loose stools has been reported in 1 in 30 patients. Most of these experiences have been mild or moderate in severity and self-limiting in nature. In all cases, these symptoms responded to symptomatic therapy or ceased when cefoperazone therapy was stopped. Nausea and vomiting have been reported rarely.

Symptoms of pseudomembranous colitis can appear during or for several weeks subsequent to antibacterial therapy.

Renal Function Tests: Transient elevations of the BUN (1 in 16) and serum creatinine (1 in 48) have been noted.

Local Reactions: Cefoperazone is well tolerated following intramuscular administration. Occasionally, transient pain (1 in 140) may follow administration by this route. When cefoperazone is administered by intravenous infusion some patients may develop phlebitis (1 in 120) at the infusion site.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of cefoperazone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Thrombocytopenia, hypoprothrombinaemia

Immune System disorders: Anaphylactic reactions, including shock and fatal cases

Hepatobiliary Disorders: Jaundice, hepatic dysfunction

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens Johnson syndrome, pruritus

Vascular Disorders: Hemorrhage