Cefoperazone Sodium Injection IP 1g (Cefozone)

Cefoperazone Sodium Injection IP 1g (Cefozone) Taj Pharma

CEFOZONE – 1

Cefoperazone Sodium Injection IP 500mg Taj Pharma
Cefoperazone Sodium Injection IP 1g Taj Pharma

COMPOSITION:

CEFOZONE – 1

a) Each vial contains:
Cefoperazone Sodium IP (Sterile)
equivalent to Anhydrous
Cefoperazone…………………..500mg
Water for Injection IP……..………….q.s.

b) Each vial contains:
Cefoperazone Sodium IP (Sterile)
equivalent to Anhydrous
Cefoperazone…………………..1000mg
Water for Injection IP……..………….q.s.

DESCRIPTION:

Cefoperazone is a semisynthetic broad-spectrum cephalosporin proposed to be effective against Pseudomonas infections. It is a third-generation antiobiotic agent and it is used in the treatment of various bacterial infections caused by susceptible organisms in the body, including respiratory tract infections, peritonitis, skin infections, endometritis, and bacterial septicemia.

CLINICAL PHARMACOLOGY:

Mechanism of Action:

Like all beta-lactam antibiotics, cefoperazone binds to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, causing the inhibition of the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins.

Pharmacokinetics:

Absorption:
Not Available

Distribution:

Widely distributed into body tissues and fluids; poor CSF penetration. Crosses the placenta and enters breast milk (low concentrations); bile (high concentrations). Protein-binding: 82-93%.

Metabolism:

No significant quanitity of metabolites have been identified in urine.

Elimination:
Mainly via the bile. Via the urine within 12-24 hrs by glomerular filtration (30% as unchanged); proportion may be increased in hepatic or biliary disease.

Half-life:
The mean serum half-life is approximately 2.0 hours, independent of the route of administration. 

Special populations:

Usage In Pregnancy

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 Cefozone. 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.

Usage In Nursing Mothers

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

Pediatric Use

Safety and effectiveness in children have not been established. For information concerning testicular changes in prepubertal rats (see Carcinogenesis, Mutagenesis, Impairment of Fertility).

Geriatric Use

Clinical studies of Cefozone (sterile Cefoperazone Sodium) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond 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.

INDICATIONS:

Indicated for the treatment of following infections caused by susceptible bacteria:

1) Respiratory tract infections caused by S. pneumoniae, H. influenzae, S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes (Group A beta-hemolytic streptococci), P. aeruginosa, Klebsiella pneumoniae, E. coli, Proteus mirabilis, and Enterobacter species.

2) Peritonitis and other intra-abdominal infections caused by E. coli, P. aeruginosa, and anaerobic gram-negative bacilli (including Bacteroides fragilis).

3) Bacterial septicemia caused by S. pneumoniae, S. agalactiae, S. aureus, Pseudomonas aeruginosa, E. coli, Klebsiella spp., Klebsiella pneumoniae, Proteus species (indole-positive and indole-negative), Clostridium spp. and anaerobic gram-positive cocci.

4) Infections of the skin and skin structures caused by S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes, and P. aeruginosa.

5) Pelvic Inflammatory Disease, Endometritis, and Other Infections of the Female Genital Tract caused by N. gonorrhoeae, S. epidermidis, S. agalactiae, E. coli, Clostridium spp., Bacteroides species (including Bacteroides fragilis), and anaerobic gram-positive cocci.

6) Urinary tract infections caused by Escherichia coli and Pseudomonas aeruginosa.

7) Enterococcal Infections. Although cefoperazone has been shown to be clinically effective in the treatment of infections caused by enterococci in cases of peritonitis and other intra-abdominal infections, infections of the skin and skin structures, pelvic inflammatory disease, endometritis and other infections of the female genital tract, and urinary tract infections, the majority of clinical isolates of enterococci tested are not susceptible to cefoperazone but fall just at or in the intermediate zone of susceptibility, and are moderately resistant to cefoperazone. However, in vitro susceptibility testing may not correlate directly with in vivo results. Despite this, cefoperazone therapy has resulted in clinical cures of enterococcal infections, chiefly in polymicrobial infections. Cefoperazone should be used in enterococcal infections with care and at doses that achieve satisfactory serum levels of cefoperazone.

DOSAGE AND ADMINISTRATION:

Usual Adult Dose for Endometritis

1 to 2 g IV or IM every 12 hours to continue until 48 hours after clinical improvement has been observed. Appropriate oral antibiotic therapy may continue until 14 days of therapy has been completed.

Usual Adult Dose for Febrile Neutropenia

1 to 2 g IV or IM every 12 hours. Therapy should be continued for 14 days, or until more specific therapy can be instituted for an identified pathogen, or until the patient has been afebrile for 24 hours after the absolute neutrophil count has reached at least 500 cells/mm3.

Usual Adult Dose for Intraabdominal Infection

1 to 2 g IV or IM every 12 hours for 7 to 14 days.

Usual Adult Dose for Joint Infection

1 to 2 g IV or IM every 12 hours for 3 to 4 weeks. Longer therapy, 6 weeks or more, may be required with prosthetic joint infections. In addition, removal of the infected joint may be required.

Usual Adult Dose for Pelvic Inflammatory Disease

1 to 2 g IV or IM every 12 hours to continue until 48 hours after clinical improvement has been observed. Appropriate oral antibiotic therapy should then commence and continue until 14 days of therapy has been completed.
Doxycycline therapy for 7 days (if not pregnant) or single dose azithromycin is also recommended to treat possible concurrent chlamydial infection.

Usual Adult Dose for Peritonitis

1 to 2 g IV or IM every 12 hours for 10 to 14 days.

Usual Adult Dose for Pneumonia

1 to 2 grams IV or IM every 12 hours for 7 to 21 days depending upon the causative organism.

Usual Adult Dose for Pyelonephritis

1 to 2 g IV or IM every 12 hours for 14 days.

Usual Adult Dose for Bacteremia

2 g IV or IM every 12 hours for 14 days.

Usual Adult Dose for Skin or Soft Tissue Infection

1 to 2 g IV or IM every 12 hours for 7 days or for 3 days after inflammation subsides depending on the nature and severity of infection. For more severe infections such as diabetic soft tissue infections, 14 to 21 days of therapy may be required.

Usual Adult Dose for Urinary Tract Infection

1 g IV or IM every 12 hours for 3 to 7 days.

Renal Dose Adjustments

No adjustment recommended

Liver Dose Adjustments

If doses greater than 4 g/24 hours are required in patients with liver disease, monitor serum levels closely.
In patients with both liver dysfunction and significant renal impairment, doses should not exceed 1 to 2 g/day without close monitoring of serum levels.

Dose Adjustments

In patients with both hepatic dysfunction and significant renal disease, dosage should not exceed 1 to 2 g/day without close monitoring of serum levels.

Precautions

If C trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because cefoperazone has no activity against this organism.
Patients should avoid alcoholic beverages for at least 72 hours after cefoperazone administration.

Dialysis

The half-life of cefoperazone is reduced slightly during hemodialysis. Dosing should be scheduled to follow a dialysis period.

Method of Administration:

Injectable Powder for injection (I.V./I.M.).

CONTRAINDICATIONS:

Cefozone is contraindicated in patients with known allergy to the cephalosporin-class of antibacterial drugs. 

WARNINGS AND PRECAUTIONS:

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including cefoperazone. These reactions are more apt to occur in individuals with a history of hypersensitivity reactions to multiple allergens. Before therapy with cefobid is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins, carbapenems or other drugs. This product should be given cautiously to beta-lactam allergic patients. If an allergic reaction occurs, cefoperazone should be discontinued and appropriate therapy instituted.

Severe and occasionally fatal skin reactions such as toxic epidermal necrolysis (TEN), Stevens Johnson Syndrome (SJS), and exfoliative dermatitis have been reported in patients on Cefozone therapy. If a severe skin reaction occurs Cefozone should be discontinued and appropriate therapy should be initiated.

Clostridium Difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefozone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

1. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficilecause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Hemorrhage

Serious hemorrhage cases, including fatalities, have been reported with cefoperazone. Monitor for signs of bleeding, thrombocytopenia, and coagulopathy. Discontinue Cefozone if there is persistent bleeding and no alternative explanations are identified.

Precautions

General

Prescribing Cefozone in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Although transient elevations of the BUN and serum creatinine have been observed, Cefozone alone does not appear to cause significant nephrotoxicity. However, concomitant administration of aminoglycosides and other cephalosporins has caused nephrotoxicity.

Cefozone is extensively excreted in bile. The serum half-life of Cefozone is increased 2–4 fold in patients with hepatic disease and/or biliary obstruction. In general, total daily dosage above 4 g should not be necessary in such patients. If higher dosages are used, serum concentrations should be monitored.

Because renal excretion is not the main route of elimination of Cefozone, patients with renal failure require no adjustment in dosage when usual doses are administered. When high doses of Cefozone are used, concentrations of drug in the serum should be monitored periodically. If evidence of accumulation exists, dosage should be decreased accordingly.

The half-life of Cefozone is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period. In patients with both hepatic dysfunction and significant renal disease, Cefozone dosage should not exceed 1–2 g daily without close monitoring of serum concentrations.

As with other antibacterial drugs, vitamin K deficiency resulting in coagulopathy has occurred in patients treated with Cefozone. The mechanism is probably related to the suppression of gut flora which normally synthesize this vitamin. Those at risk include patients with a poor nutritional status, malabsorption states (e.g., cystic fibrosis), alcoholism, and patients on prolonged hyper- alimentation regimens (administered either intravenously or via a naso-gastric tube). Hypoprothrombinemia with or without bleeding has been reported. Prothrombin time should be monitored in these patients and exogenous vitamin K administered as indicated.

A disulfiram-like reaction characterized by flushing, sweating, headache, and tachycardia has been reported when alcohol (beer, wine) was ingested within 72 hours after Cefozone administration. Patients should be cautioned about the ingestion of alcoholic beverages following the administration of Cefozone.

Prolonged use of Cefozone may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Cefozone should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

ADVERSE REACTIONS:
Skin rash, urticaria; eosinophilia, diarrhoea, nausea, vomiting; phloebitis; hypoprothrombinaemia; superinfection.
Potentially Fatal: Neuromuscular hypersensitivity; nephrotoxicity.

DRUG INTERACTIONS:
A false-positive reaction for glucose in the urine may occur with Benedict’s or Fehling’s solution.
Disulfiram-like reaction with alcohol. Potentiates anticoagulants.
Potentially Fatal: Enhances nephrotoxicity by aminoglycosides and furosemide.

OVERDOSAGE:
Information not available.

STORAGE:
Parenteral: Store below 25°C.

7. MANUFACTURED BY:
TAJ PHARMACEUTICALS LTD.
Plot No.: 615, G.I.D.C., Kerala, Bavla,
District: Ahmedabad – 438225, Gujarat, INDIA.