Cefobid^® (Powder) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Haupt Pharma Latina S.r.l. (Italy)

ATC Code

J01DD12 (Cefoperazone)

Active Substance

Cefoperazone (Rec.INN registered by WHO)

Dosage Form

Cefobid®

Powder for solution for intravenous and intramuscular administration 1 g: vial. 1 pc.

Dosage Form, Packaging, and Composition

Powder for solution for intravenous and intramuscular administration crystalline, white or white with a yellowish tint.

Glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Third generation cephalosporin

Pharmacotherapeutic Group

Antibiotic-cephalosporin

Pharmacological Action

Semi-synthetic cephalosporin antibiotic with a broad spectrum of action, intended for parenteral administration only.

The bactericidal action of cefoperazone is due to inhibition of bacterial cell wall synthesis.

Cefoperazone is active in vitro against a large number of various clinically significant microorganisms. At the same time, it exhibits resistance to the action of many beta-lactamases.

Cefoperazone is active against aerobic gram-positive bacteria: Staphylococcus aureus (penicillinase-producing and non-producing strains), Staphylococcus epidermidis, Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Streptococcus pyogenes (beta-hemolytic streptococcus group A), Streptococcus agalactiae (beta-hemolytic streptococcus group B), many strains of Enterococcus faecalis, many other strains of beta-hemolytic streptococci; aerobic gram-negative bacteria Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Providencia spp. (including Providencia rettgeri), Serratia spp. (including Serratia marcescens), Salmonella spp., Shigella spp., Pseudomonas spp. (including Pseudomonas aeruginosa), Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica; anaerobic gram-positive bacteria Peptococcus spp., Peptostreptococcus spp., Clostridium spp., Eubacterium spp., Lactobacillus spp.; anaerobic gram-negative bacteria Veillonella spp., Fusobacterium spp., Bacteroides spp. (including many strains of Bacteroides fragilis).

Pharmacokinetics

Absorption

High levels of cefoperazone are achieved in blood, bile, and urine after a single administration.

The tables show the concentrations of cefoperazone in the blood serum of healthy adult volunteers after a 15-minute uniform intravenous infusion of the drug at a dose of 1, 2, 3, or 4 g or after a single intramuscular administration at a dose of 1 or 2 g.

*time elapsed after drug administration.

0 – time corresponding to the end of drug administration;

** results obtained 15 min after drug administration.

Distribution

Cefoperazone reaches therapeutic levels in all body tissues and biological fluids studied, including ascitic and cerebrospinal (in meningitis) fluid, urine, bile, gallbladder wall, lungs, sputum, palatine tonsils and sinus mucosa, atria, kidneys, ureters, prostate gland, testicles, uterus, fallopian tubes, bones, umbilical cord blood and amniotic fluid. Repeated administration of the drug to healthy individuals does not lead to accumulation of cefoperazone.

Elimination

The T_1/2 of cefoperazone from the blood is approximately 2 hours, regardless of the route of administration.

Cefoperazone is excreted in bile and urine. The concentration of cefoperazone in bile usually reaches a maximum level 1-3 hours after administration of Cefobid^® and exceeds its concentration in the blood by 100 times during this period. The following concentrations in bile have been recorded: from 66 mcg/ml after 30 minutes to 6000 mcg/ml after 3 hours following intravenous administration of 2 g of the drug to patients without bile duct obstruction.

Twelve hours after administration in different doses and by different routes in individuals with normal renal function, the concentration of cefoperazone in urine reaches on average 20-30% of the administered dose of the drug. Urine concentrations exceeding 2200 mcg/ml were obtained 15 minutes after intravenous administration of 2 g of Cefobid^®. After intramuscular administration of 2 g of the drug, the maximum concentration in urine was approximately 1000 mcg/ml.

Pharmacokinetics in special clinical cases

Pharmacokinetic parameters do not differ between patients with normal renal excretory function and patients with renal failure (C_max, AUC, T_1/2).

In patients with impaired liver function, the T_1/2 of cefoperazone from plasma is prolonged and its excretion in urine simultaneously increases.

In patients with renal-hepatic insufficiency, Cefoperazone may accumulate in the blood plasma.

Indications

Treatment of the following infectious diseases caused by microorganisms sensitive to cefoperazone

• Infections of the upper and lower respiratory tract;
• Infections of the upper and lower urinary tract;
• Infections of the abdominal organs, (including peritonitis, cholecystitis, cholangitis);
• Septicemia;
• Meningitis;
• Skin and soft tissue infections;
• Bone and joint infections;
• Infectious and inflammatory diseases of the pelvic organs, endometritis;
• Gonorrhea;
• Genital tract infections.

Prevention of infectious postoperative complications in abdominal, gynecological, cardiovascular and orthopedic surgeries.

The broad spectrum of action of cefoperazone allows for monotherapy of most infections; however, Cefoperazone can also be used in combination with other antibiotics.

ICD codes

Dosage Regimen

The average daily dose prescribed to adults ranges from 2 to 4 g; the dose is administered in 2 doses every 12 hours.

In severe infections, the daily dose may be increased to 8 g, (in 2 administrations every 12 hours.) No complications were identified when administering Cefobid^® at a daily dose of 12 g, divided into equal doses every 8 hours, and even 16 g, divided into equal doses. Treatment with the drug can be started before the results of microorganism sensitivity testing are obtained.

For uncomplicated gonococcal urethritis, a single intramuscular administration of 500 mg of the drug is recommended.

For the prevention of infectious postoperative complications, 1 g or 2 g of the drug is administered intravenously 30-90 minutes before the start of surgery. The dose can be repeated every 12 hours, but in most cases for no more than 24 hours. For surgeries with an increased risk of infection (for example, colorectal surgery), or if the resulting infection can cause particularly great harm (for example, during open-heart surgery or joint replacement), prophylactic use can continue for 72 hours after completion of the surgery.

In impaired liver function, dose adjustment may be required in cases of severe biliary obstruction, severe liver disease, or concomitant renal impairment. The daily dose should not exceed 2 g, and there is no need to monitor the concentration of cefoperazone in the blood serum.

Patients with impaired renal function can be prescribed the drug at an average daily dose (2-4 g) without adjustment. In patients with a glomerular filtration rate below 18 ml/min, or a serum creatinine level above 3.5 mg/dl, the daily dose should not exceed 4 g. During hemodialysis, the half-life of cefoperazone from the blood serum decreases somewhat, so the drug should be administered after the end of dialysis.

In simultaneous impairment of liver and kidney function, the concentration of cefoperazone in the blood serum should be monitored and the dose adjusted if necessary. There is no need to monitor serum concentrations provided that the daily dose does not exceed 2 g.

For children, Cefobid^® should be prescribed in daily doses ranging from 50 to 200 mg per 1 kg of body weight; the drug should be administered every 8-12 hours. The maximum daily dose is 12 g.

For intravenous bolus slow administration, the maximum single dose is 50 mg/kg of body weight; the duration of administration is at least 3-5 minutes.

For newborns (less than 8 days old), the daily dose ranges from 50 to 200 mg/kg; the drug should be administered every 12 hours.

Rules for preparation and administration of solution for intramuscular administration

Sterile water for injection or bacteriostatic water for injection can be used to prepare solutions intended for intramuscular administration. In cases where it is intended to administer the drug at a concentration exceeding 250 mg/ml, it is recommended to use a lidocaine solution for preparation. This solution can be prepared using sterile water for injection in combination with a 2% lidocaine solution, which approximates a 0.5% lidocaine hydrochloride solution.

It is recommended to dilute the drug in 2 stages: first, add the required amount of sterile water for injection and shake until the powder is completely dissolved, then add the required amount of 2% lidocaine solution and mix.

* the excess volume allows complete filling of the syringe of the specified volume.

Intramuscular administration is performed deep into the gluteus maximus muscle or into the anterior surface of the thigh.

Rules for preparation and administration of solution for intravenous administration

The contents of the vial are first diluted in any compatible solution for intravenous administration (at a rate of at least 2.8 ml/1 g of cefoperazone). To facilitate dissolution, it is recommended to use 5 ml of solvent per 1 g of Cefobid^®.

The following solutions are used for initial dilution: 5% dextrose injection solution, 10% dextrose solution, 0.9% sodium chloride injection solution, 5% dextrose and 0.9% sodium chloride injection solution, 5% dextrose and 0.2% sodium chloride injection solution, sterile water for injection, Normosol R, Normosol M in 5% dextrose injection solution.

Then the entire amount of the resulting solution must be diluted with one of the following solvents for intravenous administration: 5% dextrose injection solution, 10% dextrose injection solution, 5% dextrose and lactated Ringer’s injection solution, lactated Ringer’s solution, 5% dextrose and 0.9% sodium chloride injection solution, 0.9% sodium chloride injection solution, Normosol R, Normosol M in 5% dextrose injection solution, 5% dextrose and 0.2% sodium chloride injection solution.

For intravenous drip administration, the contents of each vial of Cefobid^® (1 g) are dissolved in 20-100 ml of a compatible sterile solution for intravenous injection and administered over a period of 15 minutes to 1 hour. If sterile water is used as a solvent, then no more than 20 ml is added to the vial with the drug.

For long-term intravenous infusion, the contents of 1 vial (1 g) are dissolved either in 5 ml of sterile water for injection, or in 5 ml of bacteriostatic water for injection; the resulting solution is added to the appropriate solvent for intravenous administration.

For intravenous bolus slow administration, the drug is dissolved in an appropriate solvent with a final concentration of 100 mg/ml and administered over at least 3-5 minutes.

Adverse Reactions

From the hematopoietic system cases of a slight decrease in neutrophil levels, reversible neutropenia (with prolonged treatment), positive direct Coombs test, decreased hematocrit and hemoglobin; in some cases – transient eosinophilia and hypoprothrombinemia.

From the digestive system: mild and moderate dyspeptic phenomena (these symptoms disappeared after drug withdrawal and/or symptomatic therapy), moderately pronounced transient increase in AST, ALT and ALP activity.

Allergic reactions maculopapular rash, urticaria, eosinophilia and drug fever (most often such reactions to treatment with Cefobid^® occur in patients with a history of a tendency to allergic reactions, especially to penicillin).

Local reactions: intramuscular injection is sometimes accompanied by pain; during intravenous infusion, some patients may develop phlebitis at the infusion site.

During post-marketing surveillance, the following adverse events have also been reported.

From the digestive system: vomiting, pseudomembranous colitis.

Other: allergic reactions, anaphylactoid reactions (including shock), pruritus, Stevens-Johnson syndrome, bleeding.

Contraindications

• Hypersensitivity to cefoperazone and other cephalosporin antibiotics.

Use in Pregnancy and Lactation

The drug can be prescribed during pregnancy only if the intended benefit to the mother outweighs the potential risk to the fetus.

If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be considered.

Use in Hepatic Impairment

In patients with impaired liver function, dose adjustment may be required in cases of severe biliary obstruction, severe liver disease, or concomitant renal impairment. The daily dose should not exceed 2 g, and there is no need to monitor the serum concentration of cefoperazone.

Use in Renal Impairment

Patients with impaired renal function can be prescribed the drug at the average daily dose (2-4 g) without adjustment. In patients with a glomerular filtration rate below 18 ml/min or a serum creatinine level above 3.5 mg/dl, the daily dose should not exceed 4 g. During hemodialysis, the half-life of cefoperazone from the blood serum is somewhat reduced; therefore, the drug should be administered after the completion of dialysis.

Special Precautions

The broad spectrum of action of cefoperazone allows for monotherapy of most infections. Nevertheless, Cefobid^® can also be used in combination therapy with other antibiotics if such treatment is indicated. When used concomitantly with aminoglycosides, monitoring of renal function is recommended.

Before prescribing Cefobid^® to a patient, it is necessary to determine whether the patient has a history of hypersensitivity to cephalosporins, penicillins, and other drugs as a precaution. The drug should be prescribed with great caution to patients with hypersensitivity to penicillin. All patients with a history of various allergic reactions, and especially drug allergy, should be prescribed antibiotics with caution.

If an allergic reaction occurs, the use of Cefobid^® should be discontinued, and appropriate treatment should be initiated. Serious anaphylactic reactions require immediate administration of epinephrine (adrenaline). Oxygen, intravenous corticosteroids, and ensuring a patent airway (including intubation) should be administered if necessary.

In severe biliary obstruction or severe liver disease, the T_1/2 of cefoperazone is usually prolonged, and the urinary excretion of the drug increases.

In some patients, treatment with Cefobid^®, as well as treatment with other antibiotics, may lead to vitamin K deficiency. This is most likely due to the suppression of the intestinal flora that synthesizes this vitamin. Patients on a restricted diet, receiving prolonged parenteral nutrition, or with malabsorption (e.g., patients with cystic fibrosis) are at risk. In such patients, prothrombin time should be monitored, and exogenous vitamin K should be prescribed if necessary.

Prolonged use of cefoperazone may lead to the overgrowth of resistant microorganisms (as with treatment with other antibiotics). Therefore, patients should be carefully monitored during treatment.

During the use of the drug, a false-positive reaction for urine glucose may occur with Benedict’s or Fehling’s solution.

Disulfiram-like reactions, manifested as sudden flushing, sweating, headache, and tachycardia, have been reported with alcohol consumption during or within 5 days after using Cefobid^®. Therefore, patients should refrain from consuming alcohol and taking ethanol-containing preparations during treatment with Cefobid^®.

Use in pediatrics

Cefobid^® has been used successfully in the treatment of infants. However, large-scale studies concerning its use in neonates and premature infants have not been conducted to date. Therefore, both the expected positive effects and the possible risks associated with treatment should be considered before prescribing it to premature and newborn infants.

Overdose

Information on acute overdose with Cefobid^® is limited.

Symptoms: possible intensification of the described adverse effects. Cephalosporins in very high doses may lead to epileptic seizures.

Treatment: sedative therapy with diazepam for epileptic seizures caused by overdose. Cefoperazone is removed by hemodialysis; therefore, this procedure can be used in cases of overdose in patients with impaired renal function.

Drug Interactions

Concomitant use of probenecid does not affect the serum concentration of cefoperazone.

Pharmaceutical interaction .

Solutions of Cefobid^® and an aminoglycoside should not be mixed directly due to physical incompatibility between them.

When combination therapy with cefoperazone and an aminoglycoside is necessary, sequential fractional intravenous administration of the drugs should be performed using two separate intravenous catheters, provided they are adequately flushed with the appropriate solvents between the administration of sequential doses of the drugs. It is also suggested to administer Cefoperazone before the aminoglycoside.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Shelf Life

Shelf life – 2 years.

The stability of prepared solutions depends on the type of solvent, concentration, and storage conditions. The storage periods are indicated in the table. Upon expiration of the indicated periods, unused solution residues should be destroyed.

Reconstituted solutions are stored in glass or plastic syringes, glass or flexible plastic containers intended for parenteral solutions.

In the freezer, reconstituted solutions are stored in plastic syringes or flexible plastic containers intended for parenteral solutions.

Before use, frozen solutions of the drug should be thawed at room temperature. Unused frozen solution must be destroyed.

Solutions should not be refrozen.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.