Hi-Perazone

Cefoperazone + Sulbactam for Injection is white crystalline powder filled in plain glass vial and it contains Cefoperazone Sodium USP and Sulbactam Sodium USP as its active ingredient. Chemical name of Cefoperazone Sodium USP is Sodium (6R, 7R )-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)acetamido-3-[[(1-methyl-H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate and Sulbactam Sodium USP is Sodium (2S, 5R )-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.
Each vial contains: Cefoperazone Sodium USP Equivalent to Cefoperazone 1 g, Sulbactam Sodium USP Equivalent to Sulbactam 500 mg.

Therapeutic Classification: Antibacterial.
Pharmacology: Pharmacodynamics: The antibacterial component of Cefoperazone + Sulbactam is cefoperazone, a third generation cephalosporin, which acts against sensitive organisms during the stage of active multiplication by inhibiting the biosynthesis of cell wall mucopeptide. Sulbactam does not possess any useful antibacterial activity, except against Neisseriaceae and Acinetobacter. As sulbactam also binds with some penicillin-binding proteins, sensitive strains are also often rendered more susceptible to Cefoperazone + Sulbactam than to Cefoperazone alone. The combination of Sulbactam and Cefoperazone is active against all organisms sensitive to cefoperazone. In addition, it demonstrates synergistic activity (up to 4-fold reduction in the minimum inhibitory concentrations for the combination versus those for each component) in a variety of organisms.
Pharmacokinetics: Absorption: The mean serum concentration obtained at 30 mins. after 1 g I.V. Cefoperazone is 114 mcg/mL. The mean serum concentration obtained at 15 mins. after 500 mg and 1000 mg IV Sulbactam are 21-40 mcg/mL and 48-88 mcg/mL respectively. The average peak plasma concentration at 5 minutes after intravenous dose of 1 g is 81 mg/litre.
Distribution: The protein binding of Cefoperazone is 82-93% and that of Sulbactam is 38%.
Metabolism and Excretion: No significant quantity of metabolites of Cefoperazone has been found in the urine. Cefoperazone is excreted mainly in the bile. About 75-85% of Sulbactam is excreted in the urine during the first eight hours of administration.
Pharmacokinetics in Special Groups: Renal Insufficiency in Patients: No significant changes observed compared to normal patients.
Hepatic Insufficiency Patients: In patients with hepatic dysfunction, the serum half-life is prolonged and urinary excretion is increased. In patients combined with renal and hepatic insufficiency, Cefoperazone may accumulate in the serum.

Monotherapy: It is indicated for the treatment of the following infections when caused by susceptible organisms: Respiratory tract infections (upper and lower); Urinary tract infections (upper and lower); Peritonitis, cholecystitis, cholangitis, and other intra-abdominal infection; Septicemia; Meningitis; Skin and soft tissue infections; Bone and joint infections; Pelvic inflammatory disease, endometritis, gonorrhea, and other infections of the genital tract.
Combination Therapy: Because of the broad spectrum of activity of Cefoperazone + Sulbactam, most infections can be treated adequately with this antibiotic combination alone. However, Cefoperazone + Sulbactam may also be used concomitantly with other antibiotics if such combinations are indicated. If an aminoglycoside is used, renal function should be monitored during the course of therapy.

Adults: The usual adult dose of the combination is 2 to 4 g/day (i.e., 1-2 g/day each of Cefoperazone + Sulbactam) given IV or IM in equally divided doses every 12 hours. In severe or refractory infections the daily dosage may be increased to 8 g (i.e., 4 g/day each of Cefoperazone + Sulbactam) given IV or IM in equally divided doses every 12 hours. The recommended maximum daily dosage of Sulbactam is 4 g (8 g of the combination).
Children: The usual dosage in children is 40-80 mg/kg/day (20 to 40 mg/kg/day each of Cefoperazone and Sulbactam) every six to twelve hours. In serious or refractory infections, these dosages may be increased up to 240 mg/kg/day (160 mg/kg/day cefoperazone activity). Doses should be administered in two to four equally divided doses.
Use in Neonates: For neonates in the first week of life, the drug should be given every 12 hours. The maximum daily dosage of sulbactam in pediatrics should not exceed 80 mg/kg/day.
Renal Impairment: Dosage regimens of Cefoperazone + Sulbactam should be adjusted in patients with a marked decrease in renal function (creatinine clearance of less than 30 mL/min) to compensate for the reduced clearance of sulbactam. Patients with creatinine clearances between 15 and 30 mL/min should receive a maximum of 1 g of sulbactam every 12 hours (maximum daily dosage of 2 g sulbactam), while patients with creatinine clearances of less than 15 mL/min should receive a maximum of 500 mg of sulbactam every 12 hours (maximum daily dosage of 1 g sulbactam).
The pharmacokinetic profile of sulbactam is significantly altered by hemodialysis. The serum half-life of cefoperazone is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period.
Hepatic Impairment: Cefoperazone is extensively excreted through the bile. Dose modification may be necessary in cases of severe biliary obstruction, severe hepatic disease or in cases of renal dysfunction coexistent with either of those conditions. In such cases, dosage should not exceed 2 g/day of cefoperazone without close monitoring of serum concentrations.
Method of Administration: Intravenous Administration: For intermittent infusion, each vial of Cefoperazone + Sulbactam should be reconstituted with the appropriate amount of 5% Dextrose in Water, 0.9% Sodium Chloride Injection or Sterile Water for Injection and then diluted to 20 mL with the same solution followed by the administration over 15 to 60 minutes.
Lactated Ringer's Solution is a suitable vehicle for intravenous infusion, however, not for initial reconstitution.
For intravenous injection, each vial should be reconstituted as previously mentioned and administered over a minimum of 3 minutes.

Limited information is available on the acute toxicity of Cefoperazone Sodium and Sulbactam Sodium in humans. Overdosage of the drug would be expected to produce manifestations that are principally extensions of the adverse drug reactions reported with the drug. Since Cefoperazone and Sulbactam are both removed from the circulation by hemodialysis, these procedures may be done to enhance elimination of the drug from the body if overdosage occurs.

It is contraindicated in patients with a known allergy to penicillins, sulbactam, cefoperazone, or any of the cephalosporins.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam or cephalosporin therapy. These reactions are more apt to occur in individuals with a history of hypersensitivity reactions to multiple allergens. If an allergic reaction occurs, the drug should be discontinued and the appropriate therapy should be instituted.
As with other antibiotics, overgrowth of non-susceptible organisms may occur during the prolonged use of Cefoperazone + Sulbactam. It has not been extensively studied in premature infants or neonates. Therefore, in treating premature infants and neonates, the potential benefits and possible risks involved should be considered before instituting therapy.

Pregnancy: There are 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.
Lactation: Caution should be exercised when Cefoperazone + Sulbactam is administered to a nursing mother.

Sulbactam/cefoperazone is generally well tolerated. The majority of adverse events are of mild or moderate severity and are tolerated with continued treatment. (See Table 1.)

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The following undesirable effects have been observed and reported during treatment with sulbactam/cefoperazone with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).
All ADRs listed in the label are presented by MedDRA SOC and are presented in the order of clinical importance.

A reaction characterized by flushing, sweating, headache and tachycardia has been reported when alcohol was ingested during and as late as the fifth day after Cefoperazone administration. A similar reaction has been reported with certain other cephalosporins and patients should be cautioned concerning ingestion of alcoholic beverages in conjunction with administration of Cefoperazone + Sulbactam. For patients requiring artificial feeding orally or parenterally, solutions containing ethanol should be avoided.
Hepatic Impairment: In severe hepatic dysfunction, therapeutic concentrations of Cefoperazone are obtained in the bile and only a 2-to 4-fold increase in the half-life is seen. Dose modification may be necessary in case of severe biliary obstruction, severe hepatic disease or in case of renal dysfunction coexistent with either of those conditions.

Reconstitution: See Table 2.

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Cefoperazone + Sulbactam has been shown to be compatible with these diluents: Water for injection, 5% dextrose in 0.225% saline, and 5% dextrose in normal saline. Cefoperazone is compatible at concentrations ranging from 10 to 250 mg/mL of diluent. Sulbactam is compatible at concentrations ranging from 5 to 125 mg/ml of diluent.
Lactated Ringer's Solution: Sterile Water for Injection should be used for reconstitution. A two-step dilution is required using Sterile Water for Injection (shown in Table 2) further diluted with Lactated Ringer's Solution to a Sulbactam concentration of 5 mg/mL (use 2 mL initial dilution in 50 mL or 4 mL initial dilution in 100 mL Lactated Ringer's Solution).
Lidocaine: Sterile Water for Injection should be used for reconstitution. For a concentration of Cefoperazone of 250 mg/mL or larger, a two-step dilution is required using Sterile Water for Injection (shown in Table 2) further diluted with 2% lidocaine to yield solutions containing up to 250 mg.
Cefoperazone and 125 mg Sulbactam per mL in approximately a 0.5% lidocaine HCl solution.
Intramuscular Administration: Lidocaine Injection BP 2% is a suitable vehicle for intramuscular administration; however, it is not for initial reconstitution.
Lidocaine HCI 2% is a suitable vehicle for intramuscular administration, however, not for initial reconstitution.

Store at temperatures not exceeding 30°C. Protect from light.
Special Precautions for Storage: As reconstituted solution in vial, Cefoperazone plus Sulbactam remains stable for 24 hours when stored below room temperature.

Cephalosporins

J01DD62 - cefoperazone and beta-lactamase inhibitor ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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