Zontam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZONTAM (ZONETAM)

Composition:

Active substances: cefoperazone sodium, sulbactam sodium;

1 vial contains cefoperazone sodium equivalent to cefoperazone 500 mg and sulbactam sodium equivalent to sulbactam 500 mg;

Excipients: none.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: powder from white to almost white in color.

Pharmacotherapeutic group.
Antibacterials for systemic use. Beta-lactam antibiotics. Third-generation cephalosporins. ATC code J01D D62.

Pharmacological properties.

Pharmacodynamics.

Zontam is a combination of sodium sulbactam and cefoperazone sodium.

Sodium sulbactam is a derivative of the basic penicillin nucleus. It is an irreversible inhibitor of beta-lactamase and is administered only parenterally. Chemically, it is the sodium sulphonate of penicillinate. It contains 92 mg of sodium (4 mEq) per 1 gram. Sulbactam is a very soluble in water, crystalline, almost white powder. Molecular weight is 255.22.

Cefoperazone sodium is a broad-spectrum semi-synthetic third-generation cephalosporin antibiotic, administered only parenterally. It contains 34 mg of sodium (1.5 mEq) per 1 gram. Cefoperazone is a water-soluble, white crystalline powder. Molecular weight is 667.65.

Mechanism of action. The antibacterial component of Zontam is cefoperazone, a third-generation cephalosporin that acts against susceptible microorganisms during active multiplication by inhibiting the biosynthesis of the muropeptide cell membrane. Sulbactam has no significant intrinsic antibacterial activity, except for activity against Neisseriaceae and Acinetobacter. However, biochemical studies on cell-free bacterial systems have shown that sulbactam is an irreversible inhibitor of the major beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

The potential of sulbactam to prevent the degradation of penicillins and cephalosporins by resistant microorganisms has been confirmed in studies involving resistant strains of intact microorganisms, in which sulbactam demonstrated a pronounced synergism with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains become more vulnerable to Zontam than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms susceptible to cefoperazone. In addition, synergistic action is observed (reduction of minimum inhibitory concentrations of the combination by approximately 4-fold compared to each component alone) against various microorganisms, with the most pronounced effect against the following: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Zontam demonstrates in vitro activity against a broad spectrum of clinically significant microorganisms.

Gram-positive microorganisms:

• Staphylococcus aureus (strains producing or not producing penicillinase);
• Staphylococcus epidermidis;
• Streptococcus pneumoniae (former name Diplococcus pneumoniae);
• Streptococcus pyogenes (beta-hemolytic group A streptococcus);
• Streptococcus agalactiae (beta-hemolytic group B streptococcus);
• most other strains of beta-hemolytic streptococci;
• many strains of Streptococcus faecalis (enterococci).

Gram-negative microorganisms:

• Escherichia coli;
• Klebsiella spp.;
• Enterobacter spp.;
• Citrobacter spp.;
• Haemophilus influenzae;
• Proteus mirabilis;
• Proteus vulgaris;
• Morganella morganii (former name Proteus morganii);
• Providencia rettgeri (former name Proteus rettgeri);
• Providencia spp.;
• Serratia spp. (including S. marcescens);
• Salmonella spp. and Shigella spp.;
• Pseudomonas aeruginosa and some Pseudomonas spp.;
• Acinetobacter calcoaceticus;
• Neisseria gonorrhoeae;
• Neisseria meningitidis;
• Bordetella pertussis;
• Yersinia enterocolitica.

Anaerobic microorganisms:

• Gram-negative bacteria (including Bacteroides fragilis, other Bacteroides spp., and Fusobacterium spp.);
• Gram-positive and Gram-negative cocci (including Peptococcus spp., Peptostreptococcus spp., and Veillonella spp.);
• Gram-positive bacteria (including Clostridium spp., Eubacterium spp., and Lactobacillus spp.).

The following effective concentration ranges have been established for Zontam.

Minimum inhibitory concentrations (MICs) (μg/mL, as cefoperazone concentrations):

Disk diffusion zone diameter (mm, Kirby-Bauer):

To determine the MIC, serial dilutions of sulbactam/cefoperazone should be used by means of agar or broth dilution methods. The use of a disk diffusion susceptibility test containing 30 μg sulbactam and 75 μg cefoperazone is recommended. A laboratory report of "susceptible" indicates that the infecting microorganism is likely to respond effectively to treatment with Zontam, while a report of "resistant" indicates that such an effective response is unlikely. An "intermediate" response means that the microorganism may be susceptible to Zontam when the drug is administered at higher doses, or that the infection has developed in tissues or body fluids where high antibiotic concentrations are expected to be achieved.

Recommended quality control ranges for 30 μg/75 μg sulbactam/cefoperazone disks:

Pharmacokinetics.

The mean maximum concentrations of sulbactam and cefoperazone after a single 5-minute intravenous infusion of 2 g (in a 1:1 ratio) of Zontam (1 g sulbactam + 1 g cefoperazone) in healthy volunteers were 130 and 236.8 µg/mL, respectively. This indicates a larger volume of distribution of sulbactam (Vd = 18.0–27.6 L) compared to that of cefoperazone (Vd = 10.2–11.3 L).

The mean maximum concentrations of sulbactam and cefoperazone after a single 15-minute intravenous infusion of 4.5 g (in a 1:2 ratio) of Zontam (1.5 g sulbactam + 3 g cefoperazone) in healthy volunteers were 88.3 µg/mL and 416.1 µg/mL, respectively.

The maximum serum concentrations of sulbactam and cefoperazone after the first intramuscular injection of 1.5 g of Zontam (0.5 g sulbactam + 1 g cefoperazone) in healthy volunteers were 11 µg/mL and 45.3 µg/mL, and 29.9 µg/mL and 58.4 µg/mL, respectively, after administration of the seventh dose when the drug was given every 12 hours.

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose administered as Zontam are excreted by the kidneys. Most of the remaining cefoperazone dose is excreted via bile. After administration of sulbactam/cefoperazone, the mean elimination half-life of sulbactam is 1 hour and that of cefoperazone is 1.7 hours. Plasma concentrations are proportional to the administered dose. These data are consistent with previously published pharmacokinetic studies of these components when administered separately.

After intramuscular administration of 1.5 g of Zontam (0.5 g sulbactam and 1 g cefoperazone), maximum plasma concentrations of sulbactam and cefoperazone were reached within 15 minutes to 2 hours after injection. The mean maximum concentrations were 19 µg/mL and 64.2 µg/mL for sulbactam and cefoperazone, respectively.

After repeated administration of the drug, no significant changes in the pharmacokinetics of the components of Zontam have been reported, and no accumulation was observed when administered every 8–12 hours.

Patients with hepatic impairment.

See section "Special precautions".

Patients with renal impairment.

In patients with various degrees of renal impairment who received Zontam, total body clearance of sulbactam was highly correlated with creatinine clearance. In patients with non-functioning kidneys, the mean elimination half-life of sulbactam was significantly prolonged (on average 6.9 and 9.7 hours according to different studies). Hemodialysis significantly alters the elimination half-life, total body clearance, and volume of distribution of sulbactam. No significant differences in the pharmacokinetics of cefoperazone were observed in patients with renal insufficiency.

Elderly patients.

The pharmacokinetics of Zontam were studied in elderly patients with renal and hepatic impairment. Both components of the drug, sulbactam and cefoperazone, demonstrated a longer elimination half-life, lower clearance, and larger volume of distribution compared to those in healthy volunteers. Pharmacokinetic data for sulbactam correlate well with the degree of renal impairment, while data for cefoperazone correlate well with the degree of hepatic impairment.

Children.

Studies conducted in children demonstrated no significant changes in the pharmacokinetics of the components of Zontam compared to data in adult patients. In children, the mean elimination half-life of sulbactam ranged from 0.91 to 1.42 hours, and that of cefoperazone ranged from 1.44 to 1.88 hours.

Sulbactam and cefoperazone are well distributed into tissues and body fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, and others.

There is no evidence of any pharmacokinetic interaction between sulbactam and cefoperazone when co-administered in the form of Zontam.

Cefoperazone does not displace bilirubin from plasma protein binding sites.

Clinical characteristics.

Indications.

The drug is indicated for the treatment of infections caused by susceptible strains of microorganisms:

• respiratory tract infections (upper and lower);
• urinary tract infections (upper and lower);
• peritonitis, cholecystitis, cholangitis, and other intra-abdominal infections;
• septicemia;
• meningitis;
• skin and soft tissue infections;
• bone and joint infections;
• inflammatory diseases of the pelvic organs, endometritis, gonorrhea, and other genital infections.

Contraindications.

Zontam is contraindicated in patients with known hypersensitivity to penicillins, sulbactam, cefoperazone, or any cephalosporin.

Interaction with other medicinal products and other forms of interaction.

Combination therapy. Due to the broad spectrum of antibacterial activity of sulbactam/cefoperazone, Zontam can be used as monotherapy for adequate treatment of most infections. However, under certain indications, sulbactam/cefoperazone may be used concomitantly with other antibiotics. When aminoglycosides are used simultaneously, renal function should be monitored throughout the course of therapy (see also section "Incompatibilities").

Alcohol. Facial flushing, sweating, headache, and tachycardia have been reported when alcohol is consumed during therapy and within 5 days after administration of cefoperazone. Similar reactions have been observed with other cephalosporins. Patients should be cautious about consuming alcoholic beverages during treatment with Zontam. When using artificial nutrition (oral or parenteral), solutions containing ethanol should not be used.

Interaction with substances used in laboratory tests. A false-positive glucose urine test may occur when using Benedict's or Fehling's solution.

Special precautions for use.

Hypersensitivity. Severe, and sometimes fatal, hypersensitivity reactions (anaphylactic reactions) have been reported in patients receiving beta-lactam or cephalosporin antibiotics, including cefoperazone/sulbactam. Such reactions are more likely to occur in individuals with a history of multiple allergies.

If allergic reactions occur, administration of the drug should be discontinued and appropriate therapy initiated. Severe anaphylactic reactions require immediate administration of epinephrine. Oxygen therapy, corticosteroids, and measures to ensure airway patency, including intubation, should be provided as indicated.

Cases of severe skin reactions, sometimes fatal, such as toxic epidermal necrolysis, Stevens–Johnson syndrome, and exfoliative dermatitis, have been reported in patients treated with sulbactam/cefoperazone. In the event of a severe skin reaction, therapy with sulbactam/cefoperazone should be discontinued and appropriate treatment initiated (see section "Adverse reactions").

Use in hepatic impairment. Cefoperazone is predominantly excreted via bile. In patients with hepatic disease and/or biliary obstruction, the serum half-life of cefoperazone is usually prolonged, while renal excretion increases. Even in cases of severe hepatic dysfunction, therapeutic concentrations of cefoperazone are achieved in bile, with only a 2- to 4-fold increase in serum half-life.

Dose adjustment may be necessary in cases of severe biliary obstruction, severe liver disease, or concomitant renal impairment associated with any of these conditions.

In patients with hepatic impairment and concomitant renal dysfunction, serum cefoperazone concentrations should be monitored, and dosage adjusted as needed. In such cases, without careful monitoring of serum concentrations, the cefoperazone dose should not exceed 2 g/day.

General warnings. Cases of serious bleeding, including fatal outcomes, have been reported during treatment with cefoperazone/sulbactam. At-risk patients include those with poor nutrition, malabsorption, and those receiving prolonged parenteral (intravenous) nutrition. Such patients should be monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. If prolonged bleeding occurs without other identifiable cause, cefoperazone/sulbactam should be discontinued.

As with other antibiotics, treatment with cefoperazone/sulbactam may lead to vitamin K deficiency in some patients. This effect is likely due to suppression of intestinal flora normally responsible for vitamin K synthesis. Thus, at-risk patients include those with poor nutrition, malabsorption (e.g., in cystic fibrosis), and those receiving prolonged parenteral (intravenous) nutrition. In such patients, as well as in those receiving anticoagulants, prothrombin time (or International Normalized Ratio) should be monitored, and exogenous vitamin K administered if indicated.

As with other antibiotics, prolonged use of Zontam may lead to overgrowth of non-susceptible microorganisms. Patients should be closely monitored during therapy. As with other potent systemic agents, periodic monitoring for organ system dysfunction—including renal, hepatic, and hematopoietic systems—is recommended, particularly in premature infants and other neonates.

Clostridium difficile-associated diarrhea has been reported with nearly all antibacterial agents, including sodium sulbactam/sodium cefoperazone. The severity may range from mild diarrhea to fatal colitis. Antibacterial agents alter the normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of Clostridium difficile-associated diarrhea. Toxin-producing strains of C. difficile may increase morbidity and mortality, as these infections may be resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in patients with diarrhea following antibacterial therapy. Careful medical history is essential, as cases of C. difficile-associated diarrhea have been reported up to two months after completion of antibacterial treatment.

The medicinal product contains sodium: it may not be suitable for patients who require sodium restriction.

Children.

Zontam can be effectively used in children; however, comprehensive studies on its use in premature or full-term neonates have not been conducted. Therefore, the potential benefits and risks of using the drug should be carefully evaluated before initiating treatment in premature or full-term neonates.

In neonates with bilirubin encephalopathy, cefoperazone does not displace bilirubin from plasma protein-binding sites.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive function studies conducted in rats at doses 10 times higher than the human dose showed no evidence of impaired fertility or teratogenic effects. Sulbactam and cefoperazone cross the placental barrier, but comprehensive and well-controlled studies in pregnant women have not been conducted. Since animal studies on reproductive effects do not always predict human response, Zontam should be used during pregnancy only if clearly needed.

Breastfeeding. Only a small portion of the administered doses of sulbactam and cefoperazone passes into breast milk. Zontam should be administered with caution to breastfeeding women, despite the fact that both components of the drug pass into breast milk in small amounts.

Ability to affect reaction speed when driving or operating machinery.

Clinical experience with sulbactam/cefoperazone suggests that the drug is unlikely to impair a patient's ability to drive or operate machinery.

Method of Administration and Dosage.

Adults. The usual dose of Zontam for adults is 2-4 g per day (i.e., 1-2 g of cefoperazone per day) administered intravenously or intramuscularly in evenly divided doses every 12 hours.

In severe or refractory infections, the daily dose of Zontam may be increased up to 8 g (i.e., cefoperazone dose of 4 g) intravenously in evenly divided doses every 12 hours. The recommended maximum daily dose of sulbactam is 4 g (8 g of Zontam preparation).

Children. The usual dose of Zontam for children is 40 to 80 mg/kg body weight/day (i.e., 20-40 mg/kg body weight/day of cefoperazone), divided evenly into 2-4 doses.

For severe or refractory infections, the daily dose may be increased to 160 mg/kg body weight (80 mg/kg body weight/day of cefoperazone), divided evenly into 2–4 doses.

Neonates. For neonates during the first week of life, the drug should be administered every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day (160 mg/kg body weight/day of Zontam). If a dose of cefoperazone exceeding 80 mg/kg body weight/day is required, the additional dose of cefoperazone should be administered separately.

Zontam can be effectively used in children; however, comprehensive studies on the use of the drug in preterm or term neonates have not been conducted. Therefore, before initiating treatment in preterm or term neonates, the potential benefits and risks of using the drug should be carefully evaluated.

Hepatic impairment. See section "Special precautions".

Renal impairment. The dosing regimen of Zontam should be adjusted in patients with significantly impaired renal function (creatinine clearance less than 30 mL/min) to compensate for reduced sulbactam clearance. For patients with creatinine clearance of 15–30 mL/min, the maximum dose of sulbactam is 1 g, administered every 12 hours (maximum daily sulbactam dose – 2 g). For patients with creatinine clearance less than 15 mL/min, the maximum dose of sulbactam is 500 mg, administered every 12 hours (maximum daily sulbactam dose – 1 g). In severe infections, additional separate administration of cefoperazone may be necessary.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis.

The serum half-life of cefoperazone is slightly reduced during hemodialysis. Therefore, the dosing regimen should be adjusted according to the dialysis schedule.

Elderly patients. See section "Pharmacokinetics".

Intravenous administration. For infusion, the contents of each vial of Zontam should be dissolved in an appropriate volume of 5% glucose solution, 0.9% sodium chloride injection solution, or sterile water for injection, then further diluted to 20 mL with the same diluent and administered over 15–60 minutes.

For intravenous injection, the vial contents should be reconstituted as described above and administered over at least 3 minutes.

Lactated Ringer’s solution is an acceptable diluent for intravenous infusion but not for initial reconstitution (see section "Incompatibilities").

Intramuscular administration.

2% lidocaine hydrochloride solution is an acceptable diluent for preparing the solution for intramuscular injection but not for initial reconstitution (see section "Incompatibilities").

When using lidocaine as a diluent, a skin sensitivity test should be performed and safety information regarding lidocaine should be taken into account.

Reconstitution.

Zontam is compatible with water for injections, 5 % glucose solution, 0.9 % sodium chloride solution, 5 % glucose in 0.225 % sodium chloride solution, and 5 % glucose in 0.9 % sodium chloride solution at concentrations ranging from 10 mg cefoperazone and 5 mg sulbactam per 1 mL to 250 mg cefoperazone and 125 mg sulbactam per 1 mL.

Ringer’s lactate solution. Sterile water for injections should be used for reconstitution (see section "Incompatibility"). A two-step dilution is required using water for injections (see table above); the resulting solution should then be diluted with Ringer’s lactate solution to achieve a sulbactam concentration of 5 mg/mL (add 2 mL or 4 mL of the initially diluted solution to 50 mL or 100 mL of Ringer’s lactate solution, respectively).

Lidocaine. Sterile water for injections should be used for reconstitution (see section "Incompatibility").

Any unused product or waste material must be disposed of in accordance with local requirements.

Children. The medicinal product can be administered to children (see sections "Special precautions" and "Method of administration and dosage").

Overdose.

There is insufficient information regarding acute human intoxication with sodium cefoperazone and sodium sulbactam. Overdose with the medicinal product is expected to cause manifestations primarily representing an intensification of its adverse effects. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause neurological reactions, including seizures. Since cefoperazone and sulbactam are removed from circulation by hemodialysis, this procedure may enhance elimination of the drug from the body in cases of overdose in patients with impaired renal function.

Adverse reactions.

Sulbactam/cefoperazone is generally well tolerated. Most adverse reactions are mild to moderate in severity and are well tolerated throughout treatment.

The following adverse reactions were observed during clinical trials (comparative and non-comparative) and following post-marketing experience. All adverse reactions are listed according to the MedDRA classification system. Within each category, adverse reactions are listed in order of clinical significance.

The frequency is defined according to the classification of the Council for International Organizations of Medical Sciences (CIOMS III): very common ≥ 1/10 (≥ 10%), common ≥ 1/100 to < 1/10 (≥ 1% to < 10%), uncommon ≥ 1/1000 to < 1/100 (≥ 0.1% to < 1%), frequency not known (cannot be estimated based on available information).

* The analyses regarding laboratory test abnormalities included all available laboratory values, including patients with abnormalities at baseline. This conservative approach was adopted because the initial data did not differentiate subgroups of patients with baseline abnormalities who experienced treatment-related significant changes in laboratory parameters from those who did not.

For parameters such as white blood cells, neutrophils, platelets, hemoglobin, and hematocrit, only abnormalities were reported. Increases or decreases in levels were not differentiated.

** Fatal outcomes have been reported.

Cases of the adverse reaction "bleeding" have been reported.

Suspected adverse reactions reporting. It is very important to report suspected adverse reactions after marketing authorization of the medicinal product. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable regulatory requirements.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

Aminoglycosides. Solutions of Zontam and aminoglycosides should not be mixed directly due to physical incompatibility. If combination therapy with Zontam and aminoglycosides is required, they should be administered sequentially via separate intravenous infusion lines, using a separate secondary intravenous administration set. The primary intravenous line must be thoroughly flushed with an appropriate solution between infusions of the respective drugs. It is also advisable to maximize, as much as possible, the time intervals between administration of Zontam and aminoglycosides within a 24-hour period.

Lactated Ringer’s solution. Primary dilution with Lactated Ringer’s solution is not recommended, as this mixture is incompatible. However, a two-step dilution process, in which water for injections is used as the primary solvent, allows avoidance of incompatibility when further dilution with Lactated Ringer’s solution is performed (see section “Dosage and administration”).

Lidocaine. Primary dilution with 2% lidocaine solution is not recommended, as this mixture is incompatible. However, a two-step dilution process, in which water for injections is used as the primary solvent, allows avoidance of incompatibility when further dilution with 2% lidocaine hydrochloride solution is performed (see section “Dosage and administration”).

Packaging.

1.0 g (500 mg/500 mg) of the drug in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap fitted with a flip-off cap ensuring tamper evidence.

1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Swiss Parenterals Ltd.

Swiss Parenterals Ltd.

Manufacturer’s address and place of business.

Unit II, Plot No. 402, 412-414 Kerala Industrial Estate, GIDC, Near Bavla, Ahmedabad, Gujarat 382220, India

Unit II, Plot No. 402, 412-414 Kerala Industrial Estate, GIDC, Near Bavla, Ahmedabad, Gujarat, 382220, India

Marketing Authorization Holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of the Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom