Zidar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZIDAAR (ZIDAAR)

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime pentahydrate equivalent to ceftazidime 1 g;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from white to pale yellow in color.

Pharmacotherapeutic group. Antibacterial agent for systemic use. Third-generation cephalosporins. ATC code J01D D02.

Pharmacological Properties.

Pharmacodynamics.

Ceftazidime is a bactericidal cephalosporin antibiotic whose mechanism of action is related to inhibition of bacterial cell wall synthesis.

Acquired resistance to the antibiotic varies among different regions and may change over time, with significant differences possible among individual strains. It is advisable to use local data on antibiotic susceptibility and prevalence of beta-lactamase-producing microorganisms with extended-spectrum activity, especially when treating severe infections.

Susceptible microorganisms.

Gram-positive aerobes: Streptococcus pyogenes, Streptococcus agalactiae.

Gram-negative aerobes: Citrobacter koseri, Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Proteus mirabilis, Proteus spp., Providencia spp., Pasteurella multocida.

Strains with possible acquired resistance.

Gram-negative aerobes: Acinetobacter baumannii, Burkholderia cepacia, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Morganella morganii.

Gram-positive aerobes: Staphylococcus aureus, Staphylococcus pneumoniae, Viridans group streptococcus.

Gram-positive anaerobes: Clostridium perfringens, Peptococcus spp., Peptostreptococcus spp.

Gram-negative anaerobes: Fusobacterium spp.

Resistant microorganisms.

Gram-positive aerobes: Enterococcus spp., including E. faecalis and E. faecium, Listeria spp.
Gram-positive anaerobes: Clostridium difficile.

Gram-negative anaerobes: Bacteroides spp., including B. fragilis.

Others: Chlamydia spp., Mycoplasma spp., Legionella spp.

Pharmacokinetics.

After intramuscular injection of 500 mg and 1 g, mean peak concentrations of 18 and 37 mg/L, respectively, are rapidly achieved in patients. Within 5 minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g, serum concentrations average 46, 87, or 170 mg/L, respectively. Therapeutically effective concentrations persist in serum for up to 8–12 hours after intravenous or intramuscular administration. Plasma protein binding is approximately 10%. Concentrations exceeding the MIC for most common pathogenic microorganisms are achieved in tissues and body fluids such as bone, heart, bile, sputum, intraocular fluid, synovial fluid, pleural fluid, and peritoneal fluid. Ceftazidime rapidly crosses the placenta and is excreted into breast milk. The drug poorly penetrates the intact blood-brain barrier; in the absence of inflammation, CNS concentrations are low. However, during meningitis, ceftazidime concentrations in the CNS range from 4–20 mg/L or higher, achieving therapeutic levels.

Ceftazidime is not metabolized in the body. After parenteral administration, high and sustained serum concentrations are achieved. The elimination half-life is approximately 2 hours. The drug is excreted unchanged and in active form in urine via glomerular filtration; approximately 80–90% of the dose is recovered in urine within 24 hours. In patients with impaired renal function, elimination of ceftazidime is reduced, and dosage adjustment is required. Less than 1% of the drug is excreted in bile, significantly limiting the amount reaching the intestine.

Clinical characteristics.

Indications.

Treatment of the following infections in adults and children, including newborns:

• hospital-acquired pneumonia;
• respiratory tract infections in patients with cystic fibrosis;
• bacterial meningitis;
• chronic suppurative otitis media;
• malignant external otitis;
• complicated urinary tract infections;
• complicated skin and soft tissue infections;
• complicated intra-abdominal infections;
• bone and joint infections;
• peritonitis associated with dialysis in patients undergoing continuous ambulatory peritoneal dialysis.

Treatment of bacteremia arising in patients as a result of any of the above-mentioned infections.

Ceftazidime may be used for the treatment of patients with neutropenia and fever resulting from bacterial infection.

Ceftazidime may be used for prophylaxis of urinary tract infections during urological surgery (transurethral resection of the prostate).

When prescribing ceftazidime, its antibacterial spectrum directed primarily against gram-negative aerobes should be taken into account (see sections "Special precautions" and "Pharmacological properties").

Ceftazidime should be used in combination with other antibacterial agents if microorganisms causing the infection are expected to be outside the spectrum of ceftazidime activity.

The drug should be prescribed in accordance with current official guidelines on the use of antibacterial agents.

Contraindications.

Hypersensitivity to ceftazidime or to any of the excipients of the medicinal product.

Hypersensitivity to other cephalosporin antibiotics.

History of severe hypersensitivity (e.g., anaphylactic reactions) to other beta-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of high doses of the drug with nephrotoxic medicinal products may adversely affect renal function (see section "Special precautions"). Chloramphenicol is an antagonist of ceftazidime and other cephalosporins in vitro. The clinical significance of this phenomenon is unknown; however, if concomitant administration of Zidaar with chloramphenicol is proposed, antagonism should be considered.

Like other antibiotics, Zidaar may affect intestinal flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Ceftazidime does not interfere with enzymatic methods for determination of glucosuria; however, a minor interference may occur with copper reduction methods (Benedict, Fehling, Clinistix).

Ceftazidime does not interfere with the alkaline picrate method for creatinine determination.

Special precautions for use.

As with other beta-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. If severe hypersensitivity reactions occur, ceftazidime therapy should be discontinued immediately and appropriate emergency measures initiated. Prior to starting treatment, patients should be questioned about previous history of severe hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, or other beta-lactam antibiotics. The drug should be administered cautiously in patients who have experienced mild hypersensitivity reactions to other beta-lactam antibiotics.

Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported during treatment with ceftazidime. These reactions, which may be life-threatening or fatal, have occurred with an "unknown" frequency. Patients should be informed about the signs and symptoms and closely monitored for skin reactions. If signs or symptoms suggestive of these reactions appear, ceftazidime should be discontinued immediately and alternative therapy considered. If a serious reaction such as SJS, TEN, DRESS, or AGEP develops during ceftazidime treatment, ceftazidime therapy must never be restarted.

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections unless the causative pathogen has been shown to be susceptible to ceftazidime, or there is a high likelihood that the likely pathogen will be susceptible. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, and bone and joint infections. Additionally, ceftazidime is susceptible to hydrolysis by certain extended-spectrum beta-lactamases. Therefore, when selecting ceftazidime for treatment, information regarding the prevalence of microorganisms producing extended-spectrum beta-lactamases should be taken into account.

Concomitant administration of high doses of cephalosporins and nephrotoxic agents such as aminoglycosides or potent diuretics (e.g., furosemide) may adversely affect renal function. Clinical experience with ceftazidime has shown that this is unlikely when recommended dosages are followed. There are no data indicating that ceftazidime adversely affects renal function at normal therapeutic doses.

Ceftazidime is eliminated via the kidneys; therefore, the dose should be reduced according to the degree of renal impairment. Cases of neurological complications have been reported when the dose was not appropriately reduced (see sections "Dosage and administration" and "Side effects").

As with other broad-spectrum antibiotics, prolonged treatment with Zidaar may result in overgrowth of non-susceptible microorganisms (e.g., Candida, Enterococci); in such cases, discontinuation of therapy or other necessary measures may be required. It is essential to monitor patients closely. Cases of pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with antibiotic use. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. In cases of persistent and severe diarrhea, or if abdominal cramps occur, treatment should be stopped immediately, further investigations performed, and specific therapy for Clostridium difficile initiated if necessary. Medicinal products that inhibit intestinal peristalsis should not be administered.

As with other broad-spectrum cephalosporins and penicillins, some previously susceptible strains of Enterobacter spp. and Serratia spp. may become resistant during ceftazidime therapy. In such cases, periodic susceptibility testing should be performed.

Important information about excipients.

Zidaar contains sodium (one vial containing 1 g of ceftazidime contains 52 mg of sodium), which should be taken into account when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Data on ceftazidime use in pregnant women are limited. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, embryonal/fetal development, or postnatal development. The drug should be administered during pregnancy only if the potential benefit justifies the potential risk.

Ceftazidime is excreted in breast milk in small amounts, but effects on the breastfed infant are not expected with therapeutic doses. Ceftazidime may be used during breastfeeding.

Data on effects on fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted. However, the occurrence of side effects such as dizziness may affect the ability to drive or operate machinery (see section "Side effects").

Method of administration and dosage.

Adults and children with body weight ≥ 40 kg

*If this is associated or there is suspicion of association with the infections listed in the section "Indications".

Children < 40 kg.

*if this is associated or suspected to be associated with infections listed in the section "Indications".

Children.

The safety and efficacy of administering Zidaar by continuous intravenous infusion in infants and children ≤ 2 months of age have not been established.

Geriatric patients.

Due to reduced ceftazidime clearance, in elderly patients with acute infections, the daily dose generally should not exceed 3 g, particularly in patients aged 80 years and older.

Hepatic impairment.

Dosage adjustment is not required in patients with mild to moderate hepatic impairment. Clinical studies in patients with severe hepatic impairment have not been conducted. Careful clinical monitoring of efficacy and safety is recommended.

Renal impairment.

Ceftazidime is eliminated unchanged by the kidneys. Therefore, the dose should be reduced in patients with impaired renal function.

The initial loading dose should be 1 g. The maintenance dose should be based on creatinine clearance.

Recommended maintenance doses of ceftazidime in renal impairment – intermittent administration.

Adults and children with body weight ≥ 40 kg

For patients with severe infections, the single dose may be increased by 50% or the frequency of administration correspondingly increased. In such patients, monitoring of ceftazidime serum levels is recommended.

In children, creatinine clearance should be adjusted according to body surface area or body weight.

Children < 40 kg.

*This is the serum creatinine level calculated according to recommendations and may not precisely reflect the degree of renal function impairment in all patients with renal insufficiency.

** Creatinine clearance, calculated based on body surface area, or measured.

Careful clinical monitoring of efficacy and safety of use is recommended.

Recommended maintenance doses of ceftazidime in renal insufficiency – continuous infusion.

Adults and children with body weight ≥ 40 kg

Dose selection should be cautious. Careful clinical monitoring of efficacy and safety of use is recommended.

Children < 40 kg.

The safety and efficacy of Zidaar administered by continuous intravenous infusion in children with body weight < 40 kg and impaired renal function have not been established. Careful clinical monitoring of efficacy and safety of use is recommended. If continuous intravenous infusion of the drug is required in children with impaired renal function, creatinine clearance should be adjusted according to the child's body surface area or body weight.

Hemodialysis.

The serum half-life of ceftazidime during hemodialysis ranges from 3 to 5 hours.

After each hemodialysis session, a maintenance dose of ceftazidime recommended in the table below should be administered.

Peritoneal dialysis.

Ceftazidime can be used during peritoneal dialysis, including conventional peritoneal dialysis and continuous ambulatory peritoneal dialysis.

In addition to intravenous administration, ceftazidime can be added to the dialysis fluid (usually 125 to 250 mg per 2 L of dialysis solution).

For patients with renal insufficiency undergoing prolonged arteriovenous hemodialysis or high-flux hemofiltration in intensive care units, the recommended dose is 1 g per day as a single dose or divided doses. For low-flux hemofiltration, doses should be adjusted as in renal impairment.

For patients undergoing venovenous hemofiltration and venovenous hemodialysis, dosing recommendations are provided in the tables.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration.

The maintenance dose should be administered every 12 hours.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis.

The maintenance dose should be administered every 12 hours.

Administration.

Zidaar should be administered intravenously by injection or infusion, or by deep intramuscular injection. Recommended sites for intramuscular administration are the upper outer quadrant of the gluteus maximus muscle or the lateral part of the thigh.

Ceftazidime solutions may be administered directly into the vein or into an intravenous infusion system if the patient is receiving parenteral fluids.

The dosage depends on the severity of the infection, the susceptibility, location, and type of infection, as well as the patient's age and renal function.

Preparation instructions.

Zidaar is compatible with most commonly used intravenous infusion solutions. However, sodium bicarbonate for injection should not be used as a solvent (see section "Incompatibilities").

Vials are produced under reduced pressure. During dissolution of the drug, carbon dioxide is released and the pressure inside the vial increases. Small bubbles of carbon dioxide in the dissolved preparation can be disregarded.

*Note. Reconstitution should be performed in two steps (see text below).

The solution color varies from light yellow to amber depending on concentration, diluent, and storage conditions. Provided recommendations are followed, the drug's activity is not affected by variations in its coloration.

Ceftazidime at concentrations from 1 mg/mL to 40 mg/mL is compatible with the following solutions: 0.9% sodium chloride solution; M/6 sodium lactate solution; Hartmann's solution; 5% glucose solution; 0.225% sodium chloride and 5% glucose solution; 0.45% sodium chloride and 5% glucose solution; 0.9% sodium chloride and 5% glucose solution; 0.18% sodium chloride and 4% glucose solution; 10% glucose solution; 10% glucose 40 and 0.9% sodium chloride solution; 10% glucose 40 and 5% glucose solution; 6% dextran 70 and 0.9% sodium chloride solution; 6% dextran 70 and 5% glucose solution.

Ceftazidime at concentrations from 0.05 mg/mL to 0.25 mg/mL is compatible with intraperitoneal dialysis fluid (lactate).

For intramuscular administration, ceftazidime can be reconstituted with 0.5% or 1% lidocaine hydrochloride solution.

The stability of both drugs is maintained when ceftazidime at a concentration of 4 mg/mL is mixed with the following agents: hydrocortisone (hydrocortisone sodium phosphate) 1 mg/mL in 0.9% sodium chloride injection or 0.5% glucose solution; cefuroxime (cefuroxime sodium) 3 mg/mL in 0.9% sodium chloride injection; cloxacillin (cloxacillin sodium) 4 mg/mL in 0.9% sodium chloride injection; heparin 10 IU/mL or 50 IU/mL in 0.9% sodium chloride injection; potassium chloride 10 mEq/L or 40 mEq/L in 0.9% sodium chloride injection.

Preparation of solutions for intramuscular or intravenous bolus injection

1. Insert the needle of the syringe through the vial stopper and add the recommended volume of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Invert the vial. With the syringe plunger fully depressed, insert the needle into the vial. Withdraw the entire solution into the syringe, keeping the needle tip submerged in the solution at all times. Small bubbles of carbon dioxide may be disregarded.

Preparation of solutions for intravenous infusion (1 g and 2 g vials) in two steps

1. Insert the needle of the syringe through the vial stopper and add 10 mL of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Do not insert the air vent needle through the stopper until the drug is completely dissolved. Insert the air vent needle through the stopper into the vial to relieve internal pressure.
4. Transfer the resulting solution into an intravenous infusion system, ensuring a total solution volume of at least 50 mL, and administer by intravenous infusion over 15–30 minutes.

Note.

To maintain sterility of the preparation, it is essential not to insert the air vent needle through the stopper before the drug is fully dissolved.

The reconstituted solution may be stored for up to 24 hours at temperatures below 25°C or for up to 7 days at temperatures up to 4°C.

Children.

Can be used in children from the first days of life.

Overdose.

Symptoms.

Overdose may lead to neurological complications such as encephalopathy, seizures, and coma. Symptoms of overdose may occur in patients with renal impairment if the dose is not appropriately reduced (see sections "Dosage and Administration" and "Special Precautions").

Treatment.

Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

Adverse effects are classified by their frequency of occurrence – from very common to uncommon, and by organ systems: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1000 and < 1/100; rare ≥ 1/10000 and < 1/1000; very rare < 1/10000; frequency not known.

Infections and infestations

Uncommon – candidiasis (including vaginitis and candidal stomatitis).

Blood and lymphatic system disorders

Common – eosinophilia and thrombocytosis.

Uncommon – leukopenia, neutropenia, and thrombocytopenia.

Frequency not known – lymphocytosis, hemolytic anemia, and agranulocytosis.

Immune system disorders

Frequency not known – anaphylaxis (including bronchospasm and/or arterial hypotension).

Nervous system disorders

Uncommon – dizziness, headache.

Frequency not known – paresthesia.

Neurological complications such as tremor, myoclonia, seizures, encephalopathy, and coma have been reported in patients with renal impairment who did not receive appropriate dose reduction of ceftazidime.

Vascular disorders

Common – phlebitis or thrombophlebitis at the injection site.

Gastrointestinal disorders

Common – diarrhea.

Uncommon – nausea, vomiting, abdominal pain, and colitis.

As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis (see section "Special precautions").

Frequency not known – taste disturbances.

Renal and urinary disorders

Uncommon – transient increase in blood urea levels.

Very rare – interstitial nephritis, acute renal failure.

Hepatobiliary disorders

Common – transient elevation of one or more liver enzymes (ALT, AST, LDH, GGT, alkaline phosphatase).

Frequency not known – jaundice.

Skin and subcutaneous tissue disorders

Common – maculopapular rash or urticaria.

Uncommon – pruritus.

Frequency not known – angioedema, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP).

General disorders and administration site conditions

Common – pain and/or inflammation at the site of intramuscular injection.

Uncommon – fever.

Investigations

Common – positive Coombs test.

Uncommon – as with some other cephalosporins, transient increases in blood urea, blood urea nitrogen (BUN), and/or serum creatinine have occasionally been observed.

A positive Coombs test occurs in approximately 5% of patients and may interfere with blood grouping.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Zidaar is less stable in sodium bicarbonate solution for injection than in other intravenous solutions and therefore is not recommended as a solvent.

Ceftazidime and aminoglycosides should not be mixed in the same infusion system or syringe. Precipitation has been observed when vancomycin was added to a ceftazidime solution. Therefore, infusion systems and intravenous catheters should be flushed between administration of these two agents.

Packaging.

Vials of 1000 mg, 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. Zeiss Pharmaceuticals Pvt. Ltd.

Manufacturer's address.

Plot No. 72, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan, (H. P.), India.

Marketing Authorization Holder.

AAR PHARMA FZ-LLC.

Address of Marketing Authorization Holder.

Premises 702, 7th Floor, Building: DSC Tower, Post Box - 478837, Dubai, United Arab Emirates.