Denizid

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

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime pentahydrate (in a sterile mixture with anhydrous sodium carbonate), equivalent to ceftazidime 1 g;

Excipient: anhydrous sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder, white to cream-colored.

Pharmacotherapeutic group. Antibacterial agent for systemic use. Other beta-lactam antibiotics. 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 across different regions and may change over time, with significant differences observed among individual strains. Local data on antibiotic susceptibility should be used whenever possible, especially when treating severe infections.

Susceptible microorganisms

Gram-positive aerobes: Streptococcus pyogenes, Streptococcus agalactiae.

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

Strains capable of developing resistance

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

Gram-positive aerobes: Staphylococcus aureus, Staphylococcus pneumoniae.

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 1 g of the drug, mean peak serum concentrations of 37 mg/L are rapidly achieved. Within 5 minutes after intravenous bolus administration of 1 g or 2 g, mean serum concentrations of 87 mg/L or 170 mg/L, respectively, are achieved. Therapeutically effective concentrations persist in serum for up to 8–12 hours after both intravenous and intramuscular administration. Plasma protein binding is approximately 10%. Therapeutic concentrations of ceftazidime exceeding the minimum inhibitory concentration (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, concentrations in the central nervous system (CNS) are low. However, during meningitis, ceftazidime concentrations in the CNS range from 4 to 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 administered dose is recovered in urine within 24 hours. In patients with impaired renal function, ceftazidime elimination is reduced, necessitating dose adjustment. Less than 1% of the drug is excreted in bile, significantly limiting the amount reaching the intestinal tract.

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.

Denizid 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 of activity, primarily directed against gram-negative aerobes, should be taken into account (see sections "Pharmacological properties" and "Special instructions").

Ceftazidime should be used in combination with other antibacterial agents if it is expected that some of the microorganisms causing the infection are not covered by the spectrum of ceftazidime.

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

Contraindications.

Hypersensitivity to ceftazidime or to any of the excipients of the drug.

Hypersensitivity to 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 types of interactions.

Concomitant administration of high doses of the drug with nephrotoxic medicinal products may adversely affect renal function (see section "Special instructions").

Chloramphenicol is an in vitro antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown; however, if simultaneous administration of Denizid with chloramphenicol is required, the possibility of antagonism should be considered.

Like other antibiotics, Denizid 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 detection of glucosuria; however, a slight interference may occur with copper reduction methods (Benedict's, Fehling's, Clinitest).

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 should be taken.

Before initiating therapy, patients should be questioned about previous hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, or other beta-lactam antibiotics. The drug should be administered with caution to patients who have experienced minor hypersensitivity reactions to other beta-lactam antibiotics.

During treatment with ceftazidime, severe skin adverse reactions, 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 with an "unknown" frequency. These reactions may be life-threatening or fatal.

Patients should be informed about the signs and symptoms of such reactions, and careful monitoring for skin reactions is required.

If signs or symptoms suggestive of these reactions occur, ceftazidime should be discontinued immediately, and alternative therapies should be 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, except when the causative pathogen is unknown or there is a high likelihood that the potential pathogen will be susceptible to ceftazidime. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, or bone and joint infections. Furthermore, 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 drugs, such as aminoglycosides or potent diuretics (e.g., furosemide), may adversely affect renal function. Clinical experience with ceftazidime has shown that this phenomenon is unlikely when recommended dosages are observed. There are no data indicating that ceftazidime adversely affects renal function at usual therapeutic doses.

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

As with other broad-spectrum antibiotics, prolonged treatment with Denizid may lead to overgrowth of resistant microorganisms (e.g., Candida, Enterococci). In such cases, discontinuation of therapy or other necessary interventions may be required. Close monitoring of the patient is essential.

Cases of pseudomembranous colitis of varying severity, ranging from mild to life-threatening, have been reported during antibiotic therapy. Therefore, this diagnosis should be considered in patients who develop diarrhea during or after antibiotic use. If prolonged or severe diarrhea occurs, or if abdominal cramps develop, treatment should be discontinued immediately, further diagnostic evaluation should be performed, and specific therapy for Clostridium difficile should be initiated if necessary. Medicinal products that inhibit intestinal peristalsis should not be administered.

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

The product contains sodium (a 1 g ceftazidime vial 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 the use of ceftazidime in pregnant women are limited. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, embryonal or postnatal development. The drug should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Ceftazidime is excreted in breast milk in small amounts, but no adverse effects on the breastfed infant are expected with therapeutic doses. Ceftazidime may be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted. However, the occurrence of adverse reactions such as dizziness may impair the ability to drive or operate machinery (see section "Adverse reactions").

Dosage and method of administration.

Adults and children ≥ 40 kg

Children <40 kg

*If this is related or suspected to be related to infections listed in the section "Indications".

Children

The safety and efficacy of Denizid administered by continuous intravenous infusion in infants and children aged ≤ 2 months have not been established.

Geriatric patients

Due to reduced ceftazidime clearance, the daily dose in elderly patients with acute infections should generally 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 during treatment is recommended.

Renal impairment

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

The initial dose should be 1 g. The maintenance dose should be based on glomerular filtration rate.

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, which may not precisely reflect the degree of renal function impairment in 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

The dose should be administered with caution. Careful clinical monitoring of the efficacy and safety of the medicinal product is recommended.

Children < 40 kg

The safety and efficacy of administering Denizid by continuous intravenous infusion in children with impaired renal function and body weight < 40 kg have not been established. Careful clinical monitoring of the efficacy and safety of the medicinal product is recommended.

If children with impaired renal function require administration of the drug by continuous intravenous infusion, 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.

A maintenance dose of ceftazidime, as recommended in the table below, should be administered after each hemodialysis session.

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis, both in standard regimens and in 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 daily, administered either as a single dose or in divided doses. For low-flux hemofiltration, dosing should follow recommendations for impaired renal function.

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

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

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

Acquired resistance to antibiotics varies among different regions and may change over time, with significant differences observed even among individual strains. Local antibiotic susceptibility data should be used whenever possible, especially when treating severe infections.

Preparation of the Solution

Denizid 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 manufactured under reduced pressure. As the drug dissolves, carbon dioxide is released and pressure in the vial increases. Small bubbles of carbon dioxide in the reconstituted solution can be disregarded.

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

The solution color may vary from light yellow to amber, depending on concentration, diluent, and storage conditions. Provided the 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 peritoneal dialysis fluid (lactate).

For intramuscular administration, Denizid 1 g vial may be reconstituted with 0.5% or 1% lidocaine hydrochloride solution.

When using lidocaine solution as a diluent for intramuscular administration, the safety information regarding lidocaine must be taken into account.

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.

The contents of one Denizid 1 g vial, reconstituted with 1.5 mL of water for injections, may be added to a metronidazole solution (500 mg in 100 mL), and both drugs retain their activity.

Preparation of solutions for intramuscular or intravenous bolus injection

1. Insert the needle of the syringe through the vial stopper and inject 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 gas may be disregarded.

Preparation of solutions for intravenous infusion (1 g vials)

1. Insert the needle of the syringe through the vial stopper and inject 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. After complete dissolution, insert an air vent needle through the stopper into the vial to equalize internal pressure.
4. Without removing the air vent needle, add diluent to bring the total volume to 50 mL. Remove the air vent needle, shake the vial, and set up the infusion system as usual.

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

The prepared solution may be stored for up to 8 hours at temperatures not exceeding 25°C and for up to 24 hours at temperatures between 2°C and 8°C.

Children.

Can be administered to children from the first days of life.

Overdose.

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 "Special precautions for use" and "Dosage and administration"). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

Adverse reactions have been classified by organ systems and frequency of occurrence: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

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, 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 an appropriately reduced dose 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 increase in 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 – angioneurotic edema, 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, 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 the medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as patients’ legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Ceftazidime is less stable in sodium bicarbonate injection solution 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 drugs.

Packaging.

1 vial of powder in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer's name and address.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorization Holder.

Ananta Medicare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.