Ceftum

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTUM® (CEFTUM)

Composition:

Active substance: ceftazidime;

1 vial contains sterile injectable ceftazidime (sterile mixture of ceftazidime pentahydrate and anhydrous sodium carbonate), calculated as ceftazidime – 1.0 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white powder or white with a creamy shade, with a characteristic odor.

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 across different regions and may change over time, with significant differences observed among individual strains. It is advisable to use local data on antibiotic susceptibility, 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 with possible acquired 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, Streptococcus 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 500 mg and 1 g, mean peak serum 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, mean serum concentrations of 46, 87, or 170 mg/L, respectively, are achieved. Therapeutically effective concentrations persist in serum for up to 8–12 hours after intravenous or intramuscular administration. Plasma protein binding is approximately 10%. Therapeutic concentrations of ceftazidime 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, concentrations in the CNS are low. However, during meningitis, ceftazidime concentrations in the CNS reach 4–20 mg/L or higher, which corresponds to 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 excreted 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 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.

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

Ceftazidime may be used for prophylaxis of infectious complications during prostate surgery (transurethral resection).

When prescribing ceftazidime, consideration should be given to its antibacterial spectrum, which is directed primarily against aerobic Gram-negative organisms (see sections "Special precautions" and "Pharmacological properties").

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 medicinal product 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 (chloromycetin) is an in vitro antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown; however, if concomitant use of Ceftum® with chloramphenicol is proposed, the possibility of antagonism should be considered.

Like other antibiotics, Ceftum® 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 glucose determination; however, a minor interference may occur with copper reduction methods (Benedict, Fehling, 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 initiated.

Serious 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 ceftazidime treatment. These reactions may be life-threatening or fatal, with an incidence rate of "unknown".

Patients should be informed about the signs and symptoms and closely monitored for skin reactions.

If signs or symptoms suggestive of these reactions occur, ceftazidime should be discontinued immediately and alternative therapy considered.

Prior to initiating therapy, patients should be assessed for history of severe hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, or other beta-lactam antibiotics. The drug should be administered with caution to patients who have experienced non-severe hypersensitivity reactions to other beta-lactam antibiotics.

If a serious reaction such as SJS, TEN, DRESS, or AGEP occurs during ceftazidime treatment, ceftazidime therapy must never be restarted.

Ceftazidime is not an appropriate agent for monotherapy of certain types of infections unless the causative pathogen is unknown and likely to be susceptible to ceftazidime, or there is a high probability that the likely 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. Additionally, ceftazidime is susceptible to hydrolysis by certain extended-spectrum beta-lactamases. Therefore, when selecting ceftazidime for therapy, information regarding the prevalence of microorganisms producing extended-spectrum beta-lactamases should be considered.

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 followed. There are no data indicating that ceftazidime adversely affects renal function at usual therapeutic doses.

Ceftazidime is eliminated by 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 "Adverse reactions").

As with other broad-spectrum antibiotics, prolonged treatment with Ceftum® may lead to overgrowth of non-susceptible microorganisms (e.g., Candida, Enterococci); in such cases, discontinuation of therapy or other necessary measures may be required. Continuous monitoring of the patient is essential.

Cases of pseudomembranous colitis, ranging from mild to life-threatening, have been reported with antibiotic use. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. In case of prolonged and severe diarrhea or if abdominal cramps occur, treatment should be discontinued immediately, further investigations performed, and specific therapy for Clostridium difficile initiated if necessary. Medications that inhibit intestinal motility 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.

Ceftum® contains sodium (1 vial with 1 g ceftazidime contains 0.063 g 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 or postnatal development. The drug should be administered to pregnant women only if the benefit outweighs the potential risk.

Ceftazidime is excreted in breast milk in small amounts; therefore, no 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, adverse reactions such as dizziness may affect the ability to drive or operate machinery (see section "Adverse reactions").

Administration and dosage.

Adults and children ≥ 40 kg

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 the medicinal product Ceftum® by continuous intravenous infusion in infants and children ≤ 2 months of age have not been established.

Geriatric patients

Due to reduced ceftazidime clearance, for geriatric patients with acute infections, the daily dose generally should not exceed 3 g, especially 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 of use 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 ≥ 40 kg body weight

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 ≥ 40 kg body weight

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

Children < 40 kg

The safety and efficacy of the medicinal product Ceftum® 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 administration of the drug by continuous intravenous infusion 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 is 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, including 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 into several 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.

Dosage recommendations for ceftazidime in patients undergoing long-term venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration.

Ceftum® 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.

Antibiotic resistance varies across different regions and may change over time, with significant differences observed among individual strains. It is advisable to use local (regional) data on antibiotic susceptibility, especially when treating severe infections.

Instructions for preparation

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

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

*Note. Dissolution should be carried out in two steps (see text).

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, ceftazidime may be dissolved in 0.5% or 1% lidocaine hydrochloride solution.

The stability of both agents 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 vial of Ceftum**®** 1 g, dissolved in 3 mL of water for injections, may be added in a volume of 1.5 mL to a metronidazole solution (500 mg in 100 mL), with both drugs retaining their activity.

Preparation of solutions for intramuscular or intravenous bolus injection

1. Insert the syringe needle 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. Draw the entire solution into the syringe, keeping the needle 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)

1. Insert the syringe needle 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. Without removing the air vent needle, adjust the total volume to 50 mL. Remove the air vent needle, shake the vial, and set up the infusion system.

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

Children.

May be used in 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 "Administration and dosage" and "Special instructions"). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

Adverse effects have been classified according to 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 aphthous 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.

Cases of 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

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 – 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.

Laboratory findings

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 adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. In the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

Ceftum® is less stable in sodium bicarbonate injection solution than in other intravenous infusion solutions; therefore, it is not recommended as a solvent.

Ceftazidime and aminoglycosides should not be mixed in the same infusion system or syringe.

Cases of precipitate formation have been observed when vancomycin was added to a ceftazidime solution; therefore, infusion systems and intravenous catheters should be flushed between administrations of these drugs.

Packaging. 1.0 g in vials. 10 vials per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.