Abitazim

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

Composition:

Active substance: ceftazidime;

1 vial contains 1.164 g of ceftazidime pentahydrate, equivalent to 1 g of ceftazidime;

Excipient: anhydrous sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or pale yellow powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftazidime. 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 possible among individual strains. Local (regional) data on antibiotic susceptibility and prevalence of microorganisms producing extended-spectrum beta-lactamases should be consulted, 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, Streptococcus 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 serum concentrations of 18 mg/L and 37 mg/L are rapidly achieved, respectively. Within 5 minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g, mean serum concentrations of 46 mg/L, 87 mg/L, or 170 mg/L are achieved, respectively. Therapeutically effective serum concentrations persist for up to 8–12 hours after both intravenous and 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, CNS concentrations are low. However, during meningitis, ceftazidime concentrations in the CNS reach 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, in its active form, primarily via glomerular filtration into urine; 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, resulting in minimal exposure of the intestinal tract to the drug.

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 prostate surgery (transurethral resection).

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

Ceftazidime should be used in combination with other antibacterial agents if it is expected that a number of microorganisms causing the infection are not covered by the spectrum of ceftazidime. The drug should be prescribed in accordance with current official recommendations 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 ceftazidime with nephrotoxic medicinal products may adversely affect renal function (see section "Special precautions"). Chloramphenicol is an in vitro antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown; however, if concomitant use of ceftazidime with chloramphenicol is proposed, the possibility of antagonism should be considered.

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

Ceftazidime does not interfere with enzymatic methods for glucose in urine testing; however, a slight interference may occur when using 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 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 mild hypersensitivity reactions to other beta-lactam antibiotics.

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections until it has been established that the causative pathogen is susceptible to ceftazidime, or when there is a high likelihood 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, and bone and joint infections. In addition, 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 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 followed. There is no evidence that ceftazidime adversely affects renal function at usual therapeutic doses.

Ceftazidime is eliminated by the kidneys; therefore, the dose 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 "Side effects").

As with other broad-spectrum antibiotics, prolonged treatment with Abitazim 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. Careful and continuous monitoring of the patient is essential. Cases of pseudomembranous colitis, varying 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 case of prolonged and severe diarrhea or if abdominal cramps occur, treatment should be discontinued immediately, further evaluation 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.

Serious skin reactions (SSRs), 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 therapy. These reactions may be life-threatening or fatal and occur at 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 occur, ceftazidime should be discontinued immediately and alternative therapy considered.

If a serious reaction such as SJS, TEN, DRESS, or AGEP develops during ceftazidime therapy, ceftazidime treatment must not be restarted under any circumstances.

Important information on excipients.

Abitazim contains sodium (one vial with 1 g of ceftazidime contains 52.44 mg (2.28 mmol) of sodium), which should be taken into consideration when treating patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Data on ceftazidime use in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal or fetal development, or postnatal development. The medicinal product 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 effects on the breastfed infant are not 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, certain side effects (e.g., dizziness) may occur, which could impair the ability to drive or operate machinery (see section "Side effects").

Method of administration and dosage.

Table 1

Adults and children with body weight ≥ 40 kg

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

Table 2

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 Abitazim administered by continuous intravenous infusion in infants and children aged ≤ 2 months 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.

Table 3

Adults and children with body weight ≥ 40 kg body weight

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

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

Table 4

Children with body weight < 40 kg

* Serum creatinine level calculated according to recommendations, which 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 directly.

Careful clinical monitoring of the drug's efficacy and safety is recommended.

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

Table 5

Adults and children with body weight ≥ 40 kg.

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

Children with body weight < 40 kg.

The safety and efficacy of the drug Abitazim administered by continuous intravenous infusion in children with body weight < 40 kg and renal impairment have not been established. Careful clinical monitoring of the drug’s efficacy and safety is recommended.

If continuous intravenous infusion of ceftazidime is required in children with renal impairment, 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 tables 6–7 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 may be added to the dialysis fluid (usually 125 mg 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. Dosing recommendations for patients undergoing venovenous hemofiltration and venovenous hemodialysis are provided in tables 6–7.

Table 6

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration.

The maintenance dose should be administered every 12 hours.

Table 7

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration.

Abitazim 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 gluteal muscle or the lateral aspect 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.

Instructions for solution preparation.

Abitazim is compatible with most intravenous infusion solutions. However, sodium bicarbonate for injection should not be used as a solvent (see section "Incompatibility"). 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 drug product may be disregarded.

Table 8

Note. Reconstitution for intravenous infusion should be performed in two steps (see below).

The color of the solution varies from light yellow to amber depending on concentration, diluent, and storage conditions.

The activity of the medicinal product is not affected by variations in its coloration, provided the recommendations are followed.

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).

Ceftazidime for intramuscular administration may be dissolved in 0.5% or 1% lidocaine hydrochloride solution.

The efficacy of medicinal products is maintained when ceftazidime at a concentration of 4 mg/mL is mixed with the following substances: 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 the Abitazim 1 g vial, reconstituted in 3 mL of water for injections, can be added in a volume of 1.5 mL to a metronidazole solution (500 mg in 100 mL), with both medicinal products retaining their activity.

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 submerged in the solution at all times. Small bubbles of carbon dioxide may be disregarded.

Preparation of solutions for intravenous infusion (1 g vial) 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 medicinal product is completely dissolved. Insert the air vent needle through the stopper into the vial to relieve internal pressure.
4. Add the resulting solution to an intravenous infusion system to achieve a total solution volume of at least 50 mL and administer by intravenous infusion over 15–30 minutes.

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

The reconstituted solution may be stored for 24 hours at a temperature not exceeding 25°C or for 7 days at 4°C.

Children.

May be administered to 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 "Special precautions" and "Dosage and administration").

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

Adverse Reactions.

Adverse reactions 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 (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, haemolytic anaemia and agranulocytosis.

Immune system disorders:

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

Nervous system disorders:

Uncommon – dizziness, headache.

Frequency not known – paraesthesia.

Neurological complications such as tremor, myoclonus, seizures, encephalopathy and coma have been reported in patients with renal impairment who had not received appropriate dose reductions of ceftazidime.

Cardiac disorders:

Common – phlebitis or thrombophlebitis at the site of drug administration.

Gastrointestinal disorders:

Common – diarrhoea.

Uncommon – nausea, vomiting, abdominal pain and colitis.

As with other cephalosporins, colitis may be related to Clostridium difficile and may present as pseudomembranous colitis (see section "Special warnings and precautions for use").

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 oedema, 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 marketing authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

The reconstituted solution can be stored for 24 hours at a temperature not exceeding 25 °C or for 7 days at 4 °C.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibilities.

Ceftazidime is less stable in sodium bicarbonate injection solution than in other intravenous infusion solutions; therefore, sodium bicarbonate injection solution 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, it is recommended to flush infusion systems and intravenous catheters between administration of these two medicinal products.

Packaging.

1 g of powder in a vial, 1 or 10 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ACS DOBFAR S.P.A.

Manufacturer's address and location of operations.

NUCLEO INDUSTRIALE S. ATTO (LOC. S. NICOLÒ A TORDINO),
64100 TERAMO (TE), Italy

or

VIA ALLEANDRO FLEMING, 2, VERONA (VR), 37135, Italy.