Lorazidim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LORAZIDIME (Lorazidime®)

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime pentahydrate equivalent to 500 mg or 1000 mg of ceftazidime;

Excipient: sodium carbonate anhydrous.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other
β-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 observed among individual strains. It is advisable to use local (regional) 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. Five minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g, mean serum concentrations reach 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 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, pleural, and peritoneal fluids. Ceftazidime rapidly crosses the placenta and is excreted into breast milk. The drug poorly penetrates the intact blood-brain barrier, and concentrations in the CNS are low in the absence of inflammation. However, during meningitis, ceftazidime concentrations in the CNS range from 4–20 mg/L and above, which corresponds to therapeutic levels.

Ceftazidime is not metabolized in the body. After parenteral administration, high and sustained serum concentrations of ceftazidime 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 excreted in urine within 24 hours. In patients with impaired renal function, ceftazidime elimination 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 infections.

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

Ceftazidime may be used for the prophylaxis of infectious complications 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 instructions» 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 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 β-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 instructions»).

Chloramphenicol is an in vitro antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown; however, if concomitant administration of Lorazidim with chloramphenicol is considered, potential antagonism should be taken into account.

Like other antibiotics, Lorazidim 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 determining glucosuria; 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 β-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 initiated.

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

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections unless the causative pathogen is unknown and its susceptibility to this drug is not established, or unless 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 β-lactamases. Therefore, when selecting ceftazidime for therapy, information regarding the prevalence of microorganisms producing extended-spectrum β-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 effect 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 adjusted 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 Lorazidim may lead to overgrowth of non-susceptible 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, 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. If prolonged and 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 previously susceptible strains of Enterobacter spp. and Serratia spp. may become resistant during ceftazidime therapy. In such cases, periodic susceptibility testing should be performed.

Lorazidim contains sodium (one vial containing 500 mg of ceftazidime contains 24 mg of sodium; one vial containing 1 g of ceftazidime contains 48 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, embryonic 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 with therapeutic doses, no effect on the breastfed infant is expected. 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 affect the ability to drive or operate machinery (see section «Adverse reactions»).

Method of 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 Lorazidim by continuous intravenous infusion in infants and children ≤ 2 months of age have not been established.

Geriatric patients

Due to reduced ceftazidime clearance, for elderly patients with acute infections, the daily dose generally should not exceed 3 g, particularly in patients aged

80 years.

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 administration 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 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 serum ceftazidime 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 administration is recommended.

Recommended maintenance doses of ceftazidime in renal impairment – 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 administering Lorazidim 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 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 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 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.

Lorazidim 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, provided the patient is receiving parenteral fluids.

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

Acquired resistance to the antibiotic varies in different regions and may change over time, and may differ significantly for individual strains. It is advisable to use local data on antibiotic susceptibility, especially when treating severe infections.

Instructions for preparation

Lorazidim is compatible with most commonly used intravenous infusion solutions. However, sodium bicarbonate for injection should not be used as a solvent (see «Incompatibility»).

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

The solution colour varies from light yellow to amber depending on concentration, solvent, and storage conditions. Provided recommendations are followed, the drug's efficacy does not depend on variations in its colour.

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 and 0.9% sodium chloride solution; 10% glucose and 5% glucose solution;

6% dextran and 0.9% sodium chloride solution; 6% dextran and 5% glucose solution.

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

Ceftazidime for intramuscular administration 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 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 a 500 mg Lorazidim vial, dissolved in 1.5 mL of water for injections, can be added 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 cap and add the recommended volume of solvent.
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, ensuring the needle remains submerged in the solution at all times.

Preparation of solutions for intravenous infusion (1 g vial)

1. Insert the syringe needle through the vial cap and add 10 mL of solvent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Do not insert an air vent needle through the cap until the drug is fully dissolved. Insert an air vent needle through the cap 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 as usual.

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

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

Children.

May be used in neonates 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 «Dosage and administration» and «Special precautions»). Serum concentrations of ceftazidime can be reduced by haemodialysis or peritoneal dialysis.

Side effects.

Infections and infestations

Candidiasis (including vaginitis and aphthous stomatitis).

Blood and lymphatic system disorders

Eosinophilia, thrombocytosis, leukopenia, neutropenia and thrombocytopenia, lymphocytosis, hemolytic anemia, and agranulocytosis.

Immune system disorders

Anaphylaxis (including bronchospasm and/or arterial hypotension).

Nervous system disorders

Dizziness, headache, paresthesia.

Neurological complications such as tremor, myoclonia, seizures, encephalopathy, and coma have been reported in patients with renal impairment for whom the ceftazidime dose was not appropriately reduced.

Vascular disorders

Phlebitis or thrombophlebitis at the site of injection.

Gastrointestinal disorders

Diarrhea, 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").

Taste disturbances.

Renal and urinary disorders

Interstitial nephritis, acute renal failure.

Hepatobiliary disorders

Transient elevation in the levels of one or more liver enzymes (ALT, AST, LDH, GGT, alkaline phosphatase). Jaundice.

Skin and subcutaneous tissue disorders

Maculopapular rash or urticaria, pruritus, angioneurotic edema, polymorphic erythema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

General disorders and administration site conditions

Pain and/or inflammation at the site of intramuscular injection, fever.

Laboratory findings

Positive Coombs test—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.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Incompatibilities.

Lorazidim 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.

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 administration of these two drugs.

Packaging.

1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer

Exir Pharmaceutical Company, Iran

Exir Pharmaceutical Company, Iran.

Manufacturer's address and place of business.

2nd Km Ring Road, Boroujerd 69189, Iran

2nd Km Ring Road, Boroujerd 69189, Iran.