Lorazidime (Powder) Instructions for Use

Marketing Authorization Holder

Exir Pharmaceutical, Co. (Iran)

ATC Code

J01DD02 (Ceftazidime)

Active Substance

Ceftazidime (Rec.INN registered by WHO)

Dosage Forms

	Lorazidime	Powder for solution for intravenous and intramuscular administration 1 g: vial 1 pc.
		Powder for solution for intravenous and intramuscular administration 2 g: vial 1 pc.
		Powder for solution for intravenous and intramuscular administration 500 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Powder for solution for i/v and i/m administration crystalline, from white to white with a creamy tint.

Excipients: sodium carbonate.

Solvent water for injections – 5 ml.

Vials of 20 ml volume (1) in a set with a solvent (amp. 1 pc.) or without it – cardboard packs.
Vials of 20 ml volume (12) – cardboard packs.

Powder for solution for i/v and i/m administration crystalline, from white to white with a creamy tint.

Excipients: sodium carbonate.

Solvent water for injections – 5 ml.

Vials of 20 ml volume (1) in a set with a solvent (amp. 1 pc.) or without it – cardboard packs.
Vials of 20 ml volume (12) – cardboard packs.

Powder for solution for i/v and i/m administration crystalline, from white to white with a creamy tint.

Excipients: sodium carbonate.

Solvent water for injections – 10 ml.

Vials of 20 ml volume (1) in a set with a solvent (amp. 1 pc.) or without it – cardboard packs.
Vials of 20 ml volume (12) – cardboard packs.

Clinical-Pharmacological Group

Third generation cephalosporin

Pharmacotherapeutic Group

Antibiotic-cephalosporin

Pharmacological Action

An antibacterial drug of the cephalosporin group of the third generation with a broad spectrum of action. It has a bactericidal effect by disrupting the synthesis of the microbial cell wall. It is resistant to the action of most beta-lactamases.

The drug is active against gram-negative bacteria Haemophilus influenzae, Haemophilus parainfluenzae (including strains resistant to ampicillin), Neisseria spp. (including Neisseria gonorrhoeae), Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp. (including Klebsiella pneumoniae), Morganella spp. (including Morganella morganii), Proteus spp. (including Proteus mirabilis /including indole-positive/, Proteus vulgaris), Providensia spp. (including Providensia rettgeri), Serratia spp., Acinetobacter spp., Pasteurella multocida, Salmonella spp., Shigella spp., Yersinia enterocolitica; gram-positive bacteria Micrococcus spp., Streptococcus spp. (including Streptococcus aureus, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes group A, Streptococcus viridans, except for Streptococcus faecalis); strains sensitive to methicillin (Staphylococcus aureus, Staphylococcus epidermidis); anaerobic bacteria Bacteroides spp. (most strains of Bacterioides fragilis are resistant), Clostridium perfmgens, Peptococcus spp., Peptostreptococcus spp. and Propionobacterium spp.

The drug is highly active against Pseudomonas aeruginosa and pathogens of nosocomial infections.

The drug is not active against methicillin-resistant strains Campilobacter spp., Chlamydia spp., Clostridium difficile, Enterococcus spp., Listeria spp. (including Listeria monocytogenes), Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis.

Pharmacokinetics

Absorption

T_max after i/m administration is reached after 1 h, after i/v administration – by the end of the infusion. C_max after i/m administration of the drug at a dose of 500 mg or 1 g is 17 µg/ml and 39 µg/ml, respectively, after i/v administration – 42 µg/ml and 69 µg/ml, respectively. A drug concentration of 4 µg/ml is maintained for 6-8 h, the therapeutic concentration in blood plasma is maintained for 8-12 h.

Distribution

After administration, the drug is rapidly distributed in the human body and reaches therapeutic concentrations in most tissues and fluids, including synovial, pericardial and peritoneal fluid, as well as in bile, sputum and urine. Distribution also occurs in bones, myocardium, gallbladder, skin and soft tissues in concentrations sufficient for the treatment of infectious diseases, especially during inflammatory processes that enhance drug diffusion. It penetrates poorly through the intact blood-brain barrier, but the therapeutic level achieved by the drug in the cerebrospinal fluid is sufficient for the treatment of meningitis.

It reversibly binds to plasma proteins (less than 15%), and has a bactericidal effect only in the free form. The degree of binding to proteins does not depend on concentration. V_d is 0.21-0.28 l/kg. The drug accumulates in soft tissues, kidneys, lungs, bones, joints, and serous cavities.

Metabolism and Excretion

The drug is not metabolized in the liver. T_1/2 with normal renal function is 1.8 h. It is excreted unchanged by the kidneys up to 80-90% (70% of the administered dose is excreted in the first 4 h) within 24 hours by glomerular filtration and tubular secretion equally.

Pharmacokinetics in Special Clinical Cases

T_1/2 in case of renal impairment is 2.2 h.

In case of liver function impairment, no changes in the pharmacokinetics of the drug were noted.

Indications

• Meningitis;
• Sepsis (septicemia);
• Severe purulent-septic conditions;
• Bone and joint infections (septic arthritis, osteomyelitis, bacterial bursitis);
• Respiratory tract infections (acute and chronic bronchitis, infected bronchiectasis, pneumonia caused by gram-negative bacteria, lung abscess, pleural empyema);
• Urinary tract infections (acute and chronic pyelonephritis, pyelitis, prostatitis, cystitis, urethritis /only bacterial/, kidney abscess);
• Skin and soft tissue infections (mastitis, wound infections, skin ulcers, phlegmon, erysipelas);
• Infected burns;
• Gastrointestinal tract, abdominal cavity and biliary tract infections (peritonitis, enterocolitis, retroperitoneal abscesses, diverticulitis, pelvic inflammatory diseases, cholecystitis, cholangitis, gallbladder empyema);
• Female genital organ infections;
• Ear, throat, nose infections (otitis media, sinusitis, mastoiditis);
• Gonorrhea (especially with increased sensitivity to antibacterial drugs of the penicillin group).

ICD codes

Dosage Regimen

The drug is used only parenterally. The dose of the drug is set individually, taking into account the severity of the disease, the location of the infection and the sensitivity of the pathogen, age, body weight, and renal function.

Adults and adolescents with complicated urinary tract infections the drug is prescribed i/m or i/v at 0.5-1 g every 8-12 h.

For uncomplicated pneumonia and skin infections i/m or i/v at 0.5-1 g every 8 h.

For cystic fibrosis, lung infections caused by Pseudomonas spp., – 100-150 mg/kg body weight/day, frequency of administration – 3 times/day (use of a dose up to 9 g/day in such patients did not cause complications).

For bone and joint infections – i/v at 2 g every 12 h.

For extremely severe or life-threatening infections – i/v at 2 g every 8 h.

After an initial loading dose of 1 g, patients with impaired renal function (including patients undergoing dialysis), may require a dose reduction as indicated below.

These indicators are approximate. In such patients, it is recommended to monitor the drug level in the serum, which should not exceed 40 mg/l.

The half-life of the drug during hemodialysis is 3-5 h. The appropriate dose of the drug should be repeated after each dialysis period.

For peritoneal dialysis, the drug can be included in the dialysis fluid at a dose of 125-250 mg per 2 l of dialysis fluid.

No dose adjustment is required for patients with impaired liver function.

Children under 1 month of age are prescribed as an i/v infusion at a dose of 30 mg/kg body weight/day (frequency of administration – 2 times); children from 2 months to 12 years are prescribed as an i/v infusion at a dose of 30-50 mg/kg/day (frequency of administration – 3 times).

Children with reduced immunity, cystic fibrosis, meningitis the drug is prescribed at a dose of up to 150 mg/kg/day every 12 h.

The maximum daily dose for children is 6 g.

Rules for preparation of solutions

Primary dilution

Secondary dilution

For i/v drip administration, the solution of the drug obtained by the method described above is additionally diluted in 50-100 ml of one of the following solvents intended for i/v administration (0.9% sodium chloride solution, Ringer’s solution, 5% or 10% dextrose solution, 5% dextrose solution with 0.9% sodium chloride solution).

Only a freshly prepared solution should be used for secondary dilution.

Adverse Reactions

From the digestive system nausea, vomiting, diarrhea or constipation, flatulence, abdominal pain, dysbacteriosis, impaired liver function (increased activity of hepatic transaminases, ALP, hypercreatininemia); rarely – stomatitis, glossitis, pseudomembranous enterocolitis.

From the hematopoietic system leukopenia, neutropenia, granulocytopenia, thrombocytopenia, hemolytic anemia, hypocoagulation.

From the urinary system impaired renal function (azotemia, increased blood urea content), oliguria, anuria.

From the nervous system headache, dizziness.

Local reactions with i/v administration – phlebitis, pain along the vein; with i/m administration – pain and infiltration.

Allergic reactions urticaria, chills or fever, rash, itching; rarely – bronchospasm, eosinophilia, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), angioedema, anaphylactic shock.

Other nosebleeds, candidiasis, superinfection.

Contraindications

• Pregnancy;
• Lactation (breastfeeding);
• Increased sensitivity to cephalosporins and penicillins.

Use in Pregnancy and Lactation

During pregnancy and lactation, the drug is used only if the intended benefit to the mother outweighs the potential risk to the fetus and child.

Use in Hepatic Impairment

No dose adjustment is required for patients with impaired liver function.

Use in Renal Impairment

After an initial loading dose of 1 g, patients with impaired renal function (including patients undergoing dialysis), may require a dose reduction as indicated below.

These indicators are approximate. In such patients, it is recommended to monitor the drug level in the serum, which should not exceed 40 mg/l.

The half-life of the drug during hemodialysis is 3-5 h. The appropriate dose of the drug should be repeated after each dialysis period.

For peritoneal dialysis, the drug can be included in the dialysis fluid at a dose of 125-250 mg per 2 l of dialysis fluid.

Pediatric Use

The drug should be used with caution in newborns under 1 month of age.

Children under 1 month of age are administered the drug via IV infusion at a dose of 30 mg/kg of body weight/day (frequency of administration – 2 times); children from 2 months to 12 years of age are administered the drug via IV infusion at a dose of 30-50 mg/kg/day (frequency of administration – 3 times).

Children with reduced immunity, cystic fibrosis, meningitis are prescribed the drug at a dose of up to 150 mg/kg/day every 12 hours.

Special Precautions

The drug should be prescribed with caution in patients with a history of bleeding, a history of gastrointestinal diseases (especially ulcerative colitis).

In patients with a documented history of hypersensitivity reaction to penicillins, an incomplete cross-hypersensitivity reaction to cephalosporins has been observed (3-7%). Although many patients with penicillin allergy manifested as rash have received cephalosporins without adverse consequences, caution is recommended when prescribing Lorazidime to this category of patients.

Cephalosporins may interfere with vitamin K synthesis due to suppression of intestinal flora, which may cause a decrease in the levels of vitamin K-dependent blood clotting factors and in rare cases lead to hypoprothrombinemia and bleeding. Administration of vitamin K corrects hypoprothrombinemia. The risk of bleeding is highest in severely ill, elderly and debilitated patients, in patients with impaired liver function, and in individuals with poor nutrition.

In some patients, pseudomembranous colitis caused by Clostridium difficile may develop during or after the use of cephalosporins. In mild cases, drug withdrawal is sufficient; in more severe cases, restoration of water-electrolyte and protein balance is recommended; if necessary, metronidazole, bacitracin, vancomycin should be administered orally.

Use in pediatrics

The drug should be used with caution in newborns under 1 month of age.

Overdose

Symptoms dizziness, paresthesia, headache, convulsive seizures, deviations in laboratory test results.

Treatment symptomatic and supportive therapy is performed. In case of severe overdose, hemodialysis may be used. There is no specific antidote.

Drug Interactions

“Loop” diuretics, aminoglycosides, vancomycin, clindamycin reduce the clearance of ceftazidime, resulting in an increased risk of nephrotoxic effects.

Pharmaceutical interactions

The drug is pharmaceutically incompatible with aminoglycosides, heparin, vancomycin.

Sodium bicarbonate solution should not be used as a solvent.

At concentrations from 1 to 40 mg/ml, Ceftazidime is pharmaceutically compatible with the following solutions: sodium chloride 0.9%, sodium lactate, Hartmann’s solution, dextrose 5%, sodium chloride 0.225% and dextrose 5%, sodium chloride 0.45% and dextrose 5%, sodium chloride 0.9% and dextrose 5%, sodium chloride 0.18% and dextrose 4%, dextrose 10%, dextran 40 (10%) in sodium chloride 0.9% solution, dextran 40 (10%) in dextrose 5% solution, dextran 70 (6%) in sodium chloride 0.9% solution, dextran 70 (6%) in dextrose 5% solution.

At concentrations from 0.05 to 0.25 mg/ml, Ceftazidime is compatible with intraperitoneal dialysis solution (lactate).

For IM administration, Ceftazidime can be diluted with 0.5% or 1% lidocaine hydrochloride solution. Both components remain active when Ceftazidime is added to the following solutions (ceftazidime concentration 4 mg/ml): hydrocortisone (hydrocortisone sodium phosphate) 1 mg/ml in sodium chloride 0.9% solution or dextrose 5% solution; cefuroxime (cefuroxime sodium) 3 mg/ml in sodium chloride 0.9% solution; cloxacillin (cloxacillin sodium) 4 mg/ml in sodium chloride 0.9% solution; potassium chloride 10 mEq/L or 40 mEq/L in sodium chloride 0.9% solution.

When mixing a solution of ceftazidime (500 mg in 1.5 ml of water for injections) and metronidazole (500 mg/100 ml), both components retain their activity.

Storage Conditions

List B. The drug should be stored in a dry place, protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.