Syronem (Powder) Instructions for Use

Marketing Authorization Holder

Panbio Pharm, LLC (Russia)

Manufactured By

Simpex Pharma, Pvt. Ltd. (India)

ATC Code

J01DH02 (Meropenem)

Active Substance

Meropenem (Rec.INN registered by WHO)

Dosage Forms

	Syronem	Powder for preparation of solution for intravenous administration 0.5 g: vial 1 or 10 pcs.
		Powder for preparation of solution for intravenous administration 1 g: vial 1 or 10 pcs.

Dosage Form, Packaging, and Composition

1 g – vials (1) – carton packs.
1 g – vials (10) – carton packs.
1 g – vials (100) – carton boxes.
1 g – vials (200) – carton boxes.

500 mg – vials (1) – carton packs.
500 mg – vials (10) – carton packs.
500 mg – vials (200) – carton boxes.
500 mg – vials (400) – carton boxes.

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Antibiotic-carbapenem

Pharmacological Action

Meropenem is a parenteral antibiotic from the carbapenem group, it has a bactericidal effect (suppresses the synthesis of the bacterial cell wall), easily penetrates the bacterial cell wall, and is resistant to the action of most beta-lactamases.

Unlike imipenem, Meropenem is practically not destroyed in the renal tubules by dehydropeptidase-1 (does not require combination with cilastatin – a specific inhibitor of dehydropeptidase-1) and, accordingly, no nephrotoxic breakdown products are formed; it has a high affinity for penicillin-binding proteins.

Bactericidal and bacteriostatic concentrations are practically the same.

It interacts with receptors – specific penicillin-binding proteins on the surface of the cytoplasmic membrane, inhibits the synthesis of the peptidoglycan layer of the cell wall, suppresses transpeptidase, promotes the release of autolytic enzymes of the cell wall, which ultimately causes its damage and death of bacteria.

The spectrum of antibacterial activity of meropenem includes most clinically significant gram-positive and gram-negative aerobic and anaerobic bacterial strains.

Gram-positive aerobes

Enterococcus faecalis (including vancomycin-resistant strains), Staphylococcus aureus (penicillinase-non-producing and penicillinase-producing (methicillin-sensitive)); Streptococcus agalactiae, Streptococcus pneumoniae (only penicillin-sensitive); Streptococcus pyogenes, Viridans group streptococci.

Gram-negative aerobes

Escherichia coli, Haemophilus influenzae (penicillinase-non-producing and penicillinase-producing), Klebsiella pneumoniae, Neisseria meningitidis, Pseudomonas aeruginosa, Proteus mirabilis.

Anaerobic bacteria

Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus spp.

Meropenem is effective in vitro against the microorganisms listed below, however, its clinical efficacy in diseases caused by these pathogens has not been proven.

Gram-positive aerobes

Staphylococcus epidermidis (penicillinase-non-producing and penicillinase-producing (methicillin-sensitive)).

Gram-negative aerobes

Acinetobacter spp., Aeromonas hydrophila, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Haemophilus influenzae (ampicillin-resistant, penicillinase-non-producing strains), Hafnia alvei, Klebsiella oxytoca, Moraxella catarrhalis (penicillinase-non-producing and penicillinase-producing), Morganella morganii, Pasteurella multocida, Proteus vulgaris, Salmonella spp., Serratia marcescens, Shigella spp., Yersinia enterocolitica.

Anaerobic bacteria

Bacteroides distasonis, Bacteroides ovatus, Bacteroides uniformis, Bacteroides urealyticus, Bacteroides vulgatus, Clostridium difficile, Clostridium perfringens, Eubacterium lentum, Fusobacterium spp., Prevotella bivia, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas asaccharolytic, Propionibacterium acnes.

Pharmacokinetics

Intravenous administration over 30 minutes of 250 mg of meropenem to healthy volunteers creates a C_max of approximately 11 µg/ml, 500 mg – 23 µg/ml and 1000 mg – 49 µg/ml (no dependence of C_max and area under the concentration-time curve (AUC) on the administered dose was noted).

When increasing the dose of meropenem from 250 to 2000 mg, the clearance decreases from 287 to 205 ml/min. With intravenous bolus administration over 5 minutes, 500 mg C_max is 52 µg/ml, 1000 mg – 112 µg/ml.

C_max in plasma after intravenous administration of 1000 mg of the drug over 2 min, 3 min, and 5 min is 110, 91 and 94 µg/ml, respectively.

Six hours after intravenous administration of 500 mg, the concentration of meropenem in blood plasma decreases to values of 1 µg/ml and below.

With repeated administration of meropenem at 8-hour intervals to patients with normal renal function, no accumulation of the drug is observed. It undergoes insignificant metabolism in the liver with the formation of a single inactive metabolite. In patients with normal renal function, T_1/2 is approximately 1 hour.

Plasma protein binding is approximately 2%.

About 70% of the intravenous dose of meropenem is excreted by the kidneys unchanged within 12 hours. Meropenem concentrations in urine exceeding 10 µg/ml are maintained for 5 hours after administration of a 500 mg dose.

Meropenem penetrates well into most tissues and biological fluids of the body, including cerebrospinal fluid in patients with bacterial meningitis, reaching concentrations exceeding those required to kill most bacteria.

Pharmacokinetic features in different age groups

The pharmacokinetics of meropenem in children is the same as in adults. T_1/2 of meropenem in children under 2 years of age is approximately 1.5-2.3 hours; a linear dependence of the pharmacokinetic parameters of meropenem is observed in the dose range of 10-40 mg/kg.

In elderly patients, the clearance of meropenem decreases, correlating with the decrease in creatinine clearance.

Renal failure

The clearance of meropenem in patients with renal failure correlates with creatinine clearance. Such patients require dose adjustment. It is eliminated by hemodialysis.

Hepatic failure

Pharmacokinetic studies in patients with liver diseases have shown that these pathological changes do not affect the pharmacokinetics of meropenem.

Indications

Syronem for intravenous administration is indicated for the treatment of infectious and inflammatory diseases in children and adults (monotherapy or in combination with other antimicrobial agents) caused by one or more pathogens sensitive to meropenem.

• Lower respiratory tract infections (including pneumonia, including hospital-acquired);
• Intra-abdominal infections (including complicated appendicitis, peritonitis, pelvic peritonitis);
• Urinary system infections (including pyelonephritis, pyelitis);
• Skin and soft tissue infections (including erysipelas, impetigo, secondarily infected dermatoses);
• Pelvic organ infections (including endometritis);
• Bacterial meningitis;
• Empirical treatment (as monotherapy or in combination with antiviral or antifungal agents) for suspected infection in adult patients with febrile episodes with neutropenia.

There is no experience with the use of the drug in children with neutropenia, with primary or secondary immunodeficiency.

ICD codes

Dosage Regimen

Syronem is administered intravenously as a bolus over 5 minutes (diluted with sterile water for injection at the rate of 1 ml per 50 mg), or by drip over 15-30 minutes (diluted with 50-200 ml of compatible infusion fluid).

Syronem can be dissolved in the following solutions

• 0.9% sodium chloride solution;
• 5% and 10% dextrose solution;
• 5% dextrose solution with 0.02% sodium bicarbonate solution;
• 0.9% sodium chloride solution with 5% dextrose solution;
• 5% dextrose solution with 0.225% sodium chloride solution;
• 5% dextrose solution with 0.15% potassium chloride solution;
• 2.5% or 10% mannitol solution.

The resulting solution is a clear, colorless or light yellow liquid. Syronem should not be mixed with other medicinal products.

When diluting Syronem, the standard regimen of asepsis and antisepsis should be observed. The diluted solution must be shaken before administration. All vials are for single use only.

Adults

Doses and duration of therapy are established depending on the type and severity of the infection and the patient’s condition.

The following daily doses are recommended

• 500 mg intravenously every 8 hours for pneumonia, urinary tract infections, infectious and inflammatory diseases of the pelvic organs, skin and soft tissue infections;
• 1 g intravenously every 8 hours for hospital-acquired pneumonia, peritonitis, suspected bacterial infection in patients with neutropenia, as well as septicemia.

For the treatment of meningitis, the recommended dose is 2 g every 8 hours.

Dosage regimen in adult patients with impaired renal function

In patients with creatinine clearance less than 51 ml/min, doses should be reduced as follows

Meropenem is eliminated by hemodialysis. If prolonged treatment with Syronem is required, it is recommended that a single dose (based on the type and severity of the infection) be administered at the end of the hemodialysis procedure to restore the effective plasma concentration of the drug.

There is no experience with the use of Syronem in patients undergoing peritoneal dialysis.

Dosage regimen in adult patients with impaired liver function

In patients with hepatic insufficiency, no dose adjustment is required (see section “Special Instructions”).

Dosage regimen in elderly patients

In elderly patients with normal renal function or a decrease in creatinine clearance not lower than 50 ml/min, no dose adjustment is required.

Dosage regimen in children

For children aged 3 months to 12 years, the recommended dose for intravenous administration is 10-20 mg/kg every 8 hours, depending on the type and severity of the infection, the sensitivity of the pathogen and the patient’s condition. In children weighing more than 50 kg, the drug should be used in a dose similar to that used in adults.

For meningitis, the recommended dose is 40 mg/kg every 8 hours.

The efficacy and tolerability of the drug in children under 3 months of age have not been established, therefore, the use of Syronem in children of this age category is not recommended.

There is no experience with the use of the drug in children with impaired liver and kidney function.

Adverse Reactions

Local reactions: inflammation, thrombophlebitis, pain at the injection site; tissue necrosis with concomitant increase in creatine phosphokinase (with intramuscular injection).

Systemic reactions

Allergic reactions in rare cases, systemic allergic reactions (hypersensitivity) may occur. These reactions may manifest as angioedema and anaphylactic shock, as well as skin rash, itching, urticaria. In rare cases, serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis may occur.

Digestive system: epigastric pain, nausea, vomiting, diarrhea, cholestatic hepatitis, hyperbilirubinemia, increased activity of “liver” transaminases and alkaline phosphatase, LDH, rarely – candidiasis of the oral mucosa, pseudomembranous enterocolitis.

Cardiovascular system: development or worsening of heart failure, cardiac arrest, tachycardia or bradycardia, decrease or increase in blood pressure, fainting, myocardial infarction, pulmonary artery thromboembolism.

Hematopoietic system: anemia, thrombocytosis, eosinophilia, thrombocytopenia, leukopenia and neutropenia (including isolated cases of agranulocytosis). Some patients may have a positive direct or indirect Coombs test, a decrease in partial thromboplastin time.

Urinary system: dysuria, edema, impaired renal function (hypercreatininemia, increased plasma urea concentration), hematuria.

Nervous system: headache, paresthesia, insomnia, increased excitability, anxiety, depression, impaired consciousness, hallucinations. Seizures have been reported, although a causal relationship with the use of meropenem has not been proven.

Other vaginal candidiasis.

Contraindications

• Hypersensitivity to meropenem;
• Children under 3 months of age.

With caution

• When co-administered with nephrotoxic drugs;
• In persons with gastrointestinal diseases (especially those suffering from chronic colitis), as well as with severe renal failure;
• In persons with a history of allergic reactions to other beta-lactam antibiotics.

Use in Pregnancy and Lactation

Pregnancy

The safety of using meropenem in women during pregnancy has not been studied. Animal studies have not shown any adverse effects on the developing fetus.

Syronem should not be used during pregnancy, except in cases where the potential benefit of its use to the mother outweighs the possible risk to the fetus.

Lactation

Meropenem is detected in animal breast milk in very low concentrations. Syronem should not be used in breastfeeding women, except in cases where the potential benefit of its use to the mother outweighs the possible risk to the child. If the drug is used during lactation, consideration should be given to discontinuing breastfeeding.

Use in Hepatic Impairment

In patients with hepatic insufficiency, no dose adjustment is necessary (see the “Special Precautions” section).

Use in Renal Impairment

In patients with a creatinine clearance of less than 51 ml/min, doses should be adjusted according to the “Dosage Regimen” section.

Pediatric Use

The drug is contraindicated in children under 3 months of age.

Special Precautions

Before prescribing meropenem, it is necessary to carefully collect the patient’s allergy history, paying special attention to tolerance to other beta-lactam antibiotics (caution is required when prescribing it to patients with a history of hypersensitivity reactions to them). If allergic reactions to Syronem develop, it should be discontinued and appropriate measures taken.

The use of Syronem in patients with liver disease should be carried out under the control of serum transaminase activity and bilirubin levels in the blood.

During treatment, the development of pathogen resistance is possible, therefore, long-term treatment is carried out under constant monitoring of the spread of resistant strains.

If unexplained diarrhea occurs during meropenem administration, the possibility of developing pseudomembranous colitis (a toxin produced by Clostridium difficile is one of the main causes of antibiotic-associated colitis) should be considered, the first symptom of which may be the development of diarrhea during treatment.

When using Syronem in monotherapy for severe respiratory tract infections caused by Pseudomonas aeruginosa, regular determination of the pathogen’s sensitivity is recommended.

As with the use of other antibiotics, the growth of microorganisms non-susceptible to Syronem is possible during its administration.

Use in Pediatrics

The efficacy and safety of Syronem in children under 3 months of age have not been established. There are no data regarding the use of the drug in children with impaired liver and/or kidney function. There is no experience with the use of meropenem in children with neutropenia or with primary/secondary immunodeficiency.

Effect on the Ability to Drive and Operate Machinery

No specific studies have been conducted on the effect of Syronem on the speed of psychomotor reactions; however, considering its spectrum of pharmacological activity, no significant effect on the ability to drive a car or operate other machinery is expected.

Overdose

Due to the rapid renal excretion of the drug, overdose is unlikely, but it may occur during the treatment of patients with impaired renal function. Treatment of overdose is symptomatic. In patients with renal failure, hemodialysis effectively removes Meropenem and its metabolites.

Drug Interactions

Meropenem is pharmaceutically incompatible with heparin.

Ganciclovir increases the risk of generalized seizures.

Meropenem exhibits antagonism when interacting with beta-lactam antibiotics.

Drugs that block tubular secretion slow down the excretion and increase the plasma concentration of meropenem.

Concomitant administration of meropenem with potentially nephrotoxic drugs increases the risk of nephrotoxic reactions.

The possible influence of meropenem on the plasma protein binding of other drugs has not been studied; however, considering its weak affinity (see kinetics) for plasma proteins, interaction with other drugs at this level is unlikely.

Meropenem may reduce the serum concentration of valproic acid to a subtherapeutic level, which may require adjustment of its dose.

Storage Conditions

List B. In a dry place, protected from light, at a temperature not exceeding 30°C (86°F). Keep out of reach of children.

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.