Synerpen

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

Composition:

Active substances: imipenem and cilastatin sodium;

1 vial contains imipenem (sterile) 530.10 mg, equivalent to anhydrous imipenem 500 mg; sodium cilastatin (sterile) 530.70 mg, equivalent to cilastatin 500 mg;

Excipient: sodium hydrogencarbonate.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical characteristics: white or pale yellow powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Imipenem and enzyme inhibitor. ATC code J01DH51.

Pharmacological Properties

Pharmacodynamics

SYNERPEN consists of two components: imipenem, the first representative of a new class of β-lactam antibiotics – the thienamycins, and sodium cilastatin, a specific inhibitor of the enzyme that blocks imipenem metabolism in the kidneys and significantly increases the concentration of unchanged imipenem in the urinary tract. The weight ratio of imipenem to sodium cilastatin in SYNERPEN is 1:1.

The class of thienamycin antibiotics, to which imipenem belongs, is characterized by a broader spectrum of potent bactericidal activity than that provided by any other studied antibiotic.

SYNERPEN is indicated for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria. SYNERPEN has demonstrated efficacy in treating numerous infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime, and ceftriaxone. A large number of infections caused by pathogens resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) are also effectively treated with SYNERPEN.

SYNERPEN is not indicated for the treatment of meningitis.

SYNERPEN is a potent inhibitor of bacterial cell wall synthesis and, together with modern cephalosporins and penicillins, has a broad spectrum of activity against gram-negative organisms. However, its distinguishing feature is high activity against gram-positive organisms, previously observed only with narrow-spectrum β-lactam antibiotics. The antimicrobial spectrum of SYNERPEN includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, and Bacteroides fragilis—a diverse and clinically challenging group of pathogens typically resistant to other antibiotics.

SYNERPEN is effective against a wide range of microorganisms, such as Serratia and Enterobacter species, which are inherently resistant to most β-lactam antibiotics.

The antimicrobial spectrum of SYNERPEN is broader than that of any other known antibiotic and encompasses all clinically significant pathogenic microorganisms. Microorganisms generally susceptible to SYNERPEN in vitro include:

Gram-negative aerobic bacteria

Species of Achromobacter, species of Acinetobacter (formerly Mima-Herellea), Aeromonas hydrophila, species of Alcaligenes, Bordetella bronchicanis, Bordetella bronchiseptica, Bordetella pertussis, Brucella melitensis, Burkholderia pseudomallei (formerly Pseudomonas pseudomallei), Burkholderia stutzeri (formerly Pseudomonas stutzeri), species of Campylobacter, species of Capnocytophaga, species of Citrobacter, Citrobacter koseri (formerly Citrobacter diversus), Citrobacter freundii, Eikenella corrodens, species of Enterobacter, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae, Hafnia alvei, species of Klebsiella, Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae, species of Moraxella, Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, species of Pasteurella, Pasteurella multocida, Plesiomonas shigelloides, species of Proteus, Proteus mirabilis, Proteus vulgaris, species of Providencia, Providencia alcalifaciens, Providencia rettgeri (formerly Proteus rettgeri), Providencia stuartii, species of Pseudomonas, Pseudomonas fluorescens, Pseudomonas putida, Pseudomonas aeruginosa, species of Salmonella, Salmonella typhi, species of Serratia, Serratia proteamaculans (formerly Serratia liquefaciens), Serratia marcescens, species of Shigella, species of Yersinia (formerly Pasteurella), Yersinia enterocolitica, Yersinia pseudotuberculosis.

*Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia) and strains of Burkholderia cepacia (formerly Pseudomonas cepacia) are generally not susceptible to SYNERPEN.

Gram-positive aerobic bacteria

Species of Bacillus, Enterococcus faecalis, Erysipelothrix rhusiopathiae, Listeria monocytogenes, species of Nocardia, species of Pediococcus, Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (including penicillinase-producing strains), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus group C, Streptococcus group G, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans Streptococci (including α- and γ-hemolytic strains). Enterococcus faecium and certain methicillin-resistant staphylococci are not susceptible to SYNERPEN.

Gram-negative anaerobic bacteria

Species of Bacteroides, Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bilophila wadsworthia, species of Fusobacterium, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus), Prevotella bivia (formerly Bacteroides bivius), Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Prevotella melaninogenica (formerly Bacteroides melaninogenicus), species of Veillonella.

Gram-positive anaerobic bacteria

Species of Actinomyces, species of Bifidobacterium, species of Clostridium, Clostridium perfringens, species of Eubacterium, species of Lactobacillus, species of Mobiluncus, Microaerophilic streptococcus, species of Peptococcus, species of Peptostreptococcus, species of Propionibacterium (including P. acnes).

Others

Mycobacterium fortuitum, Mycobacterium smegmatis.

In vitro studies indicate that imipenem acts synergistically with aminoglycosides against certain isolates of Pseudomonas aeruginosa.

Pharmacokinetics

In healthy volunteers, a 20-minute intravenous infusion of SYNERPEN at a dose of 500 mg resulted in peak plasma concentrations of imipenem ranging from 21 to 58 µg/mL. The plasma half-life of imipenem was approximately 1 hour. About 70% of the administered antibiotic was recovered unchanged in urine within 10 hours, with no further excretion observed thereafter. When SYNERPEN was administered every 6 hours, no accumulation of imipenem in plasma or urine was observed in patients with normal renal function. Concomitant administration of SYNERPEN and probenecid resulted in minimal increases in plasma concentrations and half-life of imipenem. When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Renal recovery varied between 5% and 40%, averaging 15–20% across several studies. The protein binding of imipenem to human serum proteins is approximately 20%.

Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits the metabolism of imipenem. Therefore, the combined administration of imipenem and cilastatin allows achieving therapeutic antibacterial levels of imipenem in urine and plasma. Peak plasma concentrations of cilastatin after a 20-minute intravenous infusion of SYNERPEN 500 mg were in the range of 21 to 55 µg/mL. The plasma half-life of cilastatin is approximately 1 hour. About 70–80% of the cilastatin dose is excreted unchanged in urine within 10 hours after administration of SYNERPEN, after which no further cilastatin is detected in urine. Approximately 10% is excreted as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of the parent compound. Concomitant administration of SYNERPEN and probenecid doubled the plasma concentration and half-life of cilastatin but did not affect its urinary recovery.

Protein binding of cilastatin to human serum proteins is approximately 40%.

Renal Impairment

After a single 250 mg/250 mg intravenous dose of SYNERPEN, the area under the concentration-time curve (AUC) for imipenem increased by 1.1-, 1.9-, and 2.7-fold, respectively, in patients with mild (creatinine clearance [CrCL] 50–80 mL/min/1.73 m²), moderate (CrCL 30–<50 mL/min/1.73 m²), and severe (CrCL <30 mL/min/1.73 m²) renal impairment compared to patients with normal renal function (CrCL >80 mL/min/1.73 m²). The AUC for cilastatin increased by 1.6-, 2-, and 6.2-fold, respectively, in patients with mild, moderate, and severe renal impairment compared to those with normal renal function. After a single 250 mg/250 mg intravenous dose of SYNERPEN administered 24 hours after hemodialysis, the AUC for imipenem and cilastatin was 3.7- and 16.4-fold higher, respectively, compared to patients with normal renal function. Renal excretion, renal clearance, and plasma clearance of both imipenem and cilastatin decrease with declining renal function following intravenous administration of SYNERPEN. Dose adjustment is necessary for patients with impaired renal function.

Hepatic Impairment

The pharmacokinetics of imipenem in patients with hepatic impairment has not been established. Due to the limited extent of hepatic metabolism of imipenem, hepatic impairment is not expected to significantly affect its pharmacokinetics. Therefore, dose adjustment in patients with hepatic impairment is not recommended.

Children

The mean clearance and volume of distribution of imipenem were approximately 45% higher in children (aged 3 months to 14 years) compared to adults. The area under the concentration-time curve (AUC) for imipenem after administration of imipenem/cilastatin at 15/15 mg/kg body weight in children was approximately 30% higher than exposure in adults receiving a 500 mg/500 mg dose. At a higher dose, exposure after administration of 25/25 mg/kg imipenem/cilastatin in children was 9% higher than exposure in adults receiving a 1000 mg/1000 mg dose.

Elderly Patients

In healthy elderly volunteers (aged 65 to 75 years with normal renal function for their age), the pharmacokinetics of a single 20-minute intravenous 500 mg/500 mg dose of SYNERPEN were consistent with those expected in patients with mild renal impairment, for whom no dose adjustments are considered necessary. Mean plasma half-lives of imipenem and cilastatin were 91 ± 7 minutes and 69 ± 15 minutes, respectively. Repeated dosing did not affect the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed.

Clinical characteristics.

Indications.

Treatment in adults and children aged 1 year and older of infections caused by microorganisms sensitive to the drug:

• intra-abdominal infections;
• lower respiratory tract infections (severe pneumonia, including hospital-acquired and ventilator-associated pneumonia);
• intrapartum and postpartum infections;
• complicated urinary tract infections;
• complicated skin and soft tissue infections;
• bone and joint infections;
• septicemia;
• endocarditis.

SYNERPEN can be used in the treatment of neutropenic patients with fever likely caused by bacterial infection.

Treatment of patients with bacteremia associated or probably associated with any of the above-mentioned infections.

Contraindications.

Hypersensitivity to any component of the drug, other carbapenem drugs, or acute manifestations of hypersensitivity (e.g., anaphylactic reactions, severe skin reactions) to other beta-lactam antibiotics (e.g., penicillins or cephalosporins).

Interaction with other medicinal products and other types of interactions.

Generalized seizures have been observed in patients who received ganciclovir concomitantly with intravenous SYNERPEN. These drugs may be used together only if the expected benefit outweighs the potential risk.

Post-marketing studies have reported decreased plasma levels of valproic acid when co-administered with carbapenems, and in some cases, sudden seizures have been reported. Therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended, and consideration should be given to alternative antibacterial or anticonvulsant therapies (see section "Special precautions for use").

Oral anticoagulants

Concomitant use of antibiotics with warfarin may enhance its anticoagulant effects. The risk may vary depending on the type of infection, age, and overall condition of the patient, making it difficult to assess the exact role of the antibiotic in increasing the international normalized ratio (INR). Frequent monitoring of INR is recommended during and after concomitant use of antibiotics with oral anticoagulants.

Concomitant administration of SYNERPEN and probenecid resulted in minimal increases in imipenem plasma concentration and imipenem plasma half-life. Renal excretion of active (unmetabolized) imipenem decreased to approximately 60% of the dose when SYNERPEN was administered with probenecid. Concomitant

administration of SYNERPEN and probenecid doubled cilastatin plasma levels and cilastatin half-life, but had no effect on cilastatin urinary excretion.

Special precautions for use.

There are clinical and laboratory data indicating partial cross-allergenicity between the drug SINEPEN and other β-lactam antibiotics, penicillins, and cephalosporins. Severe reactions (including anaphylaxis) have been observed with the use of most β-lactam antibiotics. Such reactions are most likely to occur in individuals with a history of sensitivity to multiple allergens. Prior to initiating therapy with this drug, a careful patient history should be obtained regarding previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactam antibiotics, and other allergens. If an allergic reaction occurs during treatment, the drug should be discontinued and appropriate measures initiated. Serious anaphylactic reactions require immediate emergency treatment.

Liver function should be closely monitored during treatment with imipenem/cilastatin due to the risk of hepatotoxicity (elevated transaminase levels, liver failure, and fulminant hepatitis).

Patients with pre-existing liver disease require monitoring of liver function during imipenem/cilastatin therapy. Dose adjustment is not required. A positive direct or indirect Coombs test may occur during treatment with imipenem/cilastatin.

Before initiating any empirical therapy, the antibacterial spectrum of imipenem/cilastatin should be considered, especially in life-threatening conditions. Additionally, caution should be exercised due to the limited susceptibility of certain pathogens (e.g., those associated with skin and soft tissue infections) to imipenem/cilastatin. The use of imipenem/cilastatin is appropriate for treating these types of infections only if the specific pathogen has been documented and is known to be susceptible, or when there are very strong reasons to believe that the most likely pathogen(s) are amenable to such treatment. Concomitant use of this agent against methicillin-resistant Staphylococcus aureus (MRSA) may be indicated when MRSA infection is suspected or confirmed in approved indications.

Concomitant administration of imipenem/cilastatin and valproic acid/sodium valproate is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infection is suspected or confirmed in approved indications.

Antibiotic-associated colitis and pseudomembranous colitis have been reported as complications of nearly all antibiotics; the severity may range from mild to life-threatening. Therefore, antibiotics should be used with caution in patients with a history of gastrointestinal disorders, particularly colitis. It is important to consider the possibility of pseudomembranous colitis in patients who develop diarrhea during or after antibiotic therapy. Discontinuation of imipenem/cilastatin therapy and initiation of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be administered.

The drug SINEPEN is not recommended for the treatment of meningitis.

Imipenem-cilastatin accumulates in patients with impaired renal function. If the dose is not adjusted according to renal function, adverse reactions affecting the central nervous system (CNS) may occur.

As with other β-lactam antibiotics, adverse effects on the CNS such as myoclonia, confusion, or seizures have been reported with the use of SINEPEN, particularly when recommended doses have been exceeded based on renal function and body weight. Such events have usually been observed in patients with pre-existing CNS disorders (e.g., head trauma or history of seizures) and/or in patients with impaired renal function, in whom drug accumulation may occur. Therefore, strict adherence to recommended dosing and treatment regimens is essential, especially for such patients. Anticonvulsant therapy should be continued in patients with a history of seizures.

Particular caution is required regarding neurological symptoms or seizures in children with known risk factors for seizures or who are receiving concomitant treatment with anticonvulsant drugs.

If focal tremor, myoclonia, or seizures occur during treatment, patients should undergo neurological evaluation and anticonvulsant therapy should be initiated if not already prescribed. If CNS adverse effects persist, the dose of SINEPEN should be reduced or the drug discontinued entirely.

SINEPEN is not indicated for use in patients with a creatinine clearance < 15 mL/min, except when hemodialysis will be performed within 48 hours. For patients undergoing hemodialysis, SINEPEN should only be used when the expected therapeutic benefit outweighs the potential risk of seizures.

SINEPEN 500 mg/500 mg contains 37.6 mg of sodium (1.6 mEq), which should be taken into account when administering the drug to patients on a sodium-restricted (salt-free) diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Adequate and well-controlled studies of the drug in pregnant women have not been conducted.

Reproductive toxicity was observed in studies conducted in pregnant monkeys. The potential risk to humans is unknown. SINEPEN should be used during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding.

Imipenem and cilastatin are excreted in small amounts in breast milk. When use of the drug is necessary, the benefits of breastfeeding for the infant should be weighed against the potential risks to the infant.

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted. However, certain adverse effects (such as hallucinations, drowsiness, dizziness, and vertigo) associated with the use of the drug may affect the ability of some patients to drive or operate machinery.

Method of administration and doses.

Doses

Dosing recommendations for the drug Synerpen refer to the amount of imipenem/cilastatin to be administered.

The daily dose of Synerpen is determined based on the type of infection and divided into several equal doses, taking into account the degree of pathogen(s) susceptibility and the patient's renal function.

• Adults and adolescents
• The recommended dosing regimen for patients with normal renal function (creatinine clearance ≥ 90 mL/min) is as follows:
• 500 mg/500 mg every 6 hours, or
• 1000 mg/1000 mg every 8 hours or every 6 hours.

For treatment of infections where the causative agent is known or suspected to be less susceptible bacteria (such as Pseudomonas aeruginosa), and for severe infections (e.g., febrile neutropenic patients), a dose of 1000 mg/1000 mg every 6 hours is recommended.

The dose should be reduced if creatinine clearance is < 90 mL/min (see Table 1).

The maximum daily dose should not exceed 4000 mg/4000 mg per day.

Renal impairment

To determine the reduced dose for adult patients with impaired renal function:

1. Determine the total daily dose (i.e., 2000/2000, 3000/3000, or 4000/4000 mg) normally administered to patients with normal renal function.
2. Select the appropriate reduced dosing regimen (see Table 1) according to the patient's creatinine clearance. For information on infusion duration, see below "Method of administration".

Table 1

Patients with creatinine clearance < 15 mL/min

Synerpen for intravenous administration should not be administered to patients with creatinine clearance < 15 mL/min unless they will undergo hemodialysis within the next 48 hours.

Patients undergoing hemodialysis

For treatment of patients with creatinine clearance < 15 mL/min who are undergoing hemodialysis, doses recommended for patients with creatinine clearance of 15–29 mL/min should be used (see Table 1).

Both imipenem and cilastatin are removed during hemodialysis. Synerpen should be administered to the patient immediately after the hemodialysis session and then every 12 hours following its completion. Patients undergoing hemodialysis, especially those with underlying central nervous system (CNS) disorders, require close monitoring; Synerpen should be prescribed to such patients only if the expected benefit outweighs the potential risk of seizures (see section "Special precautions").

Currently, there is insufficient data on the use of Synerpen in patients undergoing peritoneal dialysis; therefore, its use in this patient group is not recommended.

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment.

Elderly patients

Dose adjustment is not required in elderly patients with normal renal function.

Children aged 1 year and older

The recommended dose for children aged > 1 year is 15/15 or 25/25 mg/kg every 6 hours.

For treatment of infections caused by less susceptible bacterial species (such as Pseudomonas aeruginosa) or severe infections (e.g., febrile neutropenic patients), a dose of 25/25 mg/kg every 6 hours is recommended.

Children under 1 year of age

The use of Synerpen is not recommended in children under 1 year of age due to insufficient clinical data.

Children with renal impairment

The use of Synerpen is not recommended in children with renal impairment (serum creatinine > 2 mg/dL) due to insufficient clinical data.

Administration method

Before administration, Synerpen must be reconstituted and then diluted.

A dose not exceeding 500 mg/500 mg of Synerpen for intravenous use should be infused over 20–30 minutes. A dose exceeding 500 mg/500 mg should be infused over 40–60 minutes. If nausea occurs during infusion, the infusion rate should be reduced.

Reconstitution

Each vial is intended for single use only.

The contents of each vial should be transferred into 100 mL of an appropriate infusion solution (0.9% sodium chloride solution). Under exceptional circumstances, when 0.9% sodium chloride solution cannot be used for clinical reasons, 5% glucose may be used as a diluent.

It is recommended to add approximately 10 mL of 0.9% sodium chloride solution to the vial.

Shake well and transfer the resulting suspension into the infusion container.

WARNING: THE SUSPENSION IS NOT A READY-TO-USE INFUSION SOLUTION.

Repeat the procedure by adding another 10 mL of infusion solution to ensure complete transfer of the vial contents into the infusion solution. The mixture should be shaken until it becomes clear.

The concentration of the reconstituted solution after the above procedure is approximately 5 mg/mL of imipenem and cilastatin.

Diluted solutions should be used immediately. The time interval between the start of reconstitution and completion of intravenous infusion should not exceed 2 hours.

Children.

Due to insufficient clinical data, Synerpen is not recommended for use in children under 1 year of age and in children with renal impairment (serum creatinine > 2 mg/dL) (see section "Dosage and administration").

Overdose.

Symptoms of overdose are consistent with the profile of adverse reactions and may include seizures, confusion, tremor, nausea, vomiting, hypotension, and bradycardia.

There is no specific information on the treatment of overdose. The drug can be removed by hemodialysis; however, the effectiveness of this procedure in overdose has not been established. Treatment is symptomatic.

Side effects.

When administered intravenously, the most commonly reported systemic adverse reactions possibly related to imipenem/cilastatin treatment were: nausea (2.0%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), arterial hypotension (0.4%), seizures (0.4%), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Local adverse reactions included: phlebitis/thrombophlebitis (3.1%), pain at injection site (0.7%), erythema at injection site (0.4%), and venous induration (0.2%). Elevations in serum transaminase and alkaline phosphatase levels were also observed.

Adverse events are categorized by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Infections and infestations: rare: pseudomembranous colitis, candidiasis; very rare: gastroenteritis.

Blood and lymphatic system disorders: common: eosinophilia; uncommon: pancytopenia, neutropenia, leukopenia, thrombocytopenia, thrombocytosis; rare: agranulocytosis; very rare: hemolytic anemia, bone marrow suppression.

Immune system disorders: rare: anaphylactic reactions.

Psychiatric disorders: uncommon: psychiatric disorders including hallucinations and confusion.

Nervous system disorders: uncommon: seizures, myoclonic activity, dizziness, somnolence; rare: encephalopathy, paresthesia, focal tremor, taste disturbance; very rare: worsening of severe myasthenia gravis, headache; frequency not known: agitation, dyskinesia.

Ear and labyrinth disorders: rare: hearing loss; very rare: vertigo, tinnitus.

Cardiac disorders: very rare: cyanosis, tachycardia, palpitations.

Vascular disorders: common: thrombophlebitis; uncommon: arterial hypotension; very rare: flushing.

Respiratory, thoracic and mediastinal disorders: very rare: dyspnea, hyperventilation, pharyngalgia.

Gastrointestinal disorders: common: diarrhea, vomiting, nausea. Nausea and/or vomiting associated with the drug occur more frequently in patients with granulocytopenia than in those without granulocytopenia receiving the drug. Rare: discoloration of teeth and/or tongue; very rare: hemorrhagic colitis, abdominal pain, epigastric pain, glossitis, lingual papillae hypertrophy, increased salivation.

Hepatobiliary disorders: rare: liver failure, hepatitis; very rare: fulminant hepatitis.

Skin and subcutaneous tissue disorders: common: rash (e.g., exanthematous); uncommon: urticaria, pruritus; rare: toxic epidermal necrolysis, Quincke's edema, Stevens-Johnson syndrome, polymorphic erythema, exfoliative dermatitis; very rare: hyperhidrosis, skin texture changes.

Musculoskeletal and connective tissue disorders: very rare: polyarthralgia, thoracic spine pain.

Renal and urinary disorders: rare: acute renal failure, oliguria/anuria, polyuria, change in urine color (benign, should not be confused with hematuria). The impact of SYNERPEN on renal function changes is difficult to assess, as predisposing factors for prerenal azotemia or worsening renal function were usually present.

Reproductive system and breast disorders: very rare: genital pruritus.

General disorders and administration site conditions: uncommon: fever, local pain and induration at injection site, erythema at injection site; very rare: chest discomfort, asthenia/weakness.

Investigations: common: increased serum transaminase levels, increased serum alkaline phosphatase levels; uncommon: positive direct Coombs test, prolonged prothrombin time, decreased hemoglobin, increased serum bilirubin levels, increased serum creatinine levels, increased blood urea nitrogen levels.

In clinical studies involving children aged > 3 months, adverse reactions reported were entirely similar to those observed in adult patients.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life.

2 years.

Storage conditions.

Store in a light-protected place at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

Incompatibilities.

SYNERPEN for intravenous administration is chemically incompatible with lactates (salts of lactic acid) and should not be reconstituted with solvents containing lactates. However, SYNERPEN may be administered via the same intravenous line through which lactate-containing solutions are being infused.

SYNERPEN for intravenous administration must not be mixed with other antibiotics.

Packaging.

1 vial of 30 mL in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

San Pharmaceutical Industries Limited
Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

Industrial Area 3, Dewas - 455001, India
Industrial Area 3, Dewas, 455001, India.