1. Name of the medicinal product

    Meropenem Injection IP 500mg (Merokem) Taj Pharma
    Meropenem Injection IP 1g (Merokem) Taj Pharma

    1. Qualitative and quantitative composition
      a) Each vial of powder for solution for injection or infusion contains 570.78 mg meropenem trihydrate equivalent to 500mg anhydrous meropenem.

    b) Each vial of powder for solution for injection or infusion contains 1141.56 mg meropenem trihydrate equivalent to 1 g anhydrous meropenem.

    Excipients with known effect: Each vial contains 208 mg sodium carbonate approximately 4.0 mmol of sodium (approximately 90 mg).

    Each ml of reconstituted solution contains 50 mg Meropenem.

    For the full list of excipients, see section 6.1.

    1. Pharmaceutical form

    Powder for solution for injection or infusion.

    A White to pale yellow crystalline powder.

    pH of the product after reconstitution is 7.3 to 8.3

    1. Clinical particulars

    4.1 Therapeutic indications

    Meropenem is indicated for the treatment of the following infections in adults and children aged 3 months and older (see sections 4.4 and 5.1):

    • Severe pneumonia, including hospital and ventilator-associated pneumonia.
    • Broncho-pulmonary infections in cystic fibrosis
    • Complicated urinary tract infections
    • Complicated intra-abdominal infections
    • Intra- and post-partum infections
    • Complicated skin and soft tissue infections
    • Acute bacterial meningitis

    Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

    Meropenem may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

    Consideration should be given to official guidance on the appropriate use of antibacterial agents.

    4.2 Posology and method of administration

    Posology

    The tables below provide general recommendations for dosing.

    The dose of meropenem administered and the duration of treatment should take into account the type of infection to be treated, including its severity, and the clinical response.

    A dose of up to 2 g three times daily in adults and adolescents and a dose of up to 40 mg/kg three times daily in children may be particularly appropriate when treating some types of infections, such as infections due to less susceptible bacterial species (e.g. Enterobacteriaceae Pseudomonas aeruginosa or Acinetobacter spp.) or very severe infections.

    Additional considerations for dosing are needed when treating patients with renal insufficiency (see further below).

    Adults and adolescents

    Infection Dose to be administered every 8 hours
    Severe pneumonia including hospital and ventilator-associated pneumonia. 500 mg or 1 g
    Broncho-pulmonary infections in cystic fibrosis 2 g
    Complicated urinary tract infections 500 mg or 1 g
    Complicated intra-abdominal infections 500 mg or 1 g
    Intra- and post-partum infections 500 mg or 1 g
    Complicated skin and soft tissue infections 500 mg or 1 g
    Acute bacterial meningitis 2 g
    Management of febrile neutropenic patients 1 g

    Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see section 6.2, 6.3 and 6.6).

    Alternatively, doses up to 1 g can be given as an intravenous bolus injection over approximately 5 minutes. There are limited safety data available to support the administration of a 2 g dose in adults as an intravenous bolus injection.

    Renal impairment

    The dose for adults and adolescents should be adjusted when creatinine clearance is less than 51 ml/min, as shown below. There are limited data to support the administration of these dose adjustments for a unit dose of 2 g.

    Creatinine clearance (ml/min) Dose

    (based on “unit” dose range of 500 mg or 1 g or 2 g, see table above)

    Frequency
    26-50 one unit dose every 12 hours
    10-25 half of one unit dose every 12 hours
    <10 half of one unit dose every 24 hours

    Meropenem is cleared by haemodialysis and haemofiltration. The required dose should be administered after completion of the haemodialysis cycle.

    There are no established dose recommendations for patients receiving peritoneal dialysis.

    Hepatic impairment

    No dose adjustment is necessary in patients with hepatic impairment (see section 4.4).

    Dose in elderly patients

    No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 ml/min.

    Paediatric population

    Children under 3 months of age

    The safety and efficacy of meropenem in children under 3 months of age have not been established and the optimal dose regimen has not been identified. However, limited pharmacokinetic data suggest that 20 mg/kg every 8 hours may be an appropriate regimen (see section 5.2).

    Children from 3 months to 11 years of age and up to 50 kg body weight

    The recommended dose regimens are shown in the table below:

    Infection Dose to be administered every 8 hours
    Severe pneumonia including hospital and ventilator-associated pneumonia 10 or 20 mg/kg
    Broncho-pulmonary infections in cystic fibrosis 40 mg/kg
    Complicated urinary tract infections 10 or 20 mg/kg
    Complicated intra-abdominal infections 10 or 20 mg/kg
    Complicated skin and soft tissue infections 10 or 20 mg/kg
    Acute bacterial meningitis 40 mg/kg
    Management of febrile neutropenic patients 20 mg/kg

    Children over 50 kg body weight

    The adult dose should be administered.

    There is no experience in children with renal impairment.

    Method of administration

    Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see sections 6.2, 6.3, and 6.6). Alternatively, meropenem doses of up to 20 mg/kg may be given as an intravenous bolus over approximately 5 minutes. There are limited safety data available to support the administration of a 40 mg/kg dose in children as an intravenous bolus injection.

    Meropenem is a white to pale yellow crystalline powder for solution for injection or infusion in vial.

    Product after reconstitution is clear colourless to yellow solution.

    4.3 Contraindications

    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

    Hypersensitivity to any other carbapenem antibacterial agent.

    Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of betalactam antibacterial agent (e.g. penicillins or cephalosporins).

    4.4 Special warnings and precautions for use

    The selection of meropenem to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.

    Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp resistance

    Resistance to penems of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp. varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in these bacteria to penems.

    Hypersensitivity reactions

    As with all beta-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been reported (see sections 4.3 and 4.8).

    Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics.

    If a severe allergic reaction occurs, the medicinal product should be discontinued and appropriate measures taken.

    Antibiotic-associated colitis

    Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all anti- bacterial agents, including meropenem, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of meropenem (see section 4.8). Discontinuation of therapy with meropenem and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

    Seizures

    Seizures have infrequently been reported during treatment with carbapenems, including meropenem (see section 4.8).

    Hepatic function monitoring

    Hepatic function should be closely monitored during treatment with meropenem due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see section 4.8).

    Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with meropenem. There is no dose adjustment necessary (see section 4.2).

    Direct antiglobulin test (Coombs test) seroconversion

    A positive direct or indirect Coombs test may develop during treatment with meropenem.

    Concomitant use with valproic acid/sodium valproate/valpromide

    The concomitant use of meropenem and valproic acid/sodium valproate/valpromide is not recommended (see section 4.5).

    Paediatric population

    Meropenem is licensed for children over 3 months of age. There is no evidence of an increased risk of any adverse drug reaction in children based on the limited available data. All reports received were consistent with events observed in the adult population.

    This medicinal product contains 90 mg sodium per dose, equivalent to 4.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

    The maximum daily dose of this product is equivalent to ≥27% of the WHO recommended maximum daily intake for sodium.

    Meropenem is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

    4.5 Interaction with other medicinal products and other forms of interaction

    No specific medicinal product interaction studies other than probenecid were conducted.

    Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem with the effect of increasing the elimination half-life and plasma concentration of meropenem. Caution is required if probenecid is co-administered with meropenem.

    The potential effect of meropenem on the protein binding of other medicinal products or metabolism has not been studied. However, the protein binding is so low that no interactions with other compounds would be expected on the basis of this mechanism.

    Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100 % decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, co-administration of valproic acid/sodium valproate/valpromide with carbapenem agents is not considered to be manageable and therefore should be avoided (see section 4.4).

    Oral anti-coagulants

    Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti-coagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalized ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after coadministration of antibiotics with an oral anti-coagulant agent.

    Paediatric population

    Interaction studies have only been performed in adults.

    4.6 Fertility, pregnancy and lactation

    Pregnancy

    There are no or limited amount of data from the use of meropenem in pregnant women.

    Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

    As a precautionary measure, it is preferable to avoid the use of meropenem during pregnancy.

    Breastfeeding

    Small amounts of meropenem have been reported to be excreted in human milk. Meropenem should not be used in breast-feeding women unless the potential benefit for the mother justifies the potential risk to the baby.

    4.7 Effects on ability to drive and use machines

    No studies on the effect on the ability to drive and use machines have been performed. However, when driving or operating machines, it should be taken into account that headache, paraesthesia and convulsions have been reported for meropenem.

    4.8 Undesirable effects

    Summary of the safety profile

    In a review of 4,872 patients with 5,026 meropenem treatment exposures, meropenem-related adverse reactions most frequently reported were diarrhoea (2.3 %), rash (1.4 %), nausea/vomiting (1.4 %) and injection site inflammation (1.1 %). The most commonly reported meropenem-related laboratory adverse events were thrombocytosis (1.6 %) and increased hepatic enzymes (1.5-4.3 %).

    Tabulated risk of adverse reactions

    In the table below all adverse reactions are listed by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

    Table 1

    System Organ Class Frequency Event
    Infections and infestations Uncommon oral and vaginal candidiasis
    Blood and lymphatic system disorders Common thrombocythaemia
    Uncommon eosinophilia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis, haemolytic anaemia
    Immune system disorders Uncommon angioedema, anaphylaxis (see sections 4.3 and 4.4)
    Nervous system disorders Common headache
    Uncommon paraesthesiae
    Rare convulsions (see section 4.4)
    Gastrointestinal disorders Common diarrhoea, vomiting, nausea, abdominal pain
    Uncommon antibiotic-associated colitis (see section 4.4)
    Hepatobiliary disorders Common transaminases increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased.
    Uncommon blood bilirubin increased
    Skin and subcutaneous tissue disorders Common rash, pruritis
    Uncommon urticaria, toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme.
    Not known Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)
    Renal and urinary disorders Uncommon blood creatinine increased, blood urea increased
    General disorders and administration site conditions Common inflammation, pain
    Uncommon Thrombophlebitis, pain at the injection site

    Paediatric population

    Meropenem is licensed for children over 3 months of age. There is no evidence of an increased risk of any adverse drug reaction in children based on the limited available data. All reports received were consistent with events observed in the adult population.

    Reporting of suspected adverse reactions

    Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

    4.9 Overdose

    Relative overdose may be possible in patients with renal impairment if the dose is not adjusted as described in section 4.2. Limited post-marketing experience indicates that if adverse reactions occur following overdose, they are consistent with the adverse reaction profile described in section 4.8, are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered.

    In individuals with normal renal function, rapid renal elimination will occur.

    Haemodialysis will remove meropenem and its metabolite.

    1. Pharmacological properties

    5.1 Pharmacodynamic properties

    Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems,

    Mechanism of action

    Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

    Pharmacokinetic/Pharmacodynamic (PK/PD) relationship

    Similar to other beta-lactam antibacterial agents, the time that meropenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy. In preclinical models meropenem demonstrated activity when plasma concentrations exceeded the MIC of the infecting organisms for approximately 40 % of the dosing interval. This target has not been established clinically.

    Mechanism of resistance

    Bacterial resistance to meropenem may result from: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) (2) reduced affinity of the target PBPs (3) increased expression of efflux pump components, and (4) production of beta-lactamases that can hydrolyse carbapenems.

    Localised clusters of infections due to carbapenem-resistant bacteria have been reported in the European Union.

    There is no target-based cross-resistance between meropenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes. However, bacteria may exhibit resistance to more than one class of antibacterials agents when the mechanism involved include impermeability and/or an efflux pump(s).

    Breakpoints

    European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing are presented below.

    EUCAST clinical MIC breakpoints for meropenem (2015-01-01, v5)

    Organism Susceptible (S)

    (mg/l)

    Resistant (R)

    (mg/l)

    Enterobacteriaceae ≤ 2 > 8
    Pseudomonas spp. ≤ 2 > 8
    Acinetobacter spp. ≤ 2 > 8
    Streptococcus groups A, B, C, G note 6 note 6
    Streptococcus pneumoniae1 ≤ 2 > 2
    Viridans group streptococci2 ≤ 2 > 2
    Enterococcus spp
    Staphylococcus spp. note 3 note 3
    Haemophilus influenzae1,2 and Moraxella catarrhalis2 ≤ 2 > 2
    Neisseria meningitidis2,4 ≤ 0.25 > 0.25
    Gram-positive anaerobes except Clostridium difficile ≤ 2 > 8
    Gram-negative anaerobes ≤ 2 > 8
    Listeria monocytogenes ≤ 0.25 > 0.25
    Non-species related breakpoints5 ≤ 2 > 8

    1 Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25 mg/l (Susceptible) and 1 mg/l (Resistant).

    2 Isolates with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC values above the current resistant breakpoint they should be reported resistant.

    3 Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.

    4 Breakpoints relate to meningitis only.

    5 Non-species related breakpoints have been determined mainly from PK/PD data and are independent of the MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints. Non species related breakpoints are based on the following dosages: EUCAST breakpoints apply to meropenem 1000 mg x 3 daily administered intravenously over 30 minutes as the lowest dose. 2 g x 3 daily was taken into consideration for severe infections and in setting the I/R breakpoint.

    6 The beta-lactam susceptibility of streptococcus groups A, B, C and G is inferred from the penicillin susceptibility.

    — = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.

    Isolates may be reported as R without prior testing.

    The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

    The following table of pathogens listed is derived from clinical experience and therapeutic guidelines.

    Commonly susceptible species

    Gram-positive aerobes

    Enterococcus faecalis$

    Staphylococcus aureus (methicillin-susceptible)£

    Staphylococcus species (methicillin-susceptible) including Staphylococcus epidermidis

    Streptococcus agalactiae (Group B)

    Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius)

    Streptococcus pneumoniae

    Streptococcus pyogenes (Group A)

    Gram-negative aerobes

    Citrobacter freundii

    Citrobacter koseri

    Enterobacter aerogenes

    Enterobacter cloacae

    Escherichia coli

    Haemophilus influenzae

    Klebsiella oxytoca

    Klebsiella pneumoniae

    Morganella morganii

    Neisseria meningitides

    Proteus mirabilis

    Proteus vulgaris

    Serratia marcescens

    Gram-positive anaerobes

    Clostridium perfringens

    Peptoniphilus asaccharolyticus

    Peptostreptococcus species (including P. micros, P anaerobius, P. magnus)

    Gram-negative anaerobes

    Bacteroides caccae

    Bacteroides fragilis group

    Prevotella bivia

    Prevotella disiens

    Species for which acquired resistance may be a problem

    Gram-positive aerobes

    Enterococcus faecium$†

    Gram-negative aerobes

    Acinetobacter species

    Burkholderia cepacia

    Pseudomonas aeruginosa

    Inherently resistant organisms

    Gram-negative aerobes

    Stenotrophomonas maltophilia

    Legionella species

    Other micro-organisms

    Chlamydophila pneumoniae

    Chlamydophila psittaci

    Coxiella burnetii

    Mycoplasma pneumonia

    $ Species that show natural intermediate susceptibility

    £ All methicillin-resistant staphylococci are resistant to meropenem

    † Resistance rate≥ 50% in one or more EU countries.

    Glanders and melioidosis: Use of meropenem in humans is based on in vitro B.mallei and

    1. pseudomallei susceptibility data and on limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of glanders and melioidosis.

    5.2 Pharmacokinetic properties

    In healthy subjects the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg (11-27 l) and the mean clearance is 287 ml/min at 250 mg falling to 205 ml/min at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 minutes give mean Cmax values of approximately 23, 49 and 115 μg/ml respectively, corresponding AUC values were 39.3, 62.3 and 153 μg.h/ml. After infusion over 5 minutes Cmax values are 52 and 112 μg/ml after 500 and 1000 mg doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur.

    A study of 12 patients administered meropenem 1000 mg 8 hourly post-surgically for intra-abdominal infections showed a comparable Cmax and half-life to normal subjects but a greater volume of distribution 27 l.

    Distribution

    The average plasma protein binding of meropenem was approximately 2 % and was independent of concentration. After rapid administration (5 minutes or less) the pharmacokinetics are biexponential but this is much less evident after 30 minutes infusion. Meropenem has been shown to penetrate well into several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle, and peritoneal exudates.

    BiotransformationMeropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor.

    Elimination

    Meropenem is primarily excreted unchanged by the kidneys; approximately 70 % (50 –75 %) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Faecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.

    Renal insufficiency

    Renal impairment results in higher plasma AUC and longer half-life for meropenem. There were AUC increases of 2.4 fold in patients with moderate impairment (CrCL 33-74 ml/min), 5 fold in severe impairment (CrCL 4-23 ml/min) and 10 fold in haemodialysis patients (CrCL <2 ml/min) when compared to healthy subjects (CrCL >80 ml/min). The AUC of the microbiologically inactive ring opened metabolite was also considerably increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate and severe renal impairment (see section 4.2).

    Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4 times higher than in anuric patients.

    Hepatic insufficiency

    A study in patients with alcoholic cirrhosis shows no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.

    Adult patients

    Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences versus healthy subjects with equivalent renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on weight and the clearance on creatinine clearance and age.

    Paediatric populationThe pharmacokinetics in infants and children with infection at doses of 10, 20 and 40 mg/kg showed Cmax values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and half-lives similar to those observed in adults in all but the youngest subjects (<6 months t1/2 1.6 hours). The mean meropenem clearance values were 5.8 ml/min/kg (6-12 years), 6.2 ml/min/kg (2- 5 years), 5.3 ml/min/kg (6-23 months) and 4.3 ml/min/kg (2-5 months). Approximately 60 % of the dose is excreted in urine over 12 hours as meropenem with a further 12 % as metabolite. Meropenem concentrations in the CSF of children with meningitis are approximately 20 % of concurrent plasma levels although there is significant inter- individual variability.

    The pharmacokinetics of meropenem in neonates requiring anti-infective treatment showed greater clearance in neonates with higher chronological or gestational age with an overall average half-life of 2.9 hours. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20 mg/kg 8 hourly achieved 60 %T>MIC for P. aeruginosa in 95 % of pre-term and 91 % of full term neonates.

    Elderly

    Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown a reduction in plasma clearance, which correlated with age-associated reduction in creatinine clearance, and a smaller reduction in non-renal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment (see section 4.2).

    5.3 Preclinical safety data

    Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal tubular damage was seen in mice and dogs only at doses of 2000 mg/kg and above after a single administration and above and in monkeys at 500 mg/kg in a 7-day study.

    Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodent at doses exceeding 1000 mg/kg.

    The IV LD50 of meropenem in rodents is greater than 2000 mg/kg.

    In repeat dose studies of up to 6 months duration only minor effects were seen including a decrease in red cell parameters in dogs.

    There was no evidence of mutagenic potential in a conventional test battery and no evidence of reproductive toxicity including teratogenic potential in studies in rats up to 750 mg/kg and in monkeys up to 360 mg/kg.

    There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The intravenous formulation was well tolerated in animal studies.

    The sole metabolite of meropenem had a similar profile of toxicity in animal studies.

    1. Pharmaceutical particulars

    6.1 List of excipients

    Sodium carbonate, anhydrous

    6.2 Incompatibilities

    This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

    6.3 Shelf life

    2 years

    After reconstitution:

    Intravenous bolus injection administration

    A solution for bolus injection is prepared by dissolving the drug product meropenem in sterile water for injection to a final concentration of 50 mg/ml.

    Chemical and physical in-use stability for a prepared solution for bolus injection has been demonstrated upto 3 hours at controlled room temperature (15-25°C) or upto 8 hours under refrigerated conditions (2-8°C). From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately.

    If not used immediately in-use storage times and conditions are the responsibility of the user.

    Intravenous infusion administration

    A solution for infusion is prepared by dissolving the drug product meropenem in either 0.9% sodium chloride solution for infusion or 5% glucose (dextrose) solution for infusion to a final concentration of 1 to 20 mg/ml.

    Chemical and physical in-use stability for a prepared solution for infusion using 0.9% sodium chloride solution has been demonstrated for 6 hours at controlled room temperature (15-25°C) or upto12 hours under refrigerated conditions (2-8°C). In this case, the prepared solution if stored under refrigeration (i.e. 2-8°C) should be used within 1 hour after it has left the refrigerator.

    From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately in-use storage times and conditions are the responsibility of the user.

    Reconstituted solution of meropenem in 5% glucose (dextrose) solution should be used immediately, i.e. within 30 minutes following reconstitution.

    Do not freeze the reconstituted solution.

    6.4 Special precautions for storage

    The medicinal product does not require any special storage condition.

    6.5 Nature and contents of container

    1349.56 mg powder in a 40ml Type-I, tubular, clear glass vial with stopper (bromobutyl rubber with aluminum seals having white colour polypropylene discs).

    The medicinal product is supplied in pack sizes of 1 or 10 vials.

    Not all pack sizes may be marketed

    6.6 Special precautions for disposal and other handling

    Injection

    Meropenem to be used for bolus intravenous injection should be constituted with sterile water for injection.

    Infusion

    For intravenous infusion meropenem vial may be directly constituted with 0.9% sodium chloride or 5% glucose (dextrose) solutions for infusion.

    Each vial is for single use only.

    Standard aseptic techniques should be used for solution preparation and administration.

    The solution should be shaken before use. The solutions should be inspected visually for particles and discolouration prior to administration. Only clear colourless to yellow solution, free from particles should be used.

    Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

    1. Manufactured in India by:
      TAJ PHARMACEUTICALS LTD.,
      At: 615, GIDC, Kerala, Bavla Dist., Ahmedabad-438225, Gujarat, INDIA

PACKAGE LEAFLET: INFORMATION FOR THE USER
Meropenem Injection IP 500mg / 1g (Merokem) Taj Pharma

meropenem
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
  • Keep this leaflet. You may need to read it
  • If you have any further questions, ask your doctor or
  • This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or nurse.This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
  1. What Meropenem is and what it is used for
  2. What you need to know before you take Meropenem
  3. How to take Meropenem
  4. Possible side effects
  5. How to store Meropenem
  6. Contents of the pack and other information

 

  1. What Meropenem is and what it is used for

Meropenem belongs to a group of medicines called carbapenem antibiotics. It works by killing bacteria, which can cause serious infections.

Meropenem is used to treat the following in adults and children aged 3 months and older:

  • Infection affecting the lungs (pneumonia).
  • Lung and bronchial infections in patients suffering from cystic fibrosis.
  • Complicated urinary tract
  • Complicated infections in the
  • Infections that you can catch during or after the
  • Complicated skin and soft tissues
  • Acute bacterial infection of the brain (meningitis).

Meropenem may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Meropenem may be used to treat bacterial infection of the blood which might be associated with a type of infection mentioned above.

2. What you need to know before you take Meropenem
Do not take Meropenem
  • If you are allergic to meropenem or any of the other ingredients of this medicine (listed in section 6).
  • If you are allergic to other antibiotics such as penicillins, cephalosporins or carbapenems as you may also be allergic to meropenem.
Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Meropenem.

  • If you have health problems, such as liver or kidney
  • If you have had severe diarrhoea after taking other

You may develop a positive test (Coombs test) which indicates the presence of antibodies that may destroy red blood cells. Your doctor will discuss this with you.

If you are not sure if any of the above applies to you, talk to your doctor or nurse before using Meropenem.

Other medicines and Meropenem

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.

This is because Meropenem can affect the way some medicines work and some medicines can have an effect on Meropenem.  In particular, tell your doctor or nurse if you are taking any of the following medicines:

  • Probenecid (used to treat gout).
  • Valproic acid/sodium valproate/valpromide (used to treat epilepsy). Meropenem should not be used because it may decrease the effect of sodium

Oral anti-coagulant agent (used to treat or prevent blood clots).

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. It is preferable to avoid the use of meropenem during pregnancy. Your doctor will decide whether you should use meropenem.

It is important that you tell your doctor if you are breast-feeding or if you intend to breast-feed before receiving meropenem. Small amounts of this medicine may pass into the breast milk. Therefore, your doctor will decide whether you should use meropenem while breast-feeding.

Driving and using machines

No studies on the effect on the ability to drive and use machines have been performed. Meropenem has been associated with headache; tingling or pricking skin (paraesthesia). Any of these side effects could affect your ability to drive or operate machines.

Meropenem may cause involuntary muscle movements, leading the person’s body to shake rapidly and uncontrollably (convulsions).

This is usually accompanied with a loss of consciousness. Do not drive or use machines if you experience this side effect.

The maximum recommended daily dose of this medicinal product contains 540 mg sodium (found in table salt). This is equivalent to 27% of the adult recommended maximum daily dietary intake for sodium.

Meropenem 500 mg

Talk to your doctor if you need 9 or more vials daily for a prolonged period, especially if you have been advised to follow a low salt (sodium) diet.

Meropenem 1 g

Talk to your doctor if you need 5 or more vials daily for a prolonged period, especially if you have been advised to follow a low salt (sodium) diet.

  1. How to take Meropenem

Always use this medicine exactly as your doctor or nurse has told you. Check with your doctor or nurse if you are not sure.

Use in Adults

The dose depends on the type of infection that you have, where the infection is in the body and how serious the infection is. Your doctor will decide on the dose that you need.

The dose for adults is usually between 500 mg (milligrams) and 2 g (gram). You will usually receive a dose every 8 hours. However you may receive a dose less often if your kidneys do not work very well.

Use in children and adolescents

The dose for children over 3 months old and up to 12 years of age is decided using the age and weight of the child. The usual dose is between 10 mg and 40 mg of Meropenem for each kilogram (kg) that the child weighs. A dose is usually given every 8 hours. Children who weigh over 50 kg will be given an adult dose.

How to use Meropenem
  • Meropenem will be given to you as an injection or infusion into a large vein.
  • Your doctor or nurse will normally give Meropenem to
  • However, some patients, parents and carers are trained to give Meropenem at home. Instructions for doing this are provided in this leaflet (in the section called ‘Instructions for giving Meropenem to yourself or someone else at home’). Always use Meropenem exactly as your doctor has told you. You should check with your doctor if you are not
  • Your injection should not be mixed with or added to solutions that contain other
  • The injection may take about 5 minutes or between 15 and 30 minutes. Your doctor will tell you how to give
  • You should normally have your injections at the same times each
If you take more Meropenem than you should
  • If you accidentally use more than your prescribed dose, contact your doctor or nearest hospital straight away.
  • If you forget to take Meropenem
  • If you miss an injection, you should have it as soon as possible. However, if it is almost time for your next injection, skip the missed injection. Do not take a double dose (two injections at the same time) to make up for a forgotten dose.
  • If you stop taking Meropenem
  • Do not stop having Meropenem until your doctor tells you to. If you have any further questions on the use of this medicine, ask your doctor or nurse.
  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Severe allergic reactions

If you have a severe allergic reaction, stop having Meropenem and see a doctor straight away. You may need urgent medical treatment. The signs may include a sudden onset of:

  • Severe rash, itching or hives on the
  • Swelling of the face, lips, tongue or other parts of the
  • Shortness of breath, wheezing or trouble

Damage to red blood cells (not known)

The signs include:

  • Being breathless when you do not expect
  • Red or brown urine.

If you notice any of the above, see a doctor straight away. Other possible side effects:

Common (may affect up to 1 in 10 people)

  • Abdominal (stomach) pain.
  • Feeling sick (nausea).
  • Being sick (vomiting).
  • Skin rash, itchy skin.
  • Pain and inflammation.
  • Increased numbers of platelets in your blood (shown in a blood test).
  • Changes in blood tests, including tests that show how well your liver is working.

Uncommon (may affect up to 1 in 100 people)

  • Changes in your blood. These include reduced numbers of platelets (which may make you bruise more easily), increased numbers of some white blood cells, decreased numbers of other white cells and increased amounts of a substance called ‘bilirubin’. Your doctor may do blood tests from time to
  • Changes in blood tests, including tests that show how well your kidneys are working.
  • A tingling feeling (pins and needles).
  • Infections of the mouth or the vagina that are caused by a fungus (thrush).
  • Inflammation of the bowel with
  • Sore veins where Meropenem is
  • Other changes in your blood. The symptoms include frequent infections, high temperature and sore throat. Your doctor may do blood tests from time to
  • Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever and joint

Rare (may affect up to 1 in 1,000 people)

  • Fits (convulsions).

Frequency not known (cannot be estimated from available data)

Serious hypersensitivity reactions involving fever, skin rash, and changes in the blood tests that check how the liver is working (increased levels of liver enzymes) and an increase in a type of white blood cell (eosinophilia) and enlarged lymph nodes. These may be signs of a multi-organ sensitivity disorder known as DRESS syndrome.

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet.

  1. How to store Meropenem

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on vial label and carton after EXP. The expiry date refers to the last day of that month.

The medicinal product does not require any special storage condition.

Injection

After reconstitution: The reconstituted solutions for intravenous injection should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous injection should not exceed:

  • 3 hours when stored at controlled room temperature (15-25°C);
  • 8 hours when stored under refrigerated conditions (2-8°C); Do not freeze the reconstituted

Infusion

After reconstitution: The reconstituted solutions for intravenous infusion should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous infusion should not exceed:

  • 6 hours when stored at controlled room temperature (15-25°C) when meropenem is dissolved in sodium chloride;
  • 12 hours when stored at 2-8°C when meropenem is dissolved in sodium chloride. In this case, the prepared solution if stored under refrigeration (i.e. 2-8°C) should be used within 1 hour after it has left the refrigerator.
  • 30 minutes when meropenem is dissolved in glucose (dextrose).

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately.

If not used immediately in-use storage times and conditions are the responsibility of the user.

Do not freeze the reconstituted solution.

Do not throw away any medicines via waste water or house hold waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Meropenem contains

  • The active ingredient is

Each vial contains meropenem trihydrate equivalent to 500 mg anhydrous meropenem.

Each vial contains meropenem trihydrate equivalent to 1 g anhydrous meropenem.

  • The other ingredient is sodium carbonate,

What Meropenem looks like and contents of the pack

Meropenem is a white to pale yellow crystalline powder for solution for injection or infusion in vial.

Product after reconstitution is clear colourless to yellow solution. Meropenem 500 mg:

674.78 mg powder in a 30ml Type-I, tubular, clear glass vial with stopper (bromobutyl rubber with aluminum seals having taxim blue colour polypropylene discs).

Meropenem 1 g:

1349.56 mg powder in a 40ml Type-I, tubular, clear glass vial with stopper (bromobutyl rubber with aluminum seals having white colour polypropylene discs).

The medicinal product is supplied in pack sizes of 1 or 10 vials. Not all pack sizes may be marketed.

  1. Manufactured in India by:

TAJ PHARMACEUTICALS LTD.,

At: 615, GIDC, Kerala, Bavla Dist., Ahmedabad-438225, Gujarat, INDIA

Note:

This product information is intended only for residents of the India. Taj Pharmaceuticals Limited, medicines help to treat and prevent a range of conditions—from the most common to the most challenging—for people around the world

Information for Health Care Professionals

*** Please consult local Prescribing Information for any product before use. This website is an international information resource for healthcare professionals with an interest in disease management. This website is not intended to replace the advice of a qualified healthcare professional. Above brand is a trademark of the Taj group of companies (Taj Pharmaceuticals Limited).