Merotec® 250 mg Injection

Meropenem Injection IP 125 mg / 250 mg / 500 mg / 1 gm / 2 gm

Merotec 125 mg

Each vial contains :

Meropenem Trihydrate IP equivalent to Anhydrous Meropenem 125 mg

Sodium Carbonate IP equivalent to Sodium 11.275 mg

(Sterile Mixture of Meropenem & Sodium Carbonate)

This pack contains Sterile Water for Injections IP 5 ml.

Merotec 250 mg

Each vial contains :

Meropenem Trihydrate IP equivalent to Anhydrous Meropenem 250 mg

Sodium Carbonate IP equivalent to Sodium 22.55 mg

(Sterile Mixture of Meropenem & Sodium Carbonate)

This pack contains Sterile Water for Injections IP 5 ml.

Merotec 500 mg

Each vial contains :

Meropenem Trihydrate IP equivalent to Anhydrous Meropenem 500 mg

Sodium Carbonate IP equivalent to Sodium 45.10 mg

(Sterile Mixture of Meropenem & Sodium Carbonate)

This pack contains Sterile Water for Injections IP 10 ml.

Merotec 1 gm

Each vial contains :

Meropenem Trihydrate IP equivalent to Anhydrous Meropenem 1 gm

Sodium Carbonate IP equivalent to Sodium 90.20 mg

(Sterile Mixture of Meropenem & Sodium Carbonate)

This pack contains Sterile Water for Injections IP 20 ml.

Merotec 2 gm

Each vial contains :

Meropenem Trihydrate IP equivalent to Anhydrous Meropenem 2 gm

Sodium Carbonate IP equivalent to Sodium 180.4 mg

(Sterile Mixture of Meropenem & Sodium Carbonate)

This pack contains Sterile Water for Injections IP 30 ml.

Powder for Intravenous Injection or Infusion.

125 mg / 250 mg / 500 mg / 1 gm / 2 gm.

4.1 Therapeutic indication

Merotec is indicated for the treatment of adults and children with

• Pneumonia, nosocomial pneumonia,
• Urinary tract infections (UTI),
• Intra-abdominal infection,
• Gynaecological infection (such as endometriaitis),
• Skin & soft tissue infection,
• Meningitis,
• Septicaemia, and
• Empiric treatment of presumed infection in patients with febrile neutropenia

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, Acinetobacter spp.), or very severe infections.

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

Adults and adolescents

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes. 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.

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.

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.

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 :

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. 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.

Direction for use : Dissolve the whole content of vial in 5 / 5 / 10 / 20 / 30 ml of sterile water for injections.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Hypersensitivity to any other carbapenem antibacterial agent.
• Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam 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.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been reported.

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. Severe cutaneous adverse reactions (SCAR), such as StevensJohnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalised exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem. If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered.

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. 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.

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). 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.

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.

4.5 Drug 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.

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 effectsof orally administered anticoagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The riskmay varywith the underlying infection, age and general statusof the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after coadministration of antibioticswith an oral anti-coagulant agent.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Special Population

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

Breast-feeding

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: ver y 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); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Paediatric population

Meronem 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. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Relative overdose may be possible in patients with renal impairment, if the dose is not adjusted. Limited post-marketing experience indicates that if adverse reactions occur following overdose, they are consistent with the adverse reaction profile, 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.

5.1 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).

5.2 Pharmacodynamic properties

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 antibacterial agents when the mechanism involved include impermeability and/or an efflux pump(s).

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.

5.3 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.

Biotransformation

Meropenem 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.

6.1 Animal Toxicology or Pharmacology

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.

Merotec contains meropenem trihydrate. Meropenem trihydrate an antibacterial drug. It acts by inhibiting bacterial cell wall synthesis.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Merotec 125 mg : A vial of 125 mg with SWFI IP 5 ml.

Merotec 250 mg : A vial of 250 mg with SWFI IP 5 ml.

Merotec 500 mg : A vial of 500 mg with SWFI IP 10 ml.

Merotec 1 gm : A vial of 1 gm with SWFI IP 20 ml.

Merotec 2 gm : A vial of 2 gm with SWFI IP 30 ml.

8.4 Storage and handing instructions

Store below 25°C. Protect from light & moisture.

Keep out of reach of children.

• Counsel patients that antibacterial drugs including Meropenem for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for Injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Meropenem for Injection or other antibacterial drugs in the future.
• Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.
• Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with Meropenem for Injection. If treatment with Meropenem for Injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.
• Patients receiving Meropenem for Injection on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that Meropenem for Injection is well tolerated, patients should not operate machinery or motorized vehicles.

10 October 2023