MEROCRIT I.V. Injection (Meropenem)

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

MEROCRIT KIT 1 gm

Each Combipack contains:

  1. Meropenem Injection IP 1000 mg

Each vial contains:

Sterile Meropenem Trihydrate IP

Eq. to Anhydrous Meropenem 1000 mg

Sodium (As Sodium Carbonate IP) 90.2 mg

  1. Sterile water for injections IP

Sterile Water for Injections IP……20 ml

  1. I.V. Flow Regulator

MEROCRIT KIT 0.5 gm

Each Combipack contains:

  1. Meropenem Injection IP 500 mg

Each vial contains:

Sterile Meropenem Trihydrate IP

Eq. to Anhydrous Meropenem 500 mg

Sodium (As Sodium Carbonate IP) 45.1 mg

  1. Sterile water for injections IP

Sterile Water for Injections IP……10 ml

  1. I.V. Flow Regulator

Dosage Form and Strength

Powder for reconstitution and I.V. use only– 500 mg and 1,000 mg.

Clinical Particulars

Therapeutic Indications

MEROCRIT I.V. is indicated for the treatment of the following infections:

  • Pneumonia and nosocomial pneumonia
  • Urinary tract infections
  • Intra-abdominal infections
  • Gynaecological infections
  • Skin, skin structure and soft tissue infections
  • Meningitis
  • Septicaemia
  • Empiric treatment for presumed infections with febrile neutropenia

Posology and Method of Administration

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

Infection

Dose to be administered every 8 hours

Pneumonia, nosocomial pneumonia

500 mg or 1000 mg

Urinary tract infections

500 mg or 1000 mg

Intra-abdominal infections

500 mg or 1000 mg

Gynaecological infections

500 mg or 1000 mg

 

Skin, skin structure and soft tissue infections

500 mg or 1000 mg

Meningitis

2000 mg

Management of febrile neutropaenic patients

1000 mg

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.

Creatinine Clearance (mL/min)

Dose (based on ‘unit’ dose range  of 500 mg, 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.

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:

Infection

Dose to Be Administered Every 8 Hours

Pneumonia and nosocomial pneumonia

10 or 20 mg/kg

Urinary tract infections

10 or 20 mg/kg

Intra-abdominal infections

10 or 20 mg/kg

Skin, skin structure and soft tissue infections

10 or 20 mg/kg

Meningitis

40 mg/kg

Management of febrile neutropaenic 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.

Important Administration Instructions:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

For Intravenous Bolus Administration

In adults and adolescents, doses up to 1 g can be given as an I.V. 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 I.V. bolus injection.

In children, meropenem doses of up to 20 mg/kg may be given as an I.V. 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 I.V. bolus injection.

Re-constitute injection vials (500 mg and 1 gram) with sterile Water for Injection (see table below). Shake to dissolve and let stand until clear.

Volume of Sterile Water for Injection for Reconstitution of Injection Vials

Vial

Size

 

Amount of

Diluent

Added (mL)

Approximate

Withdrawable Volume

(mL)

Approximate

Average

Concentration

(mg/mL)

Hours stable

Up to 25oC

2-8oC

500 mg

10

10

50

3 hours

12 hours

1,000 mg

20

20

50

For Infusion

Meropenem is usually given by I.V. infusion over approximately 15–30 minutes. Injection vials may be directly re-constituted with compatible solutions such 0.9% sodium chloride, 5% dextrose, 10% Dextrose, and 5% Dextrose + 0.9% sodium chloride. Alternatively, an injection vial may be re-constituted with water for injection, then the resulting solution added to an I.V. container and further diluted with an appropriate infusion fluid. Do not use flexible container in series connections.

Diluent

Hours stable

Up to 25oC

2-8oC

0.9% sodium chloride

3 hours

12 hours

5% Dextrose + 0.9% sodium chloride

2 hours

4 hours

5% Dextrose

Should not be stored and used immediately

Should not be stored and used immediately

10% Dextrose

Should not be stored and used immediately

Should not be stored and used immediately

The reconstituted solution can be given by infusion set which is provided in pack follow the following steps

Contraindications

Meropenem is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions or severe skin reaction to beta (β)-lactams (e.g. penicillins or cephalosporins).

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

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. Before initiating therapy with meropenem, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to meropenem occurs, discontinue the drug immediately.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized 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.

Seizure Potential

Seizures and other adverse CNS experiences have been reported during treatment with meropenem. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function.

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or adult patients with creatinine clearance of 50mL/min or less.

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re-examine the dosage of meropenem to determine whether it should be decreased or discontinued.

Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid

The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction.

Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of meropenem is necessary, consider supplemental anti-convulsant therapy.

Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug-Resistant Bacteria

Prescribing meropenem in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Overgrowth of Nonsusceptible Organisms

As with other broad-spectrum antibacterial drugs, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.

Thrombocytopenia

In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported.

Potential for Neuromotor Impairment

Alert patients receiving meropenem on an outpatient basis regarding adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that meropenem is well tolerated, advise patients not to operate machinery or motorized vehicles.

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.

Drug Interactions

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 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 normalised 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.

Use in Special Populations

Patients with Renal Impairment

Pharmacokinetic studies with meropenem in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less).

Meropenem is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage. (see Posology and Method of Administration)

Patients with Hepatic Impairment

A pharmacokinetic study with meropenem in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

Pregnant Women

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.

Lactating Women

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.

Geriatric Patients

No overall differences in safety or effectiveness were observed between subjects (65 years and older) and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

A pharmacokinetic study with meropenem in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

Pediatric Patients

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. There is no experience in pediatric patients with renal impairment. The pharmacokinetics of meropenem, in pediatric patients 2 years of age or older, are similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years.

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.

Undesirable Effects

The following are discussed in greater detail in other sections of labeling:

  • Hypersensitivity Reactions
  • Severe Cutaneous Adverse Reactions
  • Seizure Potential
  • Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid
  • Clostridium difficile – associated Diarrhea
  • Development of Drug-Resistant Bacteria
  • Overgrowth of Nonsusceptible Organisms
  • Thrombocytopenia
  • Potential for Neuromotor Impairment

Adult Patients

Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with meropenem (500 mg or 1 gram every 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with meropenem.

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with meropenem.

LOCAL ADVERSE REACTIONS

Local adverse events that were reported with meropenem were as follows:

Inflammation at the injection site (2.4%)

Injection-site reaction (0.9%)

Phlebitis/thrombophlebitis (0.8%)

Pain at the injection site (0.4%)

Oedema at the injection site (0.2%)

SYSTEMIC ADVERSE REACTIONS

Systemic adverse events that were reported with meropenem occurring in greater than 1% of the patients were diarrhoea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnoea (1.3%), shock (1.2%), and pruritus (1.2%).

Additional systemic adverse events that were reported with meropenem and occurring in less than or equal to 1% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

Bleeding events were seen as follows: gastrointestinal haemorrhage (0.5%), melaena (0.3%), epistaxis (0.2%), and haemoperitoneum (0.2%).

BODY AS A WHOLE: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain.

CARDIOVASCULAR: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope.

DIGESTIVE SYSTEM: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction.

HAEMIC/LYMPHATIC: anaemia, hypochromic anaemia, hypervolaemia.

METABOLIC/NUTRITIONAL: peripheral oedema, hypoxia.

NERVOUS SYSTEM: insomnia, agitation, delirium, confusion, dizziness, seizure, nervousness, paraesthesia, hallucinations, somnolence, anxiety, depression, asthenia.

RESPIRATORY: respiratory disorder, dyspnoea, pleural effusion, asthma, cough increased, lung oedema.

SKIN AND APPENDAGES: urticaria, sweating, skin ulcers.

UROGENITAL SYSTEM: dysuria, kidney failure, vaginal moniliasis, urinary incontinence

ADVERSE LABORATORY CHANGES

Adverse laboratory changes that were reported and occurring in greater than 0.2% of the patients were as follows:

HEPATIC: increased alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubin.

HAEMATOLOGIC: increased platelets, increased eosinophils, decreased platelets, decreased haemoglobin, decreased haematocrit, decreased white blood cells (WBC), shortened prothrombin time and shortened partial thromboplastin time, leucocytosis, hypokalaemia.

RENAL: increased creatinine and increased blood urea nitrogen (BUN).

URINALYSIS: presence of red blood cells.

COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS

In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in greater than 5% of the patients were as follows: headache (7.8%), nausea (7.8%), constipation (7%), diarrhoea (7%), anaemia (5.5%), and pain (5.1%).

Adverse events with an incidence of greater than 1%, and not listed above, include the following: pharyngitis, accidental injury, gastrointestinal disorders, hypoglycaemia, peripheral vascular disorder.

Patients with Renal Impairment

For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported with meropenem, increased in patients with moderately severe renal impairment (creatinine clearance 10 to 26mL/min)

Pediatric Patients

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.

Systemic and Local Adverse Reactions

PAEDIATRIC PATIENTS WITH SERIOUS BACTERIAL INFECTIONS (EXCLUDING BACTERIAL MENINGITIS)

Meropenem was studied in 515 paediatric patients (3 months to less than 13 years of age) with serious bacterial infections at dosages of 10 mg/kg to 20 mg/kg every 8 hours. The types of systemic and local adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to

Meropenem, and their rates of occurrence were as follows:

Diarrhoea (3.5%)

Rash (1.6%)

Nausea and vomiting (0.8%)

PAEDIATRIC PATIENTS WITH BACTERIAL MENINGITIS

Meropenem was studied in 321 paediatric patients (3 months to less than 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of systemic and local adverse events seen in these patients were similar to the adults, with the most common adverse reactions reported as possibly, probably, or definitely related to meropenem, and their rates of occurrence were as follows:

Diarrhoea (4.7%)

Rash (mostly diaper-area moniliasis) (3.1%)

Oral moniliasis (1.9%)

Glossitis (1%)

In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the meropenem-treated group, 12/15 patients with seizures had late-onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. The meropenem group had a statistically higher number of patients with transient elevation of liver enzymes.

Adverse Laboratory Changes in Paediatric Patients

Laboratory changes seen in the paediatric studies, including the meningitis studies, were similar to those reported in the adult studies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of meropenem. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Worldwide postmarketing adverse reactions not otherwise listed in the Adverse Reactions from Clinical Trials section of this prescribing information and reported as possibly, probably, or definitely drug-related are listed within each body system in order of decreasing severity.

Blood and Lymphatic System Disorders: agranulocytosis, neutropaenia, and leucopaenia; a positive direct or indirect Coombs test, and haemolytic anaemia.

Immune System Disorders: angio-oedema.

Skin and Subcutaneous Disorders: SJS, TEN, DRESS, erythema multiforme, and AGEP.

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

In mice and rats, large I.V. doses of meropenem (2,200 mg/kg to 4,000 mg/kg) have been associated with ataxia, dyspnoea, convulsions, and mortalities.

Intentional overdosing of meropenem is unlikely although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 g given by the I.V. route every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed.

Limited postmarketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Undesirable Effects section and are generally mild in severity and resolve on withdrawal or dose reduction. Consider symptomatic treatments. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialysable and effectively removed by haemodialysis; however, no information is available on the use of haemodialysis to treat overdosage.

Pharmacological Properties

Pharmacokinetic Properties

Mechanism of Action

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonasaeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 hours to 24 hours) are typically 1 to 2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.

Meropenem does not have in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).

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.

Resistance

There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases).

Cross-resistance is sometimes observed with isolates resistant to other carbapenems.

Interaction with Other Antimicrobials

In vitro tests show meropenem to act synergistically with aminoglycoside antibacterial drugs against some isolates of Pseudomonas aeruginosa.

Antimicrobial Activity

Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates only)

Staphylococcus aureus (methicillin-susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible isolates only)

Streptococcus pyogenes

Viridans group streptococci

Gram-negative bacteria

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Neisseria meningitidis

Proteus mirabilis

Pseudomonas aeruginosa

Anaerobic bacteria

Bacteroides fragilis

Bacteroides thetaiotaomicron

Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for meropenem against isolates of similar genus or organism group. However, the efficacy of meropenem in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Gram-negative bacteria

Aeromonas hydrophila

Campylobacter jejuni

Citrobacter freundii

Citrobacter koseri

Enterobacter cloacae

Hafnia alvei

Klebsiella oxytoca

Moraxella catarrhalis

Morganella morganii

Pasteurella multocida

Proteus vulgaris

Serratia marcescens

Anaerobic bacteria

Bacteroides ovatus

Bacteroides uniformis

Bacteroides ureolyticus

Bacteroides vulgatus

Clostridium difficile

Clostridium perfringens

Eggerthella lenta

Fusobacterium species

Parabacteroides distasonis

Porphyromonas asaccharolytica

Prevotella bivia

Prevotella intermedia

Prevotella melaninogenica

Propionibacterium acnes

Pharmacokinetic Properties

Adult Patients

Plasma Concentrations

At the end of a 30 minute intravenous infusion of a single dose of meropenem in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14 to 26) for the 500 mg dose and 49 mcg/mL (range 39 to 58) for the 1 gram dose. A 5 minute intravenous bolus injection of meropenem in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18 to 65) for the 500 mg dose and 112 mcg/mL (range 83 to 140) for the 1 gram dose.

Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration.

No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 gram administered every 6 hours in healthy volunteers with normal renal function.

Distribution

The plasma protein binding of meropenem is approximately 2%.

After a single intravenous dose of meropenem, the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in Table below.

Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)

Tissue

Intravenous Dose (gram)

 

Number of Samples

Mean 1

Range

Endometrium

 

0.5

 7

 4.2

1.7 to 10.2

Myometrium

 

0.5

15

3.8

0.4 to 8.1

Ovary

0.5

 

8

 

2.8

 

0.8 to 4.8

 

Cervix

 

0.5

2

7

5.4 to 8.5

Fallopian

tube

 

0.5

9

1.7

0.3 to 3.4

Skin

 

0.5

 

22

 

 3.3

 

0.5 to 12.6

 

Interstitial

Fluid2

 

 0.5

9

 

5.5

 

3.2 to 8.6

 

Skin

1

 

10

 

5.3

 

 1.3 to 16.7

 

Interstitial

Fluid2

 

1

5

26.3

20.9 to 37.4

Colon

1

2

2.6

2.5 to 2.7

Bile

 

1

7

14.6 (3 hours)

4 to 25.7

Gall bladder

1

1

-

3.9

Peritoneal

fluid

1

9

30.2

7.4 to 54.6

Lung

1

2

 

4.8 (2 hours)

1.4 to 8.2

Bronchial

mucosa

 

1

7

4.5

1.3 to 11.1

Muscle

1

2

6.1 (2 hours)

5.3 to 6.9

Fascia

1

9

8.8

1.5 to 20

Heart valves

1

7

9.7

6.4 to 12.1

Myocardium

1

10

15.5

5.2 to 25.5

CSF

(inflamed)

20 mg/kg3

40 mg/kg4

8

5

 

1.1 (2 hours)

3.3 (3 hours)

 

0.2 to 2.8

0.9 to 6.5

 

CSF

(uninflamed)

1

4

0.2 (2 hours)

0.1 to 0.3

  1. at 1 hour unless otherwise noted
  2. obtained from blister fluid
  3. in pediatric patients of age 5 months to 8 years
  4. in pediatric patients of age 1 month to 15 years

Elimination

In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour.

Metabolism

There is one metabolite of meropenem that is microbiologically inactive.

Excretion

Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% to 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal 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.

Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.

Pediatric Patients

The 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.

Non-Clinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenesis studies have not been performed.

Mutagenesis

Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, theChinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests.

Impairment of Fertility

In fertility studies, intravenous meropenem was administered to male rats beginning 11 weeks before mating and throughout mating and to female rats from 2 weeks before mating through Gestation Day 7 at doses of 240, 500, and 1000 mg/kg/day. There was no evidence of impaired fertility at doses up to 1000 mg/kg/day (on the basis of body surface area comparison, approximately 3.2 times to the MRHD of 1 gram every 8 hours).

Description

Meropenem for Injection, IP is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration. It is (4R,5S,6S)-3- thio]-6- -4-methyl-7-oxo-1-azabicyclohept-2-ene-2-carboxylic acid trihydrate. Its molecular formula is C17H25N3O5S•3H2O with a molecular weight of 437.52.

Meropenem for Injection,IP is a white to light yellowish crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

Pharmaceutical Particulars

Incompatibilities

This medicinal product must not be mixed with other medicinal products.

Shelf-Life

As on the pack.

Packaging Information

MEROCRIT KIT 0.5 gm: Vial of 20 mL

MEROCRIT KIT 1 gm: Vial of 30 mL

Storage and Handling Instructions

Store below 25 °C, protect from moisture.

Patient Counselling Information

►WHAT MEROCRIT I.V. IS AND WHAT IT IS USED FOR?

MEROCRIT I.V. contains the active substance meropenem and belongs to a group of medicines called carbapenem antibiotics. It works by killing bacteria, which can cause serious infections.

MEROCRIT I.V. is used to treat the following in adults and children aged 3 months and older:

• Infection affecting the lungs (pneumonia)

• Urinary tract infections

• Infections in the abdomen

• Infections that you can catch during or after the delivery

• Skin and soft tissues infections

• Bacterial infection of blood (septicaemia)

• Infections with febrile neutropaenia (fever associated with low count of neutrophils (type of white blood cells)

• Acute bacterial infection of the brain (meningitis)

  • Empiric treatment for presumed infections with febrile neutropaenia

MEROCRIT I.V. may be used in the management of neutropaenic patients with fever that is suspected to be due to a bacterial infection.

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

►WHAT YOU NEED TO KNOW BEFORE YOU USE MEROCRIT I.V.

Do not use MEROCRIT I.V. if;

• you are allergic (hypersensitive) to meropenem or any of the other ingredients of this medicine.

• you are allergic (hypersensitive) 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 using MEROCRIT I.V. if

• you have health problems, such as liver or kidney problems.

• you have had severe diarrhoea after taking other antibiotics.

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

You may develop signs and symptoms of severe skin reactions. If this happens, talk to your doctor or nurse immediately so that they can treat the symptoms.

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

Other medicines and MEROCRIT I.V.

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. This is because MEROCRIT I.V. can affect the way some medicines work and some medicines can have an effect on MEROCRIT I.V.

In particular, tell your doctor, pharmacist 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). MEROCRIT I.V. should not be used because it may decrease the effect of sodium valproate.

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

Pregnancy and breastfeeding

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

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

Driving and using machines

No studies on the effect on the ability to drive and use machines have been performed.

MEROCRIT I.V. has been associated with headache and tingling or pricking skin (paraesthesia). Any of these side effects could affect your ability to drive or operate machines.

MEROCRIT I.V. may cause involuntary muscle movements that may cause 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.

MEROCRIT I.V. contains sodium

MEROCRIT I.V. 500 mg: This medicine contains 45.1 mg sodium (main component of cooking/table salt) in each 500 mg dose. This is equivalent to 2.25% of the recommended maximum daily dietary intake of sodium for an adult.

MEROCRIT I.V. 1,000 mg: This medicine contains 90.2 mg sodium (main component of cooking/table salt) in each 1,000 mg dose. This is equivalent to 4.5% of the recommended maximum daily dietary intake of sodium for an adult.

If you have a condition that requires you to monitor your sodium intake please inform your doctor, pharmacist or nurse.

►HOW TO USE MEROCRIT I.V.

Always use this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist 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 (grams). 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 MEROCRIT I.V. 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.

Using MEROCRIT I.V.

MEROCRIT I.V. will be given to you as an injection or infusion into a large vein.

• Your doctor or nurse will normally give MEROCRIT I.V. to you.

• Always use MEROCRIT I.V. exactly as your doctor has told you. You should check with your doctor if you are not sure.

• Your injection should not be mixed with or added to solutions that contain other medicines.

• The injection may take about 5 minutes or between 15 and 30 minutes.

• You should normally have your injections at the same times each day.

If you use more MEROCRIT I.V. than you should

If you accidentally use more than your prescribed dose, contact your doctor or nearest hospital straight away.

If you forget to use MEROCRIT I.V.

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 have a double dose (two injections at the same time) to make up for a forgotten dose.

If you stop using MEROCRIT I.V.

Do not stop having MEROCRIT I.V. until your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

►POSSIBLE SIDE EFFECTS

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

Severe allergic reactions

If you have any of these signs and symptoms, tell your doctor or nurse straight away. You may need urgent medical treatment. The signs and symptoms may include a sudden onset of:

• Severe rash, itching or hives on the skin.

• Swelling of the face, lips, tongue or other parts of the body.

• Shortness of breath, wheezing or trouble breathing.

• Serious skin reactions which include the following:

  • 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 (drug rash with eosinophilia and systemic symptoms) syndrome.
  • Severe red scaly rash, skin bumps that contain pus, blisters or peeling of skin, which may be associated with a high fever and joint pains.
  • Severe skin rashes that can appear as reddish circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms (Stevens-Johnson syndrome) or a more severe form (toxic epidermal necrolysis).

Damage to red blood cells (not known)

The signs include

• being breathless when you do not expect it.

• 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).

• Diarrhoea.

• Headache.

• 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 blood cells, and increased amounts of a substance called ‘bilirubin’. Your doctor may do blood tests from time to time.

• Changes in blood tests, including tests that show how well your kidneys are working.

• A tingling sensation (pins and needles).

• Infections of the mouth or the vagina that are caused by a fungus (thrush).

• Inflammation of the bowel, with diarrhoea.

• Sore veins where MEROCRIT I.V. is injected.

• Other changes in your blood. The symptoms include frequent infections, high temperature and sore throat. Your doctor may do blood tests from time to time.

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

• Fits (convulsions).

• Acute disorientation and confusion (delirium).

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

►HOW TO STORE MEROCRIT I.V.

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

Do not use this medicine after the expiry date stated on the container. The expiry date refers to the last day of that month.

Store below 25 °C, protect from moisture.

Injection

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

• 3 hours when stored at up to 25°C; or

• 12 hours when stored under refrigerated conditions (2°–8°C).

Infusion

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

For MEROCRIT I.V. diluted using 0.9% sodium chloride -

  • 3 hours when stored at up to 25°C; or
  • 12 hours when stored under refrigerated conditions (2–8°C). 

For MEROCRIT I.V. diluted using 5% Dextrose and 0.9% sodium chloride –

  • 2 hours when stored at up to 25°C; or
  • 4 hours when stored under refrigerated conditions (2–8°C).

The solution should be used immediately when MEROCRIT I.V. is diluted using 5% dextrose or 10% 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 wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

►CONTENTS OF THE PACK AND OTHER INFORMATION

What MEROCRIT Kit I.V. contains

MEROCRIT I.V. 0.5 gm: The active substance is meropenem trihydrate equivalent to 500 mg anhydrous meropenem.

MEROCRIT I.V. 1 gm: The active substance is meropenem trihydrate equivalent to 1,000 mg anhydrous meropenem.

The other ingredient is sodium carbonate.

Sterile Water for Injection IP (Manufactured Separately & Packed with this Product)

I.V.  Flow Regulator (Manufactured Separately & Packed with this Product)

What MEROCRIT I.V. looks like and packaging

MEROCRIT I.V. is a white to light-yellowish powder for solution for injection or infusion available in a vial.

Details of The Manufacturer

Brooks Steriscience Limited

Village : Manglej, Nareshwar Road, Off NH-8

Taluka : Karjan, Dist : Vadodara - 391210, India.

Marketed by

CIPLA LTD.

Cipla House, Peninsula Business Park, Ganpatrao

Kadam Marg, Lower Parel, Mumbai - 400 013, INDIA

Details of Permission or Licence Number with Date

G/28/1581

Date of Revision

03rd June 2021