MEROTRIT

For the use of Registered Medical Practitioners or Hospital only

MEROTRIT

MEROTRIT injection I.P.

COMPOSITION

MEROTRIT 0.5 gm

Each vial Contains

Meropenem Trihydrate I.P. equivalent to Anhydrous Meropenem……………………………………….500 mg

Also contains Sodium Carbonate (Sodium 45.1 mg)

MEROTRI 1 gm

Each vial Contains

Meropenem Trihydrate I.P. equivalent to Anhydrous Meropenem……………………………………….1 gm

Also contains Sodium Carbonate (Sodium 90.2 mg)

MEROTRIT 125 mg

Each vial Contains

Meropenem Trihydrate I.P. equivalent to Anhydrous Meropenem……………………………………….125 mg

Also contains Sodium Carbonate (Sodium 11.275 mg)

DOSAGE FORM

Powder for reconstitution (I.V.)

PHARMACOLOGY

Pharmacodynamics

Meropenem is a broad-spectrum carbapenem antibiotic. The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa and PBPs 1,2 and 4 of Staphylococcus aureus. Meropenem has significant stability to hydrolysis by β-lactamases of most categories, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria. Meropenem should not be used to treat methicillin-resistant staphylococci (MRSA). In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Aerobic and facultative Gram-positive microorganisms

Enterococcus faecalis (excluding vancomycin-resistant isolates). Staphylococcus aureus

(β-lactamase and non- β-lactamase producing methicillin-susceptible isolates only). Streptococcus agalactiae, Streptococcus pneumonia (penicillin-susceptible isolates only).

NOTE: Penicillin-resistant isolates had meropenem MIC 90 values of 1 or 2 ɯg/mL, which is above the 0.12 ɯg/mL susceptible breakpoint for this species.

Streptococcus pyogenes, Viridans group streptococci

Aerobic and facultative Gram-negative microorganisms

Escherichia coli, Haemophilus influenza (β-lactamase and non- β-lactamase producing).

Klebsilella penumoniae, Neisseria meningitides, Pseudomonas aeruginosa, Proteus mirabilis

Anaerobic microorganisms

Bacteriodes fragilis, Bacteroides thefaiotaomicron, Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentration (MIC) lest than or equal to the susceptible breakpoints for meropenem. However, the safety and effectiveness of meropenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trails.

Aerobic and facultative Gram-positive microorganisms

Staphylococcus epidermidis (β-lactamase and non- β-lactamase producing, methicillin-susceptible isolates only).

Aerobic and facultative Gram-negative microorganisms

Acinetobacter species, Aeromonas hydrophila, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Halfnia alvei, Klebsiella oxytoca, Moraxella catarrhalis (β-lactamase and non- β-lactamase producing isolates ) Morganella morganil, Pasteurella multocida, Proteus vulgaris, Salmonella species, Serratia marcescens, Shigella species, Yersinia enterocolitica

Anaerobic microorganisms

Bacteroides distasonis, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgates, Clostridium difficile, Clostridium perfringens, Eubacterium lentum, Fusobacterium species, Prevotella bivia, Prevotella intermedia, Prevotella melaninogenica, Porphyromonas asaccharolytica, Propionibacterium acnes.

Pharmacokinetics

At the end of a 30-minute intravenous infusion of a single dose of meropenem I.V. in normal volunteers, ean peak plasma concentrations are approximately 23 ɯg/mL (range 14 – 26) for the approximately 45 ɯg/mL (range 18-65) for the 500 mg dose and 112 ɯg/mL (range 83-140) for the 1 g dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 ɯg/mL at 6 hours after administration. Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. Plasma protein binding of meropenem is approximately 2%. In subjects with normal renal function, the elimination half-life of meropenem I.V. is approximately 1 hour. Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 ɯg/mL are maintained for up to 5 hours after a 500 mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 6 hours in volunteers with normal renal function. There is one metabolite that is microbiologically incactive.

INDICATIONS

Meropenem is indicated as single agent therapy for the treatment of the following infections when caused by susceptible isolates of the designated microorganisms.

Skin and Skin Structure Infections : Complicated skin and skin structure infections due to Staphylococcus aureus (β-lactamase and non- β-lactamase producing, methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, Viridans group streptococci, Enterococcus faecalis ( excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.

Intra-abdominal Infections : Complicated appendicitis and peritonitis caused by viridians group streptococcik Escherichia coli, Klebsiella penumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron and Peptostreptococcus species.

Bacterial Meningitis ( Paediatric patients >/=3 months only)

Bacterial meningitis caused by Streptococcus pneumonia, Haemophilus influenzae (β-lactamase and non- β-lactamase producing isolates )and Neisseria meningitides.

The efficacy of meropenem as mono therapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumonia has not been established.

Meropenem has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis. Appropriate cultures should usually be performed before initiating antimicrobial treatment in order to isolate and identify the organisms causing infection and determine their susceptibility to Meropenem.

Meropenem is useful as presumptive therapy in the indicated condition (i.e. intra-abdominal infections) prior to the identification of the causative organisms because of its broad spectrum of bactericidal activity.

Antimicrobial therapy should be adjusted, if appropriate, once the results of culture(s) and antimicrobial susceptibility testing are known.

DOSAGE AND ADMINISTRATION

Adults : The recommended dose of Meropenem I.V. is 500 mg given every 8 hours for skin and skin structure infections and 1 g given every 8 hours for intra-abdominal infections. Meropenem I.V. should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection ( 5 to 20 mL) over approximately 3-5 minutes.

Use in Adults with Renal impairment : Dosage should be reduced in patients with creatinine clearance less than 51mL/min.

Recommended Meropenem I.V. Dosage Schedule for Adults With Impaired Renal Function
Creatinine Clearance (mL/min)	Dose (dependent on type of infection)	Dosing Interval
>/=51	Recommended dose (500 mg cSSSI and 1 g Intra-abdominal)	Every 8 hours
26-50	Recommended dose	Every 12 hours
10-25	One-half Recommended dose	Every 12 hours
<10	One-half Recommended dose	Every 24 hours

When only serum creatinine is available, the following formula (Cockcroft and Gault equation ) may be used to estimate creatinine clearance.

There is inadequate information regarding the use of Meropenem I.V. in patients on haemodialysis. There is no experience with peritoneal dialysis.

Paediatric use : For paediatric patients from 3 months of age and older, the Meropenem I.V. dose is 10, 20 or 40 mg/kg every 8 hours (maximum dose is 2 g every 8 hours), depending on the type of infection (complicated skin and skin structure, intra-abdominal or meningitis). Paediatric patients weighing overy 50 kg should be administered Meropenem I.V. at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 g every 8 hours for intra-abdominal infections and 2 g every 8 hours for meningitis. Meropenem I.V. should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes. There is no experience in paediatric patients with renal impairment.

Recommended Meropenem I.V. Dosage Schedule for Paediatric patients With normal renal Function
Type of Infection	Dose (mg/kg)	Up to a Maximum Dose	Dosing Interval
Complicated skin and skin structure	10	500 mg	Every 8 hours
Intra-abdominal	20	1 g	Every 8 hours
Meningitis	40	2 g	Every 8 hours

For Intravenous Bolus Administration

Constitute injection vials ( 500 mg and 1 g ) with sterile Water for Injection. Shake to dissolve and let stand until clear.

Vial

Size

Amount of

Diluent

Added (mL)

Approximate

Withdrawable

Volume (mL)

Approximate Average

Concentration

(mg/mL)

500 mg

1 g

For Infusion

Infusion vials (500 mg and 1 g) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be constituted, then the resulting solution added to an I.V. container and further diluted with an appropriate infusion fluid.

Intravenous Bolus Administration

Meropenem I.V. injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL) may be stored for up to 2 hours at controlled room temperature 15-25°C (59-77°F) or for up to 12 hours at 4°C(39°F).

Intravenous Infusion Administration

Stability in infusion vials : Meropenem I.V. infusion vials constituted with Sodium Chloride injection 0.9% ( Meropenem I.V. concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 2 hours at controlled room temperature 15-25°C (59-77°F)or for up to 18 hours at 4°C (39°F). Infusion vials of meropenem I.V. constituted with Dextrose Injection 5% (Meropenem I.V. concentrations ranging from 2.5 to 50 mg/mL) are stable for up to1 hour at controlled room temperature 15-25°C (59-77°F) or for up to 8 hours at 4°C (39°F).

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 to β-lactams.

WARNINGS AND PRECAUTIONS

Saizures 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. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including meropenem and may range in severity from mild to life-threatening. Therefore, it is administration of antibacterial agents. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mid cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severs cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Drug interactions

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended. There is evidence that meropenem may reduce serum levels of valproic acid to sub therapeutic levels ( therapeutic range considered to be 50 to 100 ɯg/mL total valproate).

Renal impairment

Please refer under DOSAGE AND ADMINISTRATION

Hepatic impairment

No dosage adjustment is necessary in patients with impaired hepatic function.

Pregnancy Category B

They are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation

Because many drugs are excreted in human milk, caution should be exercised when Meropenem is administered to a nursing woman.

Paediatric use

The safety and effectiveness of Meropenem have been established for paediatric patients > 3 months of age.

Geriatric use

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.

UNDESIRABLE EFFECTS

Local adverse reactions that were reported irrespective of the relationship to therapy with meropenem I.V. 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%, Edema at the injection site 0.2%.

Systemic Adverse Reactions

Systemic adverse clinical reactions that were reported irrespective of the relationship to meropenem I.V. occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%) and pruritus (1.2%). Additional adverse systemic clinical reactions that are reported irrespective of relationship to therapy with meropenem I.V. and occurring in less than or equal to 1.0% 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%), melena (0.3%), epistaxis (0.2%), haemoperitoneum (0.2%), summing to 1.2%.

OVERDOSAGE

Accidental overdosage could occur during therapy, particularly in patients with renal impairment. Treatment of overdosage should be symptomatic. In subjects with renal impairment haemodialysis will remove meropenem and its metabolite.

INCOMPATIBILITY

Meropenem I.V. should not be mixed with or physically added to solutions containing other drugs.

SHELF-LIFE

See on pack

STOREAGE AND HANDLING INSTRUCTIONS

Store in dry cool place. Protect from light

Manufactured & Marketed by

FIDULIS BIO INC

At dhandha, Idar road, Himatnagar – 383001

A Subsidiary of

FIDULIS BIO INC

Level 1, 139, Macquarie St. Sydney, NSW 2000. PO Box R1784

Royal Exchange NSW 1225, Australia