MEROAGE0 5gm

Eachvial Contains

Meropenem Trihydrate IP equivalentto Anhydrous  Meropenem                                   ……500mg Also contains Sodium Carbonate (Sodium45.1mg)

MEROAGE 1gm

Eachvial Contains

Meropenem Trihydrate IP equivalent to Anhydrous Meropenem………………………………1gm Also contains Sodium Carbonate (Sodium90.2mg)

MEROAGE 125mg

Eachvial Contains

Meropenem Trihydrate IP equivalent to Anhydrous Meropenem………………………………125mg Also contains Sodium Carbonate (Sodium11.275mg)

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	10	10	50
1 g	20	20	50

 

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