Branded Medicine

 

Sterile Powder for Injection

 

Composition:

Each vial contains:

TRIPENEM 0.5

Meropenem bulk equivalent to

Meropenem anhydrate 0.5 g

TRIPENEM 1

Meropenem bulk equivalent to

Meropenem anhydrate 1 g

 

 

Pharmacology:

Meropenem is a carbapenem antibiotic for parenteral use, that is relatively stable to human dehydropeptidase-1 (DHP-1) and therefore does not require the addition of an inhibitor of DHP-1.

Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its high level of stability to all serine beta-lactamases and its marked affinity for the Penicillin Binding Proteins (PBPs) explain the potent bactericidal action of meropenem against a broad spectrum of aerobic and anaerobic bacteria.

Minimum bactericidal concentrations (MBC) are commonly the same as the minimum inhibitory concentrations (MIC). For 76% of the bacteria tested, the MBC: MIC ratios were 2 or less.

Meropenem is stable in susceptibility tests and these tests can be performed using normal routine methods. In vitro tests show that Meropenem acts synergistically with various antibiotics. It has been demonstrated both in vitro and in vivo that meropenem has a post-antibiotic effect.

A single set of meropenem susceptibility criteria are recommended based on pharmacokinetics and correlation of clinical and microbiological outcomes with zone diameter and minimum inhibitory concentrations (MIC) of the infecting organisms.

 

 




 

CATEGORIZATION

METHOD OF ASSESSMENT

Zone Diameter (mm)

MIC breakpoints (mg/l)

Susceptible

Intermediate

Resistant

>=14

12 to 13

<=11

<=4

8

>=16

 

 

The in vitro antibacterial spectrum of meropenem includes the majority of clinically significant Gram-positive and Gram-negative, aerobic and anaerobic strains of bacteria, as shown below:

Gram-positive aerobes:

Bacillus spp., Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus liquifaciens, Enterococcus avium, Listeria monocytogenes, Lactobacillus spp., Nocardia asteroides, Staphylococcus aureus (penicillinase negative and positive), Staphylococci-coagulase-negative; including, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus xylosus, Staphylococcus warneri, Staphylococcus hominis, Staphylococcus simulans, Staphylococcus intermedius, Staphylococcus sciuri, Staphylococcus lugdunensis, Streptococcus pneumoniae (penicillin susceptible and resistant), Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus equi, Streptococcus bovis, Streptococcus mitis, Streptococcus mitior, Streptococcus milleri, Streptococcus sanguis, Streptococcus viridans, Streptococcus salivarius, Streptococcus morbillorum, Streptococcus Group G, Streptococcus Group F, Rhodococcus equi.

Gram-negative aerobes:

Achromobacter xylosoxidans, Acinetobacter anitratus, Acinetobacter lwoffii, Acinetobacter baumannii, Aeromonas hydrophila, Aeromonas sorbria, Aeromonas caviae, Alcaligenes faecalis, Bordetella bronchiseptica, Brucella melitensis, Campylobacter coli, Campylobacter jejuni, Citrobacter freundii, Citrobacter diversus, Citrobacter koseri, Citrobacter amalonaticus, Enterobacter aerogenes, Enterobacter (Pantoea) agglomerans, Enterobacter cloacae, Enterobacter sakazakii, Escherichia coli, Escherichia hermannii, Gardnerella vaginalis, Haemophilus influenzae (including beta-lactamase positive and ampicillin resistant strains), Haemophilus parainfluenzae, Haemophilus ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including beta-lactamase positive, penicillin resistant and spectinomycin resistant strains) Hafnia alvei, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella ozaenae, Klebsiella oxytoca, Moraxella (Branhamella) catarrhalis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Proteus penneri, Providencia rettgeri, Providencia stuartii, Providencia alcalifaciens, Pasteurella multocida, Plesiomonas shigelloides, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas alcaligenes, Burkholderia (Pseudomonas) cepacia, Pseudomonas fluorescens, Pseudomonas stutzeri, Pseudomonas pseudomallei, Pseudomonas acidovorans, Salmonella spp. including Salmonella enteritidis/typhi, Serratia marcescens, Serratia liquefaciens, Serratia rubidaea, Shigella sonnei, Shigella flexneri, Shigella boydii, Shigella dysenteriae, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica.

Anaerobic bacteria:

Actinomyces odontolyticus, Actinomyces meyeri, Bacteroides-Prevotella-Porphyromonas spp., Bacteroides fragilis, Bacteroides vulgatus, Bacteroides variabilis, Bacteroides pneumosintes, Bacteroides coagulans, Bacteroides uniformis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides eggerthii, Bacteroides capsillosis, Prevotella buccalis, Prevotella corporis, Bacteroides gracilis, Prevotella melaninogenica, Prevotella intermedia, Prevotella bivia, Prevotella splanchnicus, Prevotella oralis, Prevotella disiens, Prevotella rumenicola, Bacteroides ureolyticus, Prevotella oris, Prevotella buccae, Prevotella denticola, Bacteroides levii, Porphyromonas asaccharolytica, Bifidobacterium spp., Bilophila wadsworthia, Clostridium perfringens, Clostridium bifermentans, Clostridium ramosum, Clostridium sporogenes, Clostridium cadaveris, Clostridium sordellii, Clostridium butyricum, Clostridium clostridiiformis, Clostridium innocuum, Clostridium subterminale, Clostridium tertium, Eubacterium lentum, Eubacterium aerofaciens, Fusobacterium mortiferum, Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium varium, Mobiluncus curtisii, Mobiluncus mulieris, Peptostreptococcus anaerobius, Peptostreptococcus micros, Peptostreptococcus saccharolyticus, Peptococcus saccharolyticus, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus prevotii, Propionibacterium acnes, Propionibacterium avidum, Propionibacterium granulosum.

Stenotrophomonas maltophilia, Enterococcus faecium and methicillin-resistant staphylococci have been found to be resistant to meropenem.

 

Pharmacokinetics:

A 30 minute intravenous infusion of a single dose of meropenem in healthy volunteers results in peak plasma levels of approximately 11 microgram/ml for the 250 mg dose, 23 microgram/ml for the 500 mg dose and 49 microgram/ml for the 1 g dose.

However, there is no absolute pharmacokinetic proportionality with the administered dose both as regards Cmax and AUC. Furthermore, a reduction in plasma clearance from 287 to 205 ml/min for the range of dosage 250 mg to 2 g has been observed.

A 5 minute intravenous bolus injection of meropenem in healthy volunteers results in peak plasma levels of approximately 52 microgram/ml for the 500 mg dose and 112 microgram/ml for the 1 g dose.

Intravenous infusions of 1 g over 2 minutes, 3 minutes and 5 minutes were compared in a three-way crossover trial. These durations of infusion resulted in peak plasma levels of 110, 91 and 94 microgram/ml, respectively.

After an IV dose of 500 mg, plasma levels of meropenem decline to values of 1 microgram/ml or less, 6 hours after administration.

When multiple doses are administered at 8 hourly intervals to subjects with normal renal function, accumulation of meropenem does not occur.

In subjects with normal renal function, meropenem's elimination half-life is approximately 1 hour. Plasma protein binding of meropenem is approximately 2%.

Approximately 70% of the 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 microgram/ml are maintained for up to 5 hours after the administration of a 500 mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in volunteers with normal renal function.

The only metabolite of meropenem is microbiologically inactive.

Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid of patients with bacterial meningitis, achieving concentrations in excess of those required to inhibit most bacteria.

Studies in children have shown that the pharmacokinetics of meropenem in children are similar to those in adults. The elimination half-life for meropenem was approximately 1.5 to 2.3 hours in children under the age of 2 years and the pharmacokinetics are linear over the dose range of 10 to 40 mg/kg.

Pharmacokinetic studies in patients with renal insufficiency have shown the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment.

Pharmacokinetic studies in the elderly have shown a reduction in plasma clearance of meropenem which correlated with age-associated reduction in creatinine clearance.

Pharmacokinetic studies in patients with liver disease have shown no effects of liver disease on the pharmacokinetics of meropenem.

 

Indications:

Tripenem IV is indicated as single agent therapy for the treatment, in adults and children, of the following infections caused by single or multiple susceptible strains of the designated microorganisms sensitive to meropenem:

  • Pneumonias and nosocomial pneumonias

  • Urinary tract infections

  • Intra-abdominal infections

  • Gynecological infections, such as endometritis.

  • Skin and skin structure infections

  • Meningitis

  • Septicemia

  • Bone and joint infections

  • Endocarditis

  • Empiric treatment, for presumed infections in adult patients with febrile neutropenia, used as monotherapy or in combination with anti-viral or anti-fungal agents.

Meropenem has proved efficacious alone or in combination with other antimicrobial agents in the treatment of polymicrobial infections.

There is no experience in pediatric patients with neutropenia or primary or secondary immunodeficiency.

 

Contraindications:

Meropenem IV is contraindicated in patients with known hypersensitivity.

 

Dosage:

Adults

The dosage and duration of therapy shall be established depending on type and severity of infection and the condition of the patients.

The recommended daily dosage is as follows:

500 mg IV every 8 hours in the treatment of pneumonia, UTI, gynecological infections such as endometritis, skin and skin structure infections.

1 g IV every 8 hours in the treatment of nosocomial pneumonias, peritonitis, presumed infections in neutropenic patients, septicemia.

In meningitis the recommended dosage is 2 g every 8 hours.

As with other antibiotics, particular caution is recommended in using meropenem as monotherapy in critically ill patients with known or suspected Pseudomonas aeruginosa lower respiratory tract infection.

Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infection.

 

Dosage Schedule for Adults with Impaired Renal Function

Dosage should be reduced in patients with creatinine clearance less than 51 ml/min, as scheduled below:

 

 




Creatinine Clearance

(ml/min)

Dose

(dependent on type of infection)

Frequency

26 to 50

 

10 to 25

 

<10

full recommended dose

(500 mg or 1 g or 2 g)

one-half recommended dose

(250 mg or 500 mg or 1 g)

one-half recommended dose

(250 mg or 500 mg or 1 g)

every 12 hours

 

every 12 hours

 

every 24 hours

 

 

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

 

 



Males:

Creatinine clearance (ml/min) =

Weight (kg) x (140 � age)

72 x serum creatinine (mg/dl)

 

Females: 0.85 x above value

 

Meropenem is cleared by hemodialysis; if continued treatment with Meropenem is necessary, it is recommended that the unit (recommended) dose (based on the type and severity of infection) is administered at the completion of the hemodialysis procedure to restore therapeutically effective plasma concentrations.

There is no experience with the use of meropenem in patients under peritoneal dialysis.

 

Dosage in Adults with Hepatic Insufficiency

No dosage adjustment is required in patients with hepatic insufficiency.

 

Elderly Patients

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

 

Children

For children over 3 months and up to 12 years of age the recommended dose is 10 to 20 mg/kg every 8 hours depending on type and severity of infection, susceptibility of the pathogen and the condition of the patient. In children over 50 kg weight, adult dosage should be used.

In meningitis the recommended dose is 40 mg/kg every 8 hours.

There is no experience in children with renal impairment.

 

Method of Administration

Adult

Tripenem IV can be given as an intravenous bolus injection over approximately 5 minutes or by intravenous infusion over approximately 15 to 30 minutes using the specific available presentations.

Tripenem IV to be used for bolus intravenous injection should be constituted with sterile water for injections (5 ml per 250 mg meropenem). This provides an approximate concentration of 50 mg/ml. Constituted solutions are clear, and colourless or pale yellow.

Tripenem IV for intravenous infusion may be constituted with compatible infusion fluids (50 to 200 ml).

 

Adverse Effects:

Serious adverse events are rare. During the clinical trials the following adverse events have been reported:

  • Local intravenous injection site reactions: inflammation, thrombophlebitis, pain at the site of injection.

  • Skin reactions: rash, pruritus, urticaria. Rarely, severe skin reactions such as erythema multiforme, Stevens-Johnson Syndrome and toxic epidermal necrolysis have been observed.

  • Systemic allergic reactions: rarely, systemic allergic reactions (hypersensitivity) may occur following administration of meropenem. These reactions may include angioedema and manifestations of anaphylaxis, such as shock, hypotension, and respiratory depression.

  • Gastro-intestinal: abdominal pain, nausea, vomiting, diarrhoea. Pseudomembranous colitis has been reported.

  • Blood: reversible thrombocythaemia, eosinophilia, thrombocytopenia, leucopenia and neutropenia. A positive direct or indirect Coombs test may develop in some subjects; there have been reports of reduction in partial thromboplastin time.

  • Liver function: increases in serum concentrations of bilirubin, transaminases, alkaline phosphatase and lactic dehydrogenase alone or in combination have been reported.

  • Central nervous system: headache, paresthesia. Infrequently convulsions have been reported but a causal link with meropenem has not been established.

  • Other: oral and vaginal candidosis.

 

Warnings and Precautions:

    • There is some clinical and laboratory evidence of partial cross-allergenicity between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. As with all beta-lactam antibiotics, rare hypersensitivity reactions have been reported. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. Meropenem should be used with caution in patients with such a history. If an allergic reaction to meropenem occurs, the drug should be discontinued and appropriate measures taken.

    • As with other antibiotics, overgrowth of non-susceptible organisms may occur and, therefore, continuous monitoring of each patient is necessary.

    • Use of meropenem in patients with hepatic disease should be made with careful monitoring of transaminase and bilirubin levels.

    • Use in infections caused by methicillin resistant staphylococci is not recommended.

    • Rarely, pseudomembranous colitis has been reported on meropenem as with practically all antibiotics and may vary in severity from slight to life-threatening. Therefore, antibiotics should be prescribed with care for individuals with a history of gastro-intestinal complaints, particularly colitis. It is important to consider the diagnosis of pseudomembranous colitis in the case of patients who develop diarrhea in association with the use of meropenem. Although studies indicate that a toxin produced by Clostridium difficile is one of the main causes of antibiotic-associated colitis, other causes should be considered.

    • The co-administration of meropenem with potentially nephrotoxic drugs should be considered with caution.

    • Seizures and other CNS adverse 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.

    • Pregnancy Category B

The safety of Meropenem in human pregnancy has not been evaluated. Animal studies have not shown any adverse effect on the developing fetus. The only adverse effect observed in animal reproductive studies was an increased incidence of abortions in monkeys at 13 times the expected exposure in man. Meropenem should not be used in pregnancy unless the potential benefit justifies the potential risk to the fetus. In every case, it should be used under the direct supervision of the physician.

    • Lactation

Meropenem is detectable at very low concentrations in animal breast milk.

Meropenem should not be used in breast-feeding women unless the potential benefit justifies the potential risk to the baby.

    • Pediatric use

Efficacy and tolerability in infants under 3 months old have not been established; therefore, meropenem is not recommended for use below this age.

There is no experience in children with altered hepatic or renal function.

    • Effects on Ability to Drive and Use Machines

No data are available, but it is not anticipated that meropenem will affect the ability to drive and use machines.

 

Drug Interactions:

    • Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion, with the effect of increasing the elimination half-life and plasma concentration of meropenem. As the potency and duration of action of meropenem dosed without probenecid are adequate, the co-administration of probenecid with meropenem is not recommended.

    • The potential effect of meropenem on the protein binding of other drugs or metabolism has not been studied. The protein binding of meropenem is low (approximately 2%) and therefore no interactions with other compounds based on displacement from plasma proteins would be expected.

    • Meropenem may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients.

 

Overdosage:

Accidental overdosage could occur during therapy, particularly in patients with renal impairment. Treatment of overdosage should be symptomatic. In the even of an overdose, Tripenem IV should be discontinued and general supportive treatment given until renal elimination takes place. In normal individuals, rapid renal elimination will occur; in subjects with renal impairment, haemodialysis will remove meropenem and its metabolite.

 

Compatibilities, Special Precaution for Storage and Handling:

Tripenem should not be mixed with or added to other drugs.

Tripenem compatibilities with the infusion fluids and the stability after reconstitution are listed below:

 

 




Diluent

Hours Stable up to

25oC

4oC

Solution (1 to 20 mg/ml) prepared with:

 

 

  • 0.9% sodium chloride

8

48

  • 5% glucose

3

14

  • 5% glucose and 0.225% sodium chloride

3

14

  • 5% glucose and 0.9% sodium chloride

3

14

  • 5% glucose and 0.15% potassium chloride

3

14

  • 2.5% or 10% mannitol intravenous infusion

3

14

  • 10% glucose

2

8

  • 5% glucose and 0.02% sodium bicarbonate intravenous infusion

 

2

 

8

 

 

Do not store above 30oC.

It is recommended to use freshly prepared solutions of Meropenem for IV injection and infusion.

Reconstituted product with sterile water for injection should be used immediately and must be stored for no longer than 3 hours in room temperature (30oC) and no longer than 13 hours under refrigeration, only if necessary.

Both the vial before reconstitution and the reconstituted solution should not be frozen.

Standard aseptic technique should be employed during constitution. Shake constituted solution before use.

 

Presentation and Registration Number:

TRIPENEM 0,5

Box, 1 vial @ 0,5 g No. Reg. DKL0505039944A1

TRIPENEM 1

Box, 1 vial @ 1 g No. Reg. DKL0505039944B1

 

 

ON MEDICAL PRESCRIPTION ONLY

 

STORE AT TEMPERATURE BELOW 30oC

PROTECT FROM LIGHT

 

 

 

Manufactured by:

 

PT DEXA MEDICA