Zefopenam Powder for Inj

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COMPOSITION:

Each vial contains :

Meropenem USP (Sterile)

equivalent to Anhydrous Meropenem…………………………………………………1g

Sodium Carbonate (Sterile) equivalent to Sodium (as buffer)…………………90.2 mg

Two Ampoules Contain :

Sterile Water for Injection………………………………………………………….10 ml. (Each)

DESCRIPTION:

Vial contain sterile white powder containing meropenem USP 1000 mg.

INDICATIONS :

Zefopenam is indicated for treatment of following infection in adults and children over 3 months of age.Pneumonias and Nosocomial PneumoniasUrinary tract InfectionsIntra-abdominal Infections Gynaecological Infections, such as endometritis and pelvic inflammatory disease.Skin and Skin Structure Infections Meningitis SepticaemiaEmpiric treatment, for presumed infections in adult patients with febrile neutropenia, used as monotherapy or in combination with antiviral 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 paediatric patients with neutropenia or primary or secondary immunodeficiency.

DOSAGE AND ADMINISTRATION :

Adults

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

The recommended daily dosage is as follows:

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

1 g IV every 8 hours in the treatment of nosocomial pneumonias, peritonitis, presume infections in neutropenic patients, septicaemia.In meningitis the recommended dosage is 2g every. 8 hours.As with other antibiotics, particular caution is recommended in using meropenem as monotherapy in critically ill patients with known or suspecte 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 51ml/min, as scheduled below.

Creatinine®

Clearance (ml/min)

Dose (based on the doses of 500mg, 1g, 2g)

Frequency

26-50

10-25

<10

One unit dose

One-half unit dose

every 12 hours

every 24 hours

Meropenem is cleared by hemodialysis: if continued treatment with Meropenem is necessary it is recommended that the unit 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 necessary in patients with hepatic insufficiency.

Elderly Patients

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

Children

For children over 3 months and upto 12 years of age the recommended dose is 10-20 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 40mg/kg every 8 hours. There is no experience in children with renal impairment.

Method of Administration-

Zefopenam 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 presentation

Meropenem IV to be used for bolus intravenous injection should be constituted with sterile Water for injections (5ml per 250 mg Meropenem). This provides an approximate concentration of 50 mg/mi. Constituted solutions are clear, and colourless or pale yellow. Zefopenam IV for intravenous intusion may be constituted with compatible infusion fluid (50 to 200ml).

Contraindications

Meropenem is contraindicated in patients who have demonstrated hypersensitivity to Zefopenam or anaphylactic reactions to β-lactams.

Special Precautions

There are some clinical and laboratory evidence of partial cross-allergenicity between other carbapenems and β-lactam antibiotics, penicillins and cephalosporins. As with all β-lactam antibiotics, rare hypersensitivity reactions have been reported.
Before initiating therapy with meropenem, careful injuiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics. Meropenem should be used with caution in patients with such a history. If an allergic reaction to meropenem occurs, Zefopenam should be discontinued and appropriate measures taken.
Use of meropenem with patients with hepatic disease should be made with careful monitoring of transaminase and bilirubin levels.
As with other antibiotics, overgrowth of non-susceptible organisms may occur and therefore, continuous monitoring of each patient is necessary. 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 gastrointestinal 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.
Effects on the Ability to Drive or Operate Machinery: No data is available, but it is not anticipated that meropenem will affect the ability to drive and use machines.
Use in pregnancy: 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 abortion 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.
Use in lactation: Meropenem is detectable at very low concentrations in animal breast milk. Meropenem should not be used in breastfeeding women unless the potential benefit justifies the potential risk to neonates.
Use in children: Efficacy and tolerability in infants <3 months 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. Keep all medicines away from the children.

Use In Pregnancy & Lactation

Use in pregnancy: 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 abortion 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.
Use in lactation: Meropenem is detectable at very low concentrations in animal breast milk. Meropenem should not be used in breastfeeding women unless the potential benefit justifies the potential risk to neonates.

Adverse Reactions

Serious adverse events are rare. During the clinical trials the following adverse events have been reported: Local IV Injection Site Reactions: Inflammation, thrombophlebitis, pain at the site of injection.
Systemic Allergic Reactions: Rarely, systemic allergic reactions (hypersensitivity) may occur following administration of meropenem.
These reactions may include angioedema and manifestations of anaphylaxis.
Skin Reactions: Rash, pruritus, urticaria, rarely, severe skin reactions eg, erthema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been observed.
Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea, pseudomembranous colitis have been reported.
Blood: Reversible thrombocytopenia, eosinophilia, thrombocytopenia, leucopenia and neutropenia (including very rare cases of agranulocytosis). 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 combinations have been reported.
Central Nervous System: Headache, paraesthesia. Infrequently convulsions have been reported although a casual relationship with meropenem has not been established.
Other: Oral and vaginal candidiasis.

Interactions

Probenecid competes with meropenem for active tubular secretion and thus, inhibits the renal exretion with the effect of increasing the elimination t_½and plasma concentration of meropenem. As the potency and duration of action of meropenem dosed without probenecid are adequate, the co-administration of probenacid 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 has been administered concomitantly with other medications without adverse pharmacological interactions. Meropenem may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients. However, no specific data regarding potential drug interactions is available.
Incompatibilities: Meropenem should not be mixed with or added to other drugs.
Meropenem is compatible with the following infusion fluids: Sodium chloride 0.9% solution, glucose 5% or 10 % solution, glucose 5% solution with sodium bicarbonate 0.02%, sodium chloride 0.9% and glucose 5% solution, glucose 5% solution with sodium chloride 0.225% solution, glucose 5% solution with potassium chloride 0.15% solution, and mannitol 2.5% or 10% solution.

Preg Safety (US)

Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1^st trimester (and there is no evidence of a risk in later trimesters).

Caution For Usage

Instructions for Use, Handling and Disposal: See Dosage & Administration. Standard aseptic technique should be employed during reconstitution. Shake reconstituted solution before use. The vial is not a multi-dose container any unused portion must be discarded.

Storage

Store below 30°C. Protect from Light. Do not freeze. Use immediately after reconstitution.
Shelf-Life: 24 months.

Description

Each vial contains meropenem equivalent to anhydrous meropenem 1 g and sodium carbonate equivalent to sodium (as buffer) 90.2 mg.
Meropenem injection is presented as a sterile white powder containing meropenem 1000 mg as the trihydrate blended with anhydrous sodium carbonate for reconstitution.

Mechanism of Action

Pharmacology: Pharmacodynamics: 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 to all serine β-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 concentration (MBC) are commonly the same as the minimum inhibitory concentrations (MIC). For 76% of the bacteria tested, the MBC: MIC ratios were ≤2.
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 MIC of the infecting organisms (see Table 1).

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 as follows: Gram-Positive Aerobes: Bacillus spp, Corynebacterium diphtheriae, Enterococcus liquifaciens, Enterococcus avium, Listeria monocytogenes, Lactobacillus spp, Nocardia asteroides, Staphylococcus aureus (penicillinase negative and positive), Staphylococci-coagulase negative, including 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 pyogens, 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 sorbria, Aeromonas caviae, Alcaligenes faecalis, Bordetella bronchiseptica, Brucells 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 β-lactamase positive and ampicillin resistant strains), Haemophilus parainfluenzae, Haemophilus ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including β-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 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, 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-min IV infusion of a single dose of meropenem in healthy volunteers results in peak plasma levels of approximately 11 mcg/mL for the 250-mg dose, 23 mcg/mL for the 500-mg dose and 49 mcg/mL for the 1-g dose.
However, there is no absolute pharmacokinetic proportionality with the administered dose both as regards peak plasma concentration (C_max) and area under the concentration-time curve (AUC). Furthermore, a reduction in plasma clearance from 287-205 mL/min for the range of dosage 250 mg to 2 g has been observed.
A 5-min IV bolus injection of meropenem in healthy volunteers results in peak plasma levels of approximately 52 mcg/mL for the 500-mg dose and 112 mcg/mL for the 1-g dose.
Intravenous infusions of 1 g over 2-, 3- and 5 min were compared in a 3-way crossover trial. These durations of infusion resulted in peak plasma levels of 110, 91 and 94 mcg/mL, respectively.
After an IV dose of 500 mg, plasma levels of meropenem decline to values of ≤1 mg/mL, 6 hrs 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 (t_½) is approximately 1 hr.
Plasma protein-binding of meropenem is approximately 2%. Approximately 70% of the administered dose is recovered as unchanged meropenem in the urine over 12 hrs, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hrs after administration of a 500-mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hrs or 1 g administered every 6 hrs 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 inihibit most bacteria. Studies in children have shown that the pharmacokinetics of meropenem in children are similar to those in adults. The elimination t_½for meropenem was approximately 1.5-2.3 hrs in children <2 years and the pharmacokinetics are linear over the dose range of 10-40 mg/kg.
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.
Toxicology: Preclinical Safety Data: Animal studies indicate that meropenem is well-tolerated by the kidney. In animal studies meropenem has shown nephrotoxic effects, only at high dose levels (500 mg/kg).
Effects on central nervous system (CNS), convulsions in rats and vomiting in dogs , were seen only at high doses (>2000 mg/kg).
For an IV dose the LD₅₀in rodents is >2000 mg/kg. In repeat-dose studies (up to 6 months) only in minor effects were seen including a small decrease in red cell parameters and an increase in liver weight in dogs treated with doses of 500 mg/kg.
There was no evidence of mutagenic potential in the 5 tests conducted and no evidence of reproductive and teratogenic toxicity in studies at the highest possible doses in rats and monkeys, the no effect level of a (small) reduction in F body weight in rat was 120 mg/kg. There was an increased incidence of abortions at 500 mg/kg in a preliminary study in monkeys. There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The IV formulation was well-tolerated in animal studies. The sole metabolite of meropenem had a similar profile of toxicity in animal studies.