Meropenem-Belpharm 500 mg

Medicine trade name: Meropenem - Belpharm
Active ingredient: meropenem
Medicine form: powder for preparation of injection solution 500 mg or 1000 mg
Description: white or white with yellowish tint powder
Composition for 1 bottle:
Active substance:
Meropenem (in terms of pure substance) – 500 mg or 1000 mg
Pharmaceutic group: antibiotic of carbapenem group
Code : J01DH02

Pharmacological properties

Pharmacodynamics
Meropenem exerts bactericidal effect by inhibiting wall synthesis bacterial cells of gram-positive and gram-negative bacteria by binding to penicillin binding proteins.

As with other beta-lactam antibacterial agents, time at which meropenem concentrations exceeded minimum inhibiting concentrations, indicated a high degree correlation with efficiency. In pe-clinical models meropenem demonstrated activity at blood plasma concentrations, exceeding MIC for infecting microorganisms by approximately 40 % of the dosing interval. This target value was not established clinically.

Bacterial resistance to meropenem can result from:
1. Reducing permeability of the outer membrane of gram-negative bacteria (due to reduction of porin production);
2. Reducing the affinity for target
3. Increasing expression of efflux pump components;
4. Beat-lactam production that can hydrolyze carbapenems

In European union there was registered cases of infectious diseases caused by bacteria that stable to carbapenems.

Cross resistance between meropenem and medicines, belonging to quinolones, aminoglycosides, macrolides and tetracyclines classes taking into account with target microorganisms being absent. However, bacteria can be resistance more than one class of antibacterial agent, in case, if its mechanism includes cell membrane impermeability and/or the presence of efflux pump(s).

MIC limit values, which were determined during clinical studies by European committee on determining sensitivity to antimicrobial medicines, are shown at table:

¹ Boundary values of meropenem for Streptococcus pneumoniaе¹ and Haemophilus influenzae¹ at meningitis consists 0,25 mg/l.
² Strains of microorganisms with values above sensitivity threshold ate rare or currently. Analysis of identification and antimicrobial sensitivity for any such isolate must be repeated, and if result is confirmed, isolate is sent to reference laboratory. As long as clinical data is available for verified isolates with MIS values above current resistance limits (in italics) isolates should register as sustainable.
³ Sensitivity of staphylococci to meropenem is predicted based on data sensitivity to methicillin.
⁴ Boundary values of meropenem for Neisseria meningitidis applied only to meningitis.
⁵ Boundary values not related to microorganism species were determined, over all, based on FK/FD data and do not depend on distribution of MIS individual species. They are intended to use with species not shown at table and footnotes.
“-“ analyses is not recommended, because this species is not an optimal target for meropenem.
The prevalence of acquired resistance may vary geographically and over time for other species, so it is advisable to rely on local information about microorganism resistance, especially when treating severe infections. In case of necessity when level of prevalence of microorganism resistance in local level is such that, benefit of medicinal drug at least with some types of infections id doubtful, expert advice should be sought.
In the following table there are listed pathogenic microorganisms, based on clinical experience and therapeutical protocols of treating diseases.

Typically sensitive species:
Gram-positive aerobes : Enterococcus faecalis⁶, Staphylococcus aureus (methicillin sensitive)⁷, Staphylococcus species (methicillin sensitive) Staphylococcus epidermidis, Streptococcus agalactiae (B group), Streptococcus milleri (S. anginosus, S. constellatus, S. intermedius), Streptococcus pneumoniaе, Streptococcus pyogenes (A group).

Gram-negative aerobes: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzaе, Klebsiella oxytoca, Klebsiella pneumoniaе, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens.

Gram-positive anaerobes: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus species(P. micros, P. anaerobius, P. magnus).

Gram-negative anaerobes: Bacteroides caccae, Bacteroides fragilis group, Prevotella bivia, Prevotella disiens.

Species, for which acquired resistance can be a problem:
Gram-positive aerobes: Enterococcus faecium^6,8.
Gram-negative aerobes: Acinetobacter species, Burkholderia cepacia, Pseudomonas aeruginosa.

Naturally resistance microorganisms:
Gram-positive anaerobes: Stenotrophomonas maltophilia, Legionella species.
Gram-negative anaerobes: Chlamydophila pneumoniaе, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniaе.
⁶ Species, for which natural intermediate sensitivity is identified.
⁷ All methicillin-sensitive staphylococci are stable to meropenem.
⁸ Resistance indicator >50% I one and some countries of EU.

Pharmacokinetics
In healthy people, T_1/2 is approximately 1 hour. With maximum concentration (C_max) and the area under the pharmacokinetic curve "concentration-time" (AUC) there is no absolute pharmacokinetic proportional dependence on the administered dose. With an increase in the dose from 0.25 g to 2 g, the clearance decreases from 287 to 205 ml / min. When the administration of a dose of 500, 1000 and 2000 mg for 30 minutes of C_max is approximately 23, 49 and 115 mkg / ml, which corresponds to AUC 39.3, 62.3 and 153 mkg х h / ml. When Bolus administration for 5 minutes 500 mg C_max - 52 mkg / ml, 1000 mg 112 mkg / ml. When the doses are administered for 8 hours to people with normal kidney function, the accumulation of the meropenem does not occur.

In a study, 12 patients were injected with 1000 mg Meropenem every 8 hours after surgery during intraabdominal infection, while the result comparable to C_max and T12 was shown, but a larger distribution volume of 27 liters.

Distribution
binding to plasma proteins is approximately 2% and does not depend on the concentration. After fast administration (5 minutes or less) pharmacokinetics is bioexponential. Meropenem is well penetrating the majority of tissues and body fluids, in the lungs, bronchial secretion, bile, gynecological tissues, skin, fascia, muscle and peritoneal exudate.



Metabolism
Meropenem is metabolized by hydrolysis of the beta-lactam ring to form a microbiologically inactive metabolite. In vitro Meropenem shows a reduced sensitivity to the hydrolysis of the dehydropptidase -I person compared to the imipenem.

Withdrawal from the body
Meropenem is excreted from the body unchanged by the kidneys; About 70% (50-75%) doses are excreted unchanged for 12 hours. Another 28% is restored as microbiologically inactive metabolite. The removal with feces is about 2% doses. Changed kidney clearance and probecid effect show that meropenem posted by filtration and secretion.

Renal failure
When studying pharmacokinetics in patients with renal failure, a long half-life is observed from the body. AUC increases 2,4 times in patients with moderate disorders (CrCl. 33-74 ml/min), 5 times in patients with severe disorders (CrCL, 4-23 ml/min) and 10 times in patients on hemodialysis (CC < 2 ml/min) compared to healthy people (CrCL > 80 ml/min). Dose adjustment is recommended for patients with moderate to severe renal impairment insufficiency.
Meropenem is eliminated by hemodialysis, hemodialysis time is approximately 4 times more than in patients with anuria.

Liver failure
Pharmacokinetic studies in patients with liver disease have shown that these pathological changes do not affect the pharmacokinetics of meropenem.

Adult patients
32 pharmacokinetic studies conducted in adult patients showed no significant differences in pharmacokinetics compared to healthy subjects with equivalent renal function. A population-based model based on data from 79 patients with intra-abdominal infection or pneumonia showed a relationship between central volume and mass and creatinine clearance and age.

Children
Pharmacokinetics of infants and children with infection when taking doses of 10, 20 and 40 mg/kg showed the same C_max values as in adults when taking doses of 500, 1000 g and 2000 mg, respectively. Comparison showed pharmacokinetics comparable to adults, with the exception of children <6 months T12 1,6 hours. Average clearance values of meropenem – 5,8 ml/min/kg (for children 6-12 years), 6,2 ml/min/kg (2 -5 years), 5,3 ml/min/kg (6-23 months) p 4,3 ml/min/kg (2-5 months). Approximately 60% of the dose is excreted in the urine within 12 hours as meropenem, 12% as a metabolite. The concentration of meropenem in the cerebrospinal fluid in children with meningitis is approximately 20%, but there is significant interindividual variability. In newborns who require antibiotic treatment, an increase in clearance was noted, T12 – 2,9 hours.

Elderly patients
Pharmacokinetic studies in healthy elderly patients (65-80 years) showed a decrease in plasma clearance, which correlated with decreased creatinine clearance and less non-renal clearance with age.
No dose adjustment is required for elderly patients, except in cases of severe to moderate renal impairment.

Indications for use
Meropenem is shown for treating adults and children (over 3 months) with following infectious-inflammatory diseases, caused by one or some pathogens sensitive to meropenem:

· Pneumonia, including community-acquired pneumonia;
· Bronchopulmonary infections in cystic fibrosis;
· Complicated urinary system infections;
· Complicated abdominal infections;
· Birth and postpartum infections;
· Complicated infections of skin and soft tissues;
· Acute bacterial meningitis.

Meropenem can be used for treating neutropenic patients with fever, caused by bacterial infection.

Directions for use and doses
Dosage is set individually depending on the disease, type of pathogen and clinical manifestations.
Doses to 2g 3 times a day for adults and teenagers and doses to 40mg/kg 3 times a day for children can be purposefully used for treating in-hospital infections, caused by Pseudomonas aeruginosa or Acinetobacter species.

For patients with renal failure dose adjustment is necessary.

Adults and teenagers:

Renal failure:
At renal failure dose adjustment is not required.

Dosage in elderly patients:
In elderly patients with normal renal function or creatinine clearance, more 50 ml/min dose adjustment is not required.

 
Children

Children under 3 months:
Efficiency and safety of use in children under 3 months, and optimal dosage mode was not discovered. However, limited data at pharmacokinetics allows to predict that dose 20 mg/kg every 8 hours is optimal dosage mode.

Dose for children at the age over 3 months – to 11 years with weight less thar 50 kg:

Meropenem is usually administered as a drip infusion to adults and children during 15-30 minutes. The contents of vial (bottle) should be dissolved in 0.9 % sodium chloride solution of 5% glucose (dextrose) solution to a final concentration of 1 to 20 mg/ml. the solution should be shaken before use.

Intravenous bolus administration of meropenem is allowed during 5 minutes: adults – to 1 g, children (from 3 months to 11 years with weight less than 50 kg) – in dose to 20 mg/kg body weight. There is limited data about possibility of intravenous bolus administration to adults to 2 g, children – in dose to 40 mg/kg body weight. When administered as intravenous bolus, medicine dose is dissolved in sterile water for injection to final concentration of 50 mg/ml.

Side effects
Frequency of side effects is given in the following gradation: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, < 1/1000), very rare (<1/10000).

From the gastrointestinal tract: often: pain in the epigastric region, nausea, vomiting, diarrhea, hyperbilirubinemia, increased activity of hepatic transaminases and alkaline phosphatase, LDH; uncommon: constipation, cholestatic hepatitis; very rare: pseudomembranous enterocolitis.

From the cardiovascular system: development or worsening of heart failure, cardiac arrest, tachycardia or bradycardia, decrease or increase in blood pressure, fainting, myocardial infarction, thromboembolism of the branches of the pulmonary artery.

From the urinary system; uncommon: dysuria, edema, dysfunction kidneys (hypercreatininemia, increased concentration of urea in plasma), hematuria.

Allergic reactions: skin itching, skin rash, urticaria, multiforme exudative erythema, malignant exudative erythema (Stevens-Johnson syndrome), angioedema, anaphylactic shock, toxic epidermal necrolysis.

From the nervous system: uncommon: headache, paresthesia, insomnia, drowsiness, increased hallucinations excitability, anxiety, impaired consciousness; rarely: convulsions.
From the immune system: very rarely: Quincke's edema, anaphylactic shock.

Changes in laboratory parameters: eosinophilia, thrombocytopenia, neutropenia, leukopenia; rarely: agranulocytosis, hypokalemia, leukocytosis, hypercreatininemia, hemolytic anemia, reversible thrombocytopenia, decreased partial thromboplastin time, increased transaminases, increased lactate dehydrogenase, increased bilirubin in the blood.

Infections and infestations: uncommon: oral and vaginal candidiasis,

Local reactions: inflammation, phlebitis, thrombophlebitis, pain at the injection site; tissue damage with a concomitant rise in.

Other: positive direct or indirect Coombs test, anemia, hypervolemia, dyspnea, vaginal candidiasis and candidiasis of the oral mucosa.

Contraindications
Hypersensitiveness to meropenem or other medicines of carbapenem group in anamnesis. Pregnancy, lactation period, children age under 3 months.

Medical interactions
Probenecid competes with meropenem for active tubular secretion, inhibiting renal excretion and causing an increase in the half-life and plasma concentration of meropenem. Caution must be exercised when meropenem is co-administered with probenecid.

When used together with carbapenems, a decrease in the level of valproic acid in the blood is observed by 60-100% after a few days. Therefore, the combined use of valproic acid and carbapenems should be avoided.

Oral anticoagulants: Concomitant use of antibiotics with warfarin increases the anticoagulant effects. There have been reports of increased anticoagulant effects when oral anticoagulants are administered with antibacterial agents. A risk may vary depending on the causative agent, age and general condition of the patient, so the contribution of antibiotics to international normalized ratio (INR) is difficult to estimate. It is recommended to frequently determine the INR during treatment and for some time after combined treatment with antibiotics and oral anticoagulants.

Special instructions
When prescribing meropenem for treatment of each individual patient, it is necessary to take into account the advisability of using carbapenems depending on the severity of the infection, the presence of resistance to other antibacterial medicines.

When using meropenem, as with use of almost all antibiotics, development of pseudomembranous colitis is seen, which can var by severity of from mild to life-threatening forms. It is important to remember about possibility of development of pseudomembranous colitis while diarrhea in the background of using meropenem. It is necessary to consider stopping meropenem therapy. Should not take medicines thar inhibit peristalsis.

Development of convulsions have been rarely reported during treatment with carbapenems including meropenem.

There are clinical and laboratorial signs cross allergic reactions between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. There are rare reports abouts reaction cases hypersensitivity (including fatal ones) as with use of meropenem, so other beta-lactam antibiotics. Before start of meropenem therapy it is necessary to carefully ask patient, paying particular attention to hypersensitivity reactions to beta-lactam antibiotics in anamnesis. Meropenem should be used with caution in patients with in anamnesis. If allergic reaction to meropenem occurs, it is necessary to stop administration of medicine and take appropriate measures.

Treatment of patients with liver diseases should be carried out under careful monitoring of the activity of “liver” transaminases and bilirubin concentration. During treatment, the development of resistance of pathogens is possible, and therefore long-term treatment is carried out under constant monitoring of the spread of resistant strains.

Use of the drug for infections caused by methicillin-resistant staphylococcus, not recommended. During treatment with meropenem, direct or indirect Coombs tests may be positive.

One vial of meropenem 500 mg contains 2,0 mmol sodium. One vial of meropenem 1000 mg contains 4,0 mmol sodium. This should be taken into account in people monitoring their sodium intake (on a low sodium diet).

From a microbiological point of view, the drug must be used immediately. If the medicine is not used immediately, the doctor is responsible for the period and conditions of its storage. A meropenem solution prepared with a 5% glucose (dextrose) solution should be used immediately, that is, within 1 hour after preparation.

Meropenem solution should not be frozen.

Usage during pregnancy and lactation: clinical safety of Meropenem during pregnancy has not been established. Experimental studies on animals have not shown any adverse effects on the developing fetus. During pregnancy and lactation, it is necessary to evaluate the potential benefits and possible risks of the drug for the fetus, infant and mother. In each case, the drug must be used under the direct supervision of a doctor. Meropenem is found in the breast milk of animals in very low concentrations. It is recommended to stop breastfeeding during the treatment period.

Effect on the ability to drive vehicles and other potentially dangerous mechanisms: There is no reliable data on the effect of meropenem on the ability to drive vehicles and operate machines. However, you should take into account that headache, paresthesia and convulsions may occur when taking meropenem.

Medicine should be stored out of reach of children and should not be used after expiration date.

Overdose
Accident overdose is possible during treatment, especially in patients with renal dysfunction.
Symptoms: no specific symptoms
Treatment: carrying out symptomatic therapy. Normally, medicine is rapidly eliminated through the kidneys. In patients with renal dysfunction hemodialysis effectively removes meropenem and its metabolite.

Release form
500 mg in a 10 ml glass vial or 1000 mg in a 20 ml glass vial.
1 or 5 vials together with instructions for use in a cardboard box.
Packaging for hospitals: 36 bottles with dosage of 500 mg or 25 bottles with dosage of 1000 mg with corresponding amount of instructions for use in group boxes.

Storage conditions
Store in a place protected from moisture and light at a temperature not exceeding 25 C.
Store in a place out of reach of children.

Expiration date
2 years

Do not use after expiration date, given in the package.

Conditions for dispensing from pharmacies
On prescription

Manufacturer/ name and address od organization, accepting claims (offers) regarding the quality of medicinal product in the territory of Republic of Uzbekistan

“BELPHARM” LLC, Republic of Uzbekistan, Tashkent city, Kichik Khalka yuli and Badamzar str., 37

www.belpharm.uz