Propinem - instructions for use, dose, side effects, contraindications

Antibiotic for parenteral use from the group of carbapenems, has a bactericidal effect, inhibiting the synthesis of the cell wall of Gram-positive and Gram-negative bacteria by binding to penicillin-binding proteins (PSB).

Unlike imipenem, it practically does not break down in the renal tubules with dehydropeptidase-1 (it does not need to be combined with cilastatin, a specific inhibitor of dehydropeptidase-1) and, accordingly, no nephrotoxic degradation products are formed.

The minimum bactericidal concentrations (MBCs) are usually the same as the minimum inhibitory concentrations (MICs).

The mechanism of development of resistance

The resistance of bacteria to meropenem can develop due to: a decrease in the permeability of the outer membrane of Gram-negative bacteria (due to a reduction in the number of porin channels), a decrease in affinity to the target PSB, an increase in efflux and the production of beta-lactamases capable of hydrolyzing carbapenems. Cross-resistance between meropenem and drugs belonging to the classes of quinolones, aminoglycosides, macrolides and tetracyclines, due to the mechanism of action, is absent. However, if the resistance mechanism is due to impaired permeability of the cell wall and / or efflux, bacteria can develop resistance to drugs belonging to different classes.

The only recommended criteria for sensitivity to meropenem are based on the pharmacokinetics of the drug and on the correlation of clinical and microbiological data - the diameter of the zone and MICs, determined for the respective pathogens.

Category of the pathogen	Diameter of the zone (mm)
Sensitive	≥ 14
Intermediate	From 12 to 13
Resistant	≤11

The following table shows the threshold values of MIC of meropenem in the European Union (EU) for various bacterial pathogens in clinical settings:

Pathogens	Sensitivity (mg / l)	Resistance (mg / l)
Enterobacteriaceae	≤2	>8
Pseudomonas	≤2	>8
Acinetobacter	≤2	>8
Streptococcus groups A, B, C, G	≤2	>2
Streptococcus pneumoniae¹	≤2	>2
Other streptococci	2	2
Enterococcus⁵	-	-
Staphylococcus²	Depends on the availability of sensitivity to methicillin
Haemophilus influenzae¹, Moraxella catarrhalis	≤2	>2
Neisseria meningitidis²^,³	≤0,25	>0,25
Gram-positive anaerobes except Clostridium difficile	≤2	>8
Gram-negative anaerobes	≤2	>8
Listeria monocytogenes	≤0,25	>0,25
Nonspecific thresholds⁴	≤2	>8

¹Sensitivity threshold for Streptococcus pneumoniae and Haemophilus influenzae when meningitis - 0.25 mg / l.

²Strains for which the MICs are above the sensitivity threshold are rare or not currently detectable. If such a strain is detected, the MIC test is repeated, when the result is confirmed, the strain is sent to a reference laboratory, and the strain is considered resistant until a confirmed clinical effect is obtained with respect to it.

³Values used only for meningitis.

⁴For all other pathogens, according to pharmacokinetic and pharmacodynamic data, without taking into account the specific distribution of MIC specific pathogens.

⁵ The sensitivity test is not recommended, since this agent is not an optimal target for meropenem.

The spectrum of antibacterial activity of meropenem includes the majority of clinically significant Gram-positive and Gram-negative aerobic and anaerobic strains of bacteria.

Tests in vitro show that meropenem acts synergistically with various antibiotics. In the tests in vitro and in vivo shown, that meropenem has a post-antibiotic effect.

The sensitivity to meropenem should be determined using standard methods. Interpretation of results should be carried out in accordance with local guidelines.

Pathogens sensitive to meropenem:

- Gram-positive aerobes:

Enterococcus faecalis¹ (with the exception of vancomycin-resistant strains), Staphylococcus aureus (methicillin-sensitive)², Staphylococcus spp. (methicillin-sensitive), including Staphylococcus epidermidis, Streptococcus agalactiae (group B), group Staphylococcus milleri (S. anginosus, S. constellatus, S. intermedius), Streptococcus pneumoniae, Streptococcus pyogenes (Group A).

- Gram-negative aerobes:

Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens.

- Gram-positive anaerobes:

Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus spp. (including P. micros, P anaerobius, P. magnus).

- Gram-negative anaerobes:

Bacteroides caccae, Bacteroides fragilis, Prevotella bivia, Prevotella disiens.

Pathogens for which acquired resistance is possible:

- Gram-positive aerobes:

Enterococcus faecium¹

- Gram-negative aerobes:

Acinetobacter spp., Burkholderia cepacia, Pseudomonas aeruginosa.

Pathogens with natural resistance:

- Gram-negative aerobes:

Stenotrophomonas maltophilia, Legionella spp.

Other pathogens: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.

¹Pathogens with intermediate sensitivity.

²All methicillin-resistant staphylococci are resistant to meropenem.

Pharmacokinetics:

Suction

With intravenous administration of 250 mg of meropenem for 30 minutes, the maximum concentration (C_mOh) is about 11 μg / ml, for a dose of 500 mg - about 23 μg / ml, for a dose of 1 g - about 49 μg / ml (absolute pharmacokinetic proportional dependence on the administered dose for C_mOh and AUC (the area under the pharmacokinetic curve "concentration-time") is not). When the dose is increased from 250 mg to 2 g, the plasma clearance decreases from 287 to 205 ml / min.

With intravenous bolus administration for 5 min 500 mg - C_mOh about 52 μg / ml, 1 g - about 112 μg / ml.

With repeated administration of meropenem with an interval of 8 hours, patients with normal renal function do not observe cumulation of the drug.

Distribution

The connection with plasma proteins does not depend on the concentration of the drug and is approximately 2%.

After rapid administration (no more than 5 minutes) of meropenem, its pharmacokinetics corresponds to bi-exponential. After the infusion introduction for 30 minutes, this correspondence becomes less obvious.

Meropenem penetrates most tissues and body fluids, including lung tissue, the secret of bronchi, bile, cerebrospinal fluid, female genital tissue, skin, fascia, muscle tissue and peritoneal exudate.

Metabolism

Metabolism of meropenem occurs by hydrolysis of the beta-lactam ring with the formation of a microbiologically inactive metabolite.

Excretion

Meropenem is excreted mainly by the kidneys - about 70% (50-75%) dose of the drug in unchanged form for 12 hours, the remaining 28% - in the form of a microbiologically inactive metabolite. About 2% of the dose is excreted by the intestine. In healthy patients, the half-life (T_1/2) is 1 hour.

Pharmacokinetics in children

The pharmacokinetic parameters of meropenem are similar to those of adults. The half-life of meropenem in children under 2 years is approximately 1.5-2.3 hours, a linear dependence is observed in the dose range of 10-40 mg / kg.

Pharmacokinetics in patients with renal insufficiency

In patients with renal insufficiency, clearance of meropenem correlates with creatinine clearance (CC), therefore dose adjustment is necessary.

Meropenem is excreted in hemodialysis with clearance, approximately 4 times higher than the clearance of meropenem in patients with anuria.

Pharmacokinetics in patients with hepatic impairment

In patients with hepatic insufficiency, the pharmacokinetics of meropenem does not change.

Pharmacokinetics in elderly patients

In elderly patients (65 to 80 years), the decrease in meropenem clearance correlates with the age-related decrease in CK. The need for correction of the dose is absent except for cases of moderate and severe renal failure.

Indications:

Infectious-inflammatory diseases caused by sensitive microorganisms:

- infections of the lower respiratory tract (including pneumonia, including hospital ones);

- intra-abdominal infections (including complicated appendicitis, peritonitis);

- urinary tract infection (including pyelonephritis, pyelitis);

- infections of the pelvic organs (including endometritis, pelvioperitonitis);

- bacterial meningitis;

- infections of the skin and soft tissues (including erysipelas, impetigo, secondarily infected dermatoses);

- septicemia;

- suspected bacterial infection in adults with febrile episodes on the background of neutropenia (empirical treatment) in the form of monotherapy or a combination with antiviral or antifungal drugs.

The effectiveness of the drug has been proven both in monotherapy mode and in combination with other antimicrobial agents in the treatment of polymicrobial infections.

Contraindications:

Hypersensitivity to meropenem or excipients; hypersensitivity to other drugs of the carbapenem group; severe hypersensitivity (anaphylactic reactions, severe skin reactions) to other beta-lactam antibiotics (for example, to penicillins or cephalosporins); childhood up to 3 months.

Carefully:

With simultaneous use with nephrotoxic drugs; in patients with gastrointestinal complaints (diarrhea), especially those suffering from colitis.

Pregnancy and lactation:

The use of the drug during pregnancy and during breastfeeding is possible only in cases where the intended use for the mother exceeds the potential risk to the fetus or child.

If you need to use the drug during lactation, you should decide whether to stop breastfeeding.

Dosing and Administration:

Intravenous bolus or infusion.

The dose of the drug is determined individually, taking into account the severity of the disease, the localization of infection and the sensitivity of the pathogen, age, body weight and function of the patient's kidneys.

Recommended daily doses

Adults and children over 12 years of age

- for pneumonia, urinary tract infections, pelvic infections (including endometritis), skin and soft tissue infections - 500 mg every 8 hours;

- with hospital pneumonia, peritonitis, suspected bacterial infection in patients with neutropenia, septicemia - 1000 mg every 8 hours;

- with bacterial meningitis - 2000 mg every 8 hours.

The safety of administering a dose of 2 g as a bolus injection has not been sufficiently studied.

Patients with renal insufficiency

The dose is adjusted depending on the creatinine clearance. When creatinine clearance is less than 51 ml / min, a dose reduction may be required, as indicated below:

Creatinine clearance (ml / min)	The dose (calculated on the basis of standard doses equal to 500 mg, 1 g, 2 g)	Periodicity introduction of
26-50	One standard dose	Every 12 hours
10-25	Half of the standard dose	Every 12 hours
< 10	Half of the standard dose	Every 24 hours

Meropenem is excreted in hemodialysis and haemofiltration, therefore the appropriate dose of the drug should be administered after the procedure of hemodialysis.

If continuation of treatment is required, it is recommended that the drug (depending on the type and severity of the infection) be administered at the end of the hemodialysis procedure in order to restore an effective concentration in the blood plasma.

Data on the experience of using meropenem in patients on peritoneal dialysis are not available.

When hepatic insufficiency and for elderly patients with normal renal function or creatinine clearance greater than 50 ml / min correction of the dose is not required.

Children aged 3 months to 12 years (or body weight less than 50 kg)

- the recommended dose for intravenous administration is 10-20 mg / kg every 8 hours, depending on the severity, localization of the infection, the sensitivity of the pathogen and the patient's condition;

- with bacterial meningitis, the recommended dose is 40 mg / kg every 8 hours (maximum single dose of 2 g).

Children with a body weight of more than 50 kg apply doses to adults.

The safety of administering a dose of 40 mg / kg as a bolus injection has not been sufficiently studied.

Experience in children with violations of the liver and kidneys is absent.

Method of administration

The drug can be administered as an intravenous bolus injection for at least 5 minutes, or as an intravenous infusion for 15-30 minutes.

Prepared solution is recommended to enter immediately after preparation (from the microbiological point of view), if the conditions of preparation do not exclude the possibility of microbiological contamination.

Rules for the preparation of a solution for intravenous bolus administration

To prepare a solution for intravenous bolus injections, the drug should be dissolved with sterile water for injection (5 ml per 250 mg), with a solution concentration of 50 mg / ml.

Rules for the preparation of a solution for intravenous infusion

To prepare a solution for intravenous infusion, the drug should be dissolved with 0.9% sodium chloride solution or 5% dextrose solution, with the concentration of the solution should be from 1 to 20 mg / ml.

Side effects:

The frequency of adverse reactions is presented in the following gradation: very often (≥1 / 10), often (≥1 / 100 to <1/10), infrequently (≥1 / 1000 to <1/100), rarely (≥1 / 10000 to <1/1000), very rarely (<1/10000), the frequency is unknown (the frequency can not be determined from the available data).

Infectious and parasitic diseases: infrequently - candidiasis of the oral cavity, vaginal candidiasis.

Violations of the blood and lymphatic system: often - thrombocythemia; infrequently - eosinophilia, thrombocytopenia, leukopenia, neutropenia; frequency unknown - agranulocytosis, hemolytic anemia.

Immune system disorders: frequency unknown - angioedema, anaphylactic reaction.

Disturbances from the nervous system: often - headache; infrequently - paresthesia, fainting *, hallucinations *, depression *, anxiety *, increased excitability *, insomnia *; rarely convulsions.

Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea, abdominal pain; infrequently - constipation *, cholestatic hepatitis *; frequency unknown - pseudomembranous colitis.

Disturbances from the liver and bile ducts: often - increased activity of "liver" transaminases, alkaline phosphatase and lactate dehydrogenase in the blood; infrequently, an increase in the level of bilirubin in the blood.

Disturbances from the skin and subcutaneous tissues: often - a rash, itching; infrequently - hives; frequency unknown - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Disorders from the kidneys and urinary tract: infrequently - increase the concentration of creatinine and urea in the blood.

Heart Disease: infrequently - heart failure *, cardiac arrest *, tachycardia *, bradycardia *, myocardial infarction *.

Vascular disorders: infrequently - thromboembolism of the branches of the pulmonary artery *, decrease or increase of arterial pressure *.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - dyspnea *.

General disorders and disorders at the site of administration: often - inflammation, pain; infrequently - thrombophlebitis; frequency unknown - pain at the injection site.

* The cause-and-effect relationship with the use of the drug is not established.

Overdose:

A relative overdose is possible in patients with renal insufficiency, if dose correction has not been performed (see the section "Dosing and Administration").

Symptoms: increased dose-dependent side effects.

Treatment: symptomatic.With normal kidney function, the drug is rapidly removed by the kidneys; with renal insufficiency meropenem and its metabolite are excreted from the body by hemodialysis.

Interaction:

Probenecid competes with meropenem for active tubular secretion and, thus, inhibits the excretion of meropenem by the kidneys, causing an increase in its half-life and concentration in the blood plasma. The combined use of probenecid and meropenem is not recommended.

Potential effects of meropenem on binding other drugs to proteins or their metabolism has not been studied. However, its binding to proteins is so insignificant that interaction with other substances by this mechanism is unlikely.

With simultaneous application valproic acid and carbapenems decreased its concentration in the blood from 60% to 100% after 2 days of therapy. Due to the rapid and significant decrease in the concentration of valproic acid, simultaneous use of valproic acid and meropenem should be avoided.

With the simultaneous use of antibiotics and warfarin The anticoagulant effect of the latter can intensify.In patients who simultaneously take antibacterial drugs and oral anticoagulants, including warfarin, often increased anticoagulant effect. The risk of this effect varies depending on the type of infection, age and general condition of the patient, so it is difficult to assess the effect of antibiotics on increasing the international standardized ratio (INR). During the use of meropenem and indirect anticoagulants and for some time after its termination, frequent monitoring of INR is recommended.

Meropenem is compatible with the following infusion solutions: water for injection, 0.9% sodium chloride solution, 5% dextrose solution.

Meropenem should not be mixed or added to other medications.

Special instructions:

Experience in the use of the drug in pediatric practice in patients with neutropenia or with primary or secondary immunodeficiency is not present.

As with the use of other antibiotics, when using meropenem in monotherapy in patients who are in critical condition with an identified lower respiratory tract infection caused by Pseudomonas aeruginosa or if suspected, regular testing of sensitivity is recommended.

In rare cases, with the use of meropenem, as with almost all antibiotics, pseudomembranous colitis develops, which can vary in severity from mild to life-threatening forms. It is important to remember the possibility of developing pseudomembranous colitis when diarrhea occurs against the background of the use of meropenem. With the development of pseudomembranous colitis should cancel the drug. Contraindicated use of drugs that inhibit intestinal peristalsis.

Against the background of the use of carbapenems, including meropenem, infrequent reports of seizures occurred. Caution should be exercised when using meropenem in patients with a reduced threshold of convulsive readiness.

There are clinical and laboratory signs of cross-allergic reactions between other carbapenems and beta-lactam antibiotics, penicillins and cephalosporins. There are rare reports of cases of hypersensitivity reactions (including fatal outcome) with the use of meropenem, as well as other beta-lactam antibiotics (see the "Side effect" section).Before starting therapy with meropenem, the patient should be thoroughly questioned, paying special attention to hypersensitivity reactions to beta-lactam antibiotics in the anamnesis (see "Contraindications"). If there was an allergic reaction to meropenem, it is necessary to stop the introduction of the drug and take appropriate measures.

In the treatment of meropenem, liver function should be carefully monitored in connection with the risk of hepatotoxicity of this drug (impaired liver function with cholestasis and cytolysis). The use of meropenem in patients with liver disease should be conducted under careful control of the activity of transaminases and bilirubin concentrations. No dose adjustment is required.

As with other antibiotics, excessive growth of insensitive microorganisms is possible, and therefore constant monitoring of the patient is necessary.

The prevalence of acquired antibiotic resistance of various pathogens may vary depending on the region and over time, it is desirable to have up-to-date information on the resistance of common pathogens in a particular region, especially when treating severe infections.If the prevalence is such that the effectiveness of the drug against at least a few infections becomes questionable, you should consult an expert.

It is not recommended joint use of meropenem and valproic acid because of a possible decrease in valproic acid in the blood serum. In some patients, a concentration below the therapeutic level can be achieved (see "Interaction with other drugs").

The use of the drug for infections caused by methicillin-resistant staphylococcus is not recommended.

Effect on the ability to drive transp. cf. and fur:

During the treatment period, care must be taken when driving vehicles and engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Form release / dosage:

Powder for the preparation of a solution for intravenous administration, 1000 mg.

Packaging:

1000 mg of meropenem in a colorless glass vial with a capacity of 30 ml, closed with a rubber stopper, crimped with an aluminum cap.

Each bottle in a pack of cardboard along with instructions for use.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000524

Date of registration:01.03.2011 / 09.06.2016

Expiration Date:Unlimited

The owner of the registration certificate:CITCO, LLCCITCO, LLC Russia

Manufacturer: & nbsp

PROTECH BIOSYSTEMS, PVT. Ltd. India

Representation: & nbspCITCO, LLCCITCO, LLCRussia

Information update date: & nbsp11.08.2016

Illustrated instructions

Instructions

Propinem (Propinem)