INVANZ

Active material: Ertapenem
When ATH: J01DH03
CCF: Antibiotic group of carbapenems
ICD-10 codes (testimony): A40, A41, J15, K65.0, K81.0, K81.1, K83.0, L01, L02, L03, L08.0, N10, N11, N30, N34, N41, N70, N71, N73.0, O08.0
When CSF: 06.04
Manufacturer: MERCK SHARP & DOHME (France)

Pharmaceutical form, composition and packaging

Valium for solution for injection in the form of powder or porous mass of white or almost white.

Excipients: sodium bicarbonate, Sodium hydroxide (to pH 7.5); sodium content of approximately 137 mg (6 mJekv).

Colourless glass bottles with capacity 20 ml (1) – cardboard boxes.

Pharmacological action

An antibiotic of the carbapenemov group, represents the 1-methyl β-karbapenem, Beta-laktamnyj long-acting antibiotic for parenteral, with activity against a broad spectrum of Gram-positive and Gram-negative aerobic and anaerobic bacteria.

Bactericidal activity of jertapenema is due to inhibition of cell wall synthesis and mediated by its binding to penicillin-binding proteins (PSB). Escherichia coli have he has a strong affinity to the PSB 1a , 1b , 2, 3, 4 and 5, preferably – the PSB 2 and 3. Jertapenem has a considerable resistance to the action of β-lactamases most classes (including penicillinase, cefalosporinazy and β-lactamaza extended range, but not metal-β-lactamaza).

Invanz^® effective against most strains of the following microorganisms in vitro and when called by infections.

It is active against aerobic and facultative anaerobic gram-positive microorganisms: Staphylococcus aureus(including strains, producyrute penitsillinazou/Methicillin-resistant staphylococci resistant/), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Many strains of Enterococcus faecalis and Enterococcus faecium strains most resistant.

Active against aerobic and facultative anaerobic gram-negative microorganisms: Escherichia coli, Haemophilus influenzae (including strains, producing β-laktamazu), Klebsiella pneumoniae, Moraxella catarrhalis, Proteus is wonderful.

Active in regard to anaerobic Microorganisms: Bacteroides fragilis and other Bacteroides spp., microorganisms of the genus Clostridium (other than Clostridium difficile), microorganisms of the genus Eubacterium, microorganisms of the genus Peptostreptococcus, Porphyromonas asaccharolytica, microorganisms of the genus Prevotella.

Invanz^® When the IPC ≤ 2 µg/ml is active against most (≥ 90%) strains of microorganisms of the genus Streptococcus, including Streptococcus pneumoniae, When the IPC ≤ 4 ug / ml – against the majority of (≥ 90%) strains of microorganisms of the genus Haemophilus, against the majority of (>90%) strains of aerobic and facultative anaerobic Gram-positive microorganisms (Staphylococcus spp., koagulazonegativnye Methicillin-sensitive/Methicillin-resistant staphylococci resistant/, Streptococcus pneumoniae, penicillin-resistant Streptococcus viridans). The clinical significance of these data on the values of the IPC, obtained in vitro, unknown.

Meticilin-resistant staphylococci, as well as many strains of Enterococcus faecium Enterococcus faecalisi most strains resistant to Invanzu^®.

Active also in relation to aerobic and facultative anaerobic gram-negative microorganisms: Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli (onwards, the β-lactamaza extended spectrum of activity), Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae (producing β-lactamaza extended spectrum of activity), Morganella morgani, Proteus vulgaris, Serratia wilting.

Many strains of the microorganisms listed above, having multirezistentnostju to other antibiotics, eg, penicillins, cephalosporins (incl. Generation III) and aminoglycosides, sensitive to Invazu^®.

Active against anaerobic microorganisms genus Fusobacterium.

Determined by the value of the IPC should be interpreted in accordance with the criteria, specified in tables.

Table 1.

Table 2.

^a The current lack of data on resistant strains does not make it possible to define any category except “sensitive”. If you study the results of strain IPC can be interpreted “insensitive”, These strains require further research.

^b Streptococcus pneumoniae, penicillin-sensitive (IGC<0.06 ug / ml), may be deemed to be susceptible to jertapenemu. Testing of isolates with intermediate sensitivity to penicillin or penicillin-resistant isolates for sensitivity to jertapenemu not recommended, Because reliable criteria for interpretation of no jertapenema.

^c These standards interpretation of the diameter of the zones are applicable only to tests using Agar Mueller-Hintona with the addition 5% blood of sheep, inokulirovannogo suspension of pure colonies with incubation in 5% With₂ at 35° c for 20-24 no.

^d Isolates of Streptococcus pneumoniae should be explored using 1 ICH oksacillinovogo drive. Isolates with sizes ≥ 20 mm zone susceptible to penicillin and can be considered sensitive to jertapenemu.

^{it is} Streptococcus spp., who are sensitive to penicillin (IPC ≤ 0.12 µg/ml) may be deemed to be susceptible to jertapenemu. Testing of isolates with intermediate sensitivity to penicillin or penicillin-resistant isolates for sensitivity to jertapenemu not recommended, Because reliable criteria for interpretation of no jertapenema.

^fStreptococcus spp. should be tested using a disk with 10 UNITS of penicillin. Isolates with the size 28 mm ≤ zone susceptible to penicillin and can be considered sensitive to jertapenemu.

^(g) These standards apply to the interpretation procedure mikrodiljucii broth using Haemophilus test Wednesday Haemophilus Test Medium (HTM), inokulirovannoj suspension clean colony with incubation in air with a temperature over 20-24 no.

^h These diameters zones apply to tests using the diskodiffuzionnogo method on the NTMS agar, inokulirovannom suspension of pure colonies with incubation in 5% With₂ at 35° c for 16-18 no.

ⁱⁿ These standards only apply to the interpretation of diljucii agar using Brucella agar, with the addition of gemina, Vitamin K₁ and 5% defibrinated sheep blood gemolizirovannoj or, inokulirovannogo suspension of pure colonies, or 6-24-hour fresh culture in enriched tioglikolatom Wednesday in anaerobic incubation container or Chamber 35-37° c for 42-48 no.

Pharmacokinetics

Absorption

When the/m introduction solution, cooked with 1% or 2% lidocaine, jertapenem well absorbed from the introduction. Bioavailability is approximately 92%. After the / m dose 1 г C_max is approximately 2 no.

Distribution

Jertapenem actively communicates with human plasma proteins. The degree of binding decreases with increasing concentrations of plasma jertapenema – approximately 95% When plasma concentration <100 ug/mL to about 85% When plasma concentration 300 ug / ml).

Mean concentrations (ug / ml) plasma jertapenema, achieved after a single 30-minute in/in infusion of the drug at a dose of 1 or g 2 , and after the/m introduction in one dose 1 g in healthy young adult volunteers, are presented in Table.

* in/in cefuroxim performed at a constant speed during 30 m.

The AUC is increased almost directly proportional dose (in the range of doses from 0.5 g to 2 g).

Cumulation jertapenema after in/introductions (in the range of doses from 0.5 to 2 g / day) or/m introduction to 1 g/day is not observed.

V_d about jertapenema 8 l (0.11 l / kg).

Jertapenema concentration in the breast milk of lactating women (5 Pax.), defined daily at random time points during the 5 days after the last injection, in/in the dose of 1 g was: on the last day of treatment (through 5-14 days postpartum) <0.38 ug / ml; to 5 the day after the end of treatment concentrations at jertapenema 4 women was indefinable, and in 1 women – in trace quantities (<0.13 ug / ml).

Jertapenem does not inhibit the transport of Digoxin and vinblastine, mediated p-glycoproteins, and he himself is not a substrate.

Metabolism

After the on/in infusion jertapenema with isotope labeled dose 1 g source of radioactivity in the plasma is mainly (94%) jertapenem. The main metabolite is a jertapenema derivative with open ring, formed during the hydrolysis of β-laktamnogo rings.

Deduction

Jertapenem write mainly kidneys. The Mean T_1/2 from the plasma of healthy young adult volunteers is approximately 4 no. After the on/in the jertapenema with isotope labeled dose 1 g healthy young volunteers around 80% the label appears in the urine, and 10% – with feces. From 80% jertapenema, determined in the urine, about 38% excreted unchanged, and about 37% – in the form of metabolita with β-lactam ring watch.

Healthy young adult volunteers, received jertapenem in/in the dose 1 g, the average concentration of jertapenema in the urine within 0-2 h after the introduction of this dose exceeds 984 ug / ml, and for 12-24 no – more than 52 ug / ml.

Pharmacokinetics in special clinical situations

Jertapenema concentration in plasma is comparable for men and women.

Jertapenema concentration in plasma after in/in the dose 1 and g 2 g in older adult patients (senior 65 years) slightly above (approximately 39% and 22% respectively), than in younger. Correction dose for elderly patients is not required.

Mean concentrations in the plasma jertapenema in children after the introduction of a single dose * is presented in table.

* – in/in cefuroxim performed at a constant speed during 30 m.

** – up to a maximum dose of 1 g / day.

*** – up to a maximum dose of 2 g / day.

V_d jertapenema in children aged 3 Months before 12 years – 0.2 l/kg and about 0.16 l/kg in children 13-17 years.

Pharmacokinetics of jertapenema in patients with hepatic insufficiency have not studied. Due to the low intensity of its metabolism in the liver can be expected, that violation of its functions should not affect the farmakokinetiku jertapenema and correction mode in patients with hepatic insufficiency do not require.

After a single on/in the introduction jertapenema in dose 1 g the AUC in patients with renal insufficiency light gravity (KK from 60 to 90 ml / min / 1.73 m²) is no different from that of healthy volunteers (aged 25 to 82 years).

In patients with renal insufficiency, moderate severity (CC 31-59 ml / min / 1.73 m²) AUC increased approximately 1.5 fold compared with healthy volunteers.

Patients with severe renal insufficiency (CC 5-30 ml / min / 1.73 m²) AUC increased approximately 2.6 fold compared with healthy volunteers.

In patients with end stage renal failure (CC<10 ml / min / 1.73 m²) AUC increased approximately 2.9 fold compared with healthy volunteers. After a single on/in the introduction jertapenema in dose 1 g just before hemodialysis session about 30% the administered dose is determined in dialysate.

Patients with severe renal impairment or end-stage correction is recommended dosage.

Testimony

Treatment of severe and moderate severity of infectious and inflammatory diseases, caused by susceptible strains of microorganisms (incl. to start empirical antimicrobial therapy to determine the causative agents):

- Intra-abdominal infections;

- Infections of the skin and subcutaneous tissue, including infection of lower limbs in diabetes (diabetic foot);

- Community-acquired pneumonia;

- Urinary tract infection (incl. pyelonephritis);

— acute pelvic infection (incl. Postpartum endomyometritis, Septic abortion and post-operative gynecological infections);

-bacterial septicaemia.

Dosage regimen

The average daily dose for Adult and adolescents aged 13 and older is 1 g, multiplicity of introduction – 1 time / day.

Children aged 3 Months before 12 years Invanz^® administered at a dose of 15 mg / kg 2 once a day (but not more 1 g / day).

The drug is injected through the on/in infusion or/m injection. When in/with the introduction of infusion duration shall be 30 m.

In/m introduction can be an alternative to the on/in infusion.

The normal duration of therapy ranges from 3 to 14 days depending on the severity of the disease and the type of microorganisms. If there is clinical evidence is valid transition to subsequent adequate oral antibacterial therapy.

The drug can be used to treat infections in patients with renal insufficiency. Patients with CC>30 ml / min / 1.73 m² correction dosing regime is not required. In patients with severe renal impairment (CC ≤ 30 mL/min/1.73 m²), including patients, hemodialysis, The recommended dose is 500 mg / day. No data on the use of drugs in children with renal failure.

Adult patients, hemodialysis and received the drug in a dose 500 mg/day in the coming 6 hours before dialysis session, should further introduce 150 mg of the drug after the session. If the drug is injected more than 6 hours before hemodialysis, introduction of an additional dose is not required. At the present time there is insufficient data on the recommendation of the sick, in peritoneal dialysis or Hemofiltration. No data on the use of drugs in children, hemodialysis.

If you know the concentration of creatinine in the serum, then to calculate creatinine clearance, you can apply the following formula:

For men:

QC = (weight in kg) x (140-age in years)/72 x serum creatinine (mg / dL)

For women:

QC = 0.85 x (value, designed for men)

In patients with impaired liver function dose adjustment is required. The recommended dose can be administered without regard to age and gender.

Rules for the preparation of solutions for parenteral

Adults and teens between the ages 13 and older

Preparation of the solution for i / v infusion

Do not mix or enter together with other drugs. Do not use thinners, dextrose (glucose).

Before the introduction of the lyophilizate must restore, then dilute.

Restore liofilizat by adding to the content 1 bottle 10 ml of one of the following solvents: Water for Injection, 0.9% a solution of sodium chloride injection or bacteriostatic water for injection. A bottle should shake well and immediately add the recovered solution from the vial into the prepared 50 ml 0.9% solution of sodium chloride infusion. Infusion should be completed within 6 h after the restoration of the lyophilisate.

Preparation of the solution for i / m injection

Before the introduction of the lyophilizate must dissolve.

For the preparation of injection solution to content bottle (1 g) add 3.2 ml 1% or 2% lidocaine hydrochloride solution for injection (without epinephrine), then a bottle should shake well to dissolve the contents. The content of the vial immediately gaining in the syringe and injected deep into a large muscle (eg, in the buttock muscles or in the lateral thigh muscles). Solution for i / m administration must be used within 1 no.

Children ages 3 Months before 12 years

Preparation of the solution for i / v infusion

Do not mix or enter together with other drugs. Do not use thinners, dextrose (glucose).

Before the introduction of the lyophilizate must restore, then dilute.

Restore liofilizat by adding to the content 1 bottle 10 ml of one of the following solvents: Water for Injection, 0.9% a solution of sodium chloride injection or bacteriostatic water for injection. A bottle should shake and immediately dial the volume solution, equivalent 15 mg / kg body weight (but not more 1 g / day) and dilute the 0.9 % solution of sodium chloride concentrations for infusions 20 mg/ml or less. Infusion should be completed within 6 h after the restoration of the lyophilisate.

Preparation of the solution for i / m injection

Before the introduction of the lyophilizate must dissolve.

For the preparation of injection solution to content bottle (1 g) add 3.2 ml 1% or 2% lidocaine hydrochloride solution for injection (without epinephrine), then a bottle should shake well to dissolve the contents. Immediately should select the volume, equivalent 15 mg / kg body weight (but not more 1 g / day) and enter it deep in a major muscle (eg, in the buttock muscles or in the lateral thigh muscles). Solution for i / m administration must be used within 1 no.

Reconstituted solution for a/m injection should not be used for/in iifuzij.

Parenteral drugs should be carefully inspected before use to detect particulate matter or change coloring. Color solutions varies from colorless to pale yellow (color changes within these limits does not affect the activity of the drug).

Side effect

Adult

Most adverse events, reported during clinical trials, for severity described as mild or moderate. In connection with undesirable phenomena, that presumably could be associated with drug, jertapenem terminated at 1.3% patients.

The most frequent adverse events, associated with parenteral introduction preparation, included diarrhea (4.3%), local complications after in/introductions (3.9%), nausea (2.9%) and headache (2.1%).

In injecting a jertapenema reported adverse events listed below, associated with drug, and using the following criteria to assess the incidence of adverse events: often (<10%, but >1%); rarely (<1%, but >0.1%).

Local reactions: often – postinfuzionnye phlebitis/thrombophlebitis.

CNS: often – headache; rarely – dizziness, drowsiness, insomnia (0.2%), convulsions, confusion.

From the digestive system: often – diarrhea, nausea, vomiting; rarely – candidiasis of the oral mucosa, constipation, regurgitation content, psevdomembranoznыy colitis (often manifested by diarrhea), caused by uncontrolled reproduction Slostridium difficile, dry mouth, dyspepsia, anorexia.

Cardio-vascular system: rarely – decrease in blood pressure.

The respiratory system: rarely – dyspnoea.

Dermatological reactions: rarely – эritema, itch.

By genitalia: vaginal itching.

From the body as a whole: rarely – abdominal pain, dysgeusia, weakness / fatigue, candidiasis, puffiness, fever, chest pain.

From the laboratory parameters: often – ALT increase, ACT, Alkaline phosphatase, the increase in the number of platelets; rarely – improvement direct, indirect and total bilirubin, increase in the number of eosinophils and monocytes, improved partial thromboplastin time, creatinine and blood glucose, the decrease in the number of neutrophils and leukocytes segmentojadernyh, decrease in hematocrit, hemoglobin and platelet count; bacteriuria, increased levels of serum urea nitrogen, the number of epithelial cells in urine, the number of red blood cells in the urine.

In most clinical studies parenteral therapy preceded the transition to the corresponding oral antimicrobial medication. For the whole period of treatment and within 14 days of follow-up adverse events, associated with the use of Invanza^®, included: often – rash, vaginitis (>1%); rarely – allergic reactions, general malaise, fungal infections (0.1% to 1.0%).

Children

The most frequent adverse events, associated with the use of jertapenema when it is injecting, included diarrhea (5.5%), pain at the injection site (5.5%), redness at the injection site (2.6 %).

When injecting treatment of children jertapenemom the following adverse events were reported, associated with drug:

From the digestive system: rarely – diarrhea, vomiting.

Dermatological reactions: rarely – rash.

Local reactions: rarely – эritema, pain at the injection site, phlebitis, local postingyektinaya reaction.

From the laboratory parameters: often – neutropenia; rarely – ALT increase, ACT, leukopenia, eozinofilija.

Rarely reported on the serious and fatal anaphylactic reactions in patients, treated with beta-lactam antibiotics. These reactions are more likely to occur in individuals, with a history of allergy polyvalent (in particular, in patients with hypersensitivity to penicillin, often develop severe hypersensitivity reactions when treating other beta-lactam). Before starting treatment with Invanz^® You should carefully question the patient about previous hypersensitivity reactions to other allergens, especially, of penitsillinы, cephalosporins other beta-lactams.

If you experience an allergic reaction to a drug Invanz^® it should be lifted immediately. Serious anaphylactic reactions require emergency treatment.

Contraindications

— installed hypersensitivity to the drug or to other antibiotics in the same group;

- Hypersensitivity to other beta-lactam antibiotics.

When used as a solvent of lidocaine hydrochloride in the/m introduction the drug is contraindicated in patients with hypersensitivity to installed amide local anesthetic action, patients with severe arterial gipotenziei or intracardiac conduction.

Pregnancy and lactation

Adequate clinical experience of applying Invanza^® during pregnancy is not. Use of the drug is possible only in cases, the projected benefits of therapy to the mother justifies the potential risk to the fetus.

Be wary appoint drug in lactation (breast-feeding), tk. jertapenem out of breast milk.

Cautions

Prolonged use of Invanza^®, as well as other antibiotics, can lead to excessive growth of insensitive microorganisms. In developing superinfection should adopt appropriate measures.

When applied to nearly all antibacterial drugs, including jertapenem, may develop psevdomembranoznogo colitis (the main reason of which is Toxin, produced by Clostridium difficile ). The severity of colitis can vary from slight to endangering life. Should take into account the possibility of developing such complications when an expressed diarrhoea in patients, treated with antibacterial therapy.

When the/m introduction should proceed with caution, to avoid inadvertent injection into a blood vessel.

In clinical trials the efficacy and safety of medication in the elderly (senior 65 years) were comparable with those in younger patients.

Use in Pediatrics

Use of the drug to children aged 3 Months not recommended.

Overdose

No specific information about the drug overdose no. In clinical trials the drug in a dose of random to 3 g / day did not lead to clinically significant adverse events. In clinical studies in children single in/with the introduction of the drug in the dose of 40 mg/kg up to 2 g maximum did not cause toxic reactions.

Treatment: drug should be lifted and to conduct general supportive therapy (to complete removal of jertapenema from the body). The drug can be removed from the body by hemodialysis, but information about the application of hemodialysis for treatment of an overdose is not available.

Drug Interactions

When you assign a jertapenema together with drugs, block tubular secretion, correction dosing regime is not required.

Jertapenem does not affect the metabolism of drugs, main izofermentami mediated cytochrome p 450 – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Interaction with Drug, due to inhibition of tubular secretion, violation of r-binding glycoproteins or change intensity mikrosomalnogo oxidation it is unlikely.

No special clinical studies on interaction of jertapenema with specific drugs, Besides probenecida, not performed.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

Unopened vials should be stored out of the reach of children at a temperature of no higher than 25° c. Shelf life-2.

Reconstituted solution for infusions, immediately diluted with 0.9% sodium chloride solution, can be stored at room temperature (above 25 ° C) and use within 6 h or stored for 24 h in the refrigerator (5° C) and use within 4 h after removal from the refrigerator. Solutions of the drug cannot be freeze.

Cooked solution for a/m injection can store no more than 1 no.