DORIPREKS

Active material: Doripenem
When ATH: J01DH
CCF: Antibiotic group of carbapenems
ICD-10 codes (testimony): J15, K65.0, N10, N11
When CSF: 06.04
Manufacturer: JANSSEN PHARMACEUTICA N.V. (Belgium)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Powder for solution for infusion from white to almost white or slightly yellowish, crystalline; When adding the drug to 10 ml water d/and the homogeneous suspension of white or almost white, freely passing into the syringe via a needle # 0840.

Bottles of colorless glass volume 20 ml (1) – packs cardboard.
Bottles of colorless glass volume 20 ml (10) – packs cardboard.

Pharmacological action

Synthetic carbapenem antibiotic from the group of broad-spectrum, similar in structure to other beta-lactam antibiotics. Doripenem in vitro active against aerobic and anaerobic grampolaugitionah gramotricationah and bacteria. Compared to imipenemom and meropenemom it in 2-4 times more active against Pseudomonas aeruginosa.

Doripenem has a bactericidal effect by disrupting bacterial cell wall biosynthesis. It inactivates many important penicillin-binding proteins (PSB), which leads to disruption of the synthesis of the bacterial cell wall and subsequent death of the bacterial cell. Doripenem has the greatest affinity with respect to PSB Staphylococcus aureus. The cells of Escherichia coli and Pseudomonas aeruginosa doripenem binds strongly to DPM, which is involved in maintaining the shape of a bacterial cell.

Experiments in vitro have shown, doripenem that reduces the activity of other antibiotics slightly, Other antibiotics do not reduce the activity of doripenem. Described additive activity or weak synergy with amikacin and levofloxacin against Pseudomonas aeruginosa, as well as with daptomycin, linezolid, levofloxacin and vancomycin against Gram-positive bacteria.

Mechanisms of resistance bacteria to the doripenemu include drug inactivation or mutated acquired (PSB) enzymes, gidrolizujushhimi carbapenem, reduced permeability of outer membrane and active release doripenema of bacterial cells. Doripenem is resistant to hydrolysis by most beta-laktamaz, including penicillinazy and cefalosporinazy, which produce a gram and Gram negative bacteria; the exceptions are relatively rare beta-lactamaza, able to hydrolyze doripenem.

The prevalence of acquired resistance of certain species may vary in different geographical regions and at different times, It is therefore very important to the availability of information on the structure of local resistance, especially when treating severe infections. In cases of need should seek advice of microbiologists, If the structure of the local resistance is, that the appropriateness of a particular drug is questionable.

Preparation active against aerobic Gram-positive bacteria: Enterococcus avium, Enterococcus faecalis, Staphylococcus aureus (strains, sensitive to Methicillin), Staphylococcus epidermidis (strains, sensitive to Methicillin), Staphylococcus haemolyticus (strains, sensitive to Methicillin), Streptococcus agalactiae (including strains, resistant to macrolides), Staphylococcus saprophyticus, Streptococcus intermedius, Streptococcus constellatus, Streptococcus pneumoniae (including strains, resistant to penicillin or infect), Streptococcus pyogenes, Streptococcus viridans (including strains, moderately sensitive and resistant to penicillin); Aerobic Gram-negative bacteria: Acinetobacter baumannii, Acinetobacter calcoaceticus, Aeromonas hydrophila, Citrobacter different, Citrobacter freundii (including strains, resistance to sirtazidimu), Enterobacter aerogenes, Enterobacter cloacae (including strains, resistance to sirtazidimu), Haemophilus influenzae (including strains, producing beta-lactamase, or resistant to ampicillin strains, that do not produce beta-lactamaza), Escherichia coli (including strains, resistant to levofloksacinu and strains, producyrute beta-lactamaza extended range), Klebsiella 2 * (including strains, producing beta-lactamase), Klebsiella oxytoca, Morganella morganii, Proteus is wonderful (including strains, producing ESBL), Proteus vulgaris, Rettgeri Providence, Providence stuartii, Pseudomonas aeruginosa * (including strains, resistance to sirtazidimu), Salmonella spp., Serratia wilting (including strains, resistance to sirtazidimu), Shigella spp.; Anaerobic bacteria: Bacteroides fragilis, Bacteroides caccae, Bacteroides ovatus, Bacteroides uniform, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bilophora wadsworthia, Clostridium spp., Peptostreptococcus magnus, Peptostreptococcus micros, Porphyromonas spp., Prevotella spp., Wadsworthia Suterella.

C drug steady aerobic gram-positive bacteria: ctafilokokki, resistant to metitillino, Enterococcus faecium; Aerobic gram-negative bacteria: Stenotrophomonas maltophila; acquired resistance can have and Burkhold-ERIA cepacia.

*views, against whom doripenem was active in clinical research.

Pharmacokinetics

Distribution

C_max and AUC vary linearly in the range of doses from 500 mg 1 g/in infusions for 1 or 4 no. FAQ plasma concentration (mg / l) doripenem after a 1-hour and 4-hour in / infusion 500 mg and a 4-hour infusion 1 g are shown below in table.

Doripenema mean concentrations in the plasma after the introduction of the single dose:

In patients with normal renal function were found signs of accumulation of doripenem following multiple in / infusion 500 mg or 1 g every 8 h for 7 – 10 days.

The binding of doripenem to plasma proteins averages 8.1% and it does not depend on its concentration in blood plasma. V_d is approximately 16.8 l, which is close to the volume of extracellular fluid in humans (18.2 l). Doripenem penetrates well into the uterine tissue, prostate, gall bladder and urine, and retroperitoneal fluid, reaching concentrations there, exceeding the MIC.

Metabolism

Active substance biotransformed microbiologically inactive metabolite preferably under the action of dehydropeptidase-I.

In vitro metabolism of doripenem observed under the action of CYP450 isozymes and other enzymes, in the presence, and in the absence of NADP.

Deduction

Doripenem is derived mainly kidneys unchanged. Healthy young adult target T_1/2 doripenema is about 1 no, and clearance from plasma is approximately 15.9 l /. The average renal clearance of 10.3 l /. The value of this indicator, along with the significant reduction in off doripenema when it simultaneously with Probenecid introduction suggests, that doripenem undergoes both glomerular filtration, and renal secretion. In healthy young adults after a single dose in the dose of doripenem 500 mg 71% dose was found in the urine as unchanged and doripenem 15% – a ring-opened metabolite, respectively. After the introduction of healthy young adults a single dose (500 mg) radiolabeled doripenem was found in the feces less 1% total activity.

Pharmacokinetics in special clinical situations

After the introduction of a dose of doripenem 500 mg dose to patients with impaired renal function increases AUC compared with AUC in healthy subjects with normal renal function (QC ≥80 ml / min):

Doripenem dose should be reduced in patients with moderate and severe renal impairment.

There is currently no data on the pharmacokinetics of doripenem in patients with impaired hepatic function. Doripenem hardly metabolized in liver, so it is assumed, liver disease that do not affect its pharmacokinetics.

Compared to young adults, elderly patients doripenem AUC was increased by 49%. This change is mainly due to age-related changes QC. In elderly patients with normal (for their age) renal function reduce the dose of doripenem not need.

Women doripenem AUC was on 13% better, than men. Men and women should enter the same dose of doripenem.

In the application of the drug among the various racial groups was no significant difference in the clearance of doripenem, therefore adjust the dose is not recommended.

Testimony

-Hospital (nosocomial) pneumonia, including pneumonia, associated with the IVL;

— acute intraabdominal infection;

-acute infection of urinary system, including complicated and uncomplicated pyelonephritis, incl. with concomitant bacteremia.

Dosage regimen

The drug is introduced into / in.

The recommended dosage and administration for doripenema Adult:

*for the treatment of patients with nosocomial pneumonia are recommended during infusion 1 no. If there is less risk of infection by susceptible microorganisms recommended infusion for 4 no.

**duration of therapy includes a possible transition to the corresponding oral therapy after, least, 3-x daily parenteral therapy, caused clinical improvement (the transition to oral therapy can be prescribed fluoroquinolones, broad-spectrum penicillins combined with clavulanic acid, as well as antibiotics any pharmacotherapeutic group).

¹ in patients with concomitant bakteriemiej duration of therapy can reach 14 days.

In patients with impaired renal function at CC >50 ml / min dose adjustment is required. In patients with moderate renal impairment (QC of ≥30 to ≤50 ml / min) preparation is administered in a dose of 250 mg every 8 no. In patients with severely impaired renal function (KK from >10 to <30 ml / min) preparation is administered in a dose of 250 mg every 12 no.

Doripenem is removed from the blood during dialysis; currently there is insufficient information to formulate recommendations for patients, dialysis.

In elderly patients, Kidney function that corresponds to their age, dose adjustment is required.

In Patients with liver failure no need for dose adjustment.

Terms of preparation and administration of the solution

For solution for the infusions, contains 500 mg doripenema, doripenema powder dissolved in 10 ml sterile water d/and or 0.9% sodium chloride (saline solution). Visually check the suspension for the presence of mechanical impurities (This ready-made suspension is not used for direct introduction). Prepared suspension using syringe injection and added to the infusion package, comprising 100 ml of physiological solution, or 5 % glucose solution, and gently mix to dissolve.

For solution for the infusions, contains 250 mg doripenema, to patients with moderate or severe violations of the kidneys, doripenema powder dissolved in 10 ml sterile water d/and or 0.9% sodium chloride (saline solution). Visually check the suspension for the presence of mechanical impurities (This ready-made suspension is not used for direct introduction). Prepared suspension is added to the infusion package syringe injection, comprising 100 ml of physiological solution, or 5% glucose solution, and gently mix to dissolve. Select 55 ml of infusion Pack and throw (in the remaining solution containing 250 mg doripenema).

Infusion solutions drug Doripreks^® vary from transparent and colorless to transparent and slightly yellowish solution. Possible differences in chroma solution does not affect the quality of the product. Infusion solution before the introduction of visually check the absence of inclusions and when it detects the latest cull.

Side effect

The most common adverse effects were headache (10%), diarrhea (9%) and nausea (8%).

Determining the frequency of adverse effects: Often (≥1/10); often (≥1/100, <1/10); sometimes (≥1/1000, <1/100); rarely (≥1/10 000, <1/1000); rarely (≥1/100 000, <1/10 000).

CNS: Often – headache.

Cardio-vascular system: often – phlebitis.

From the digestive system: often – nausea, diarrhea, increase in liver enzymes; sometimes – colitis, вызванный Clostridium difficile.

Dermatological reactions: often – itch, rash.

Allergic reactions: sometimes – anaphylactic shock.

Other: often – oral candidiasis, Mycosis of the vulva.

During the period of postregistracionnogo application

From the circulatory and lymphatic system: rarely – neutropenia. It is impossible to establish the relative frequency of neutropenia, caused by doripenemom due to the fact, the doctors when reporting this side effect does not indicate the number of patients, from whom he saw.

Contraindications

- Up to 18 years;

- Hypersensitivity to the drug;

-hypersensitivity to other drugs groups carbapenemov, as well as beta-lactam antibiotics.

Pregnancy and lactation

Data, doripenema relating to the use of a small number of pregnant women, indicates, that the drug has no negative impact on pregnancy, as well as the health of the fetus and newborn. There is a need for caution in treating drug Doripreks^® pregnant women.

If necessary, the use of the drug Doripreks^® lactation must stop breastfeeding.

Cautions

Patients, receiving beta-lactam antibiotics, can lead to considerable, sometimes with fatal consequences, hypersensitivity reactions (anaphylactic reactions). Before treatment the patient must ask in detail doripenemom about how to, whether it formerly hypersensitivity reactions to other or carbapenem beta-lactam antibiotics. In case of hypersensitivity reactions to it immediately doripenem cancel and therapy. Serious hypersensitivity reactions (anaphylactic shock) require urgent therapy, includes introduction of the SCS and Pressor amines (adrenaline), as well as carrying out other measures, include oksigenoterapiju, in / in a liquid, as well as, if necessary, – introduction of antihistamines and maintain airway patency.

Psevdomembranoznыy colitis, called Clostridium difficile, may occur in the treatment of nearly all antibacterial drugs and vary from slight to threatening life. It is therefore necessary to be aware of this deterioration, If the patient has, receiving doripenem, diarrhea occurs.

Avoid prolonged use of doripenema to prevent excessive breeding of resistant microorganisms to it.

Before applying the product, it is recommended to conduct bacteriological study. You must select the appropriate samples to conduct bacteriological researches with the purpose of allocation of pathogens, identify them and determine their sensitivity to doripenemu. In the absence of such data, the empirical choice of drugs should be based on local epidemiological data and local structure sensitivity of microorganisms.

Effects on ability to drive vehicles and management mechanisms

Study on evaluation of influence of doripenema on these functions have not been conducted. Expected, that doripenem, probably, does not affect the ability to drive a car and working with machinery.

Overdose

Doripenema overdose not described . In the case of an overdose of the drug should be discontinued and symptomatic therapy to complete removal of kidney doripenema. You should monitor the patient's clinical condition.

Doripenem is removed from the body using hemodialysis, at present, however, does not describe any cases of application of hemodialysis in an overdose doripenema.

Drug Interactions

Probenetsid competes with doripenem for renal tubular secretion and reduces the renal clearance of doripenem. Probenecid increases the AUC of doripenem in the 75% and T_1/2 plasma – on 53%. Therefore, it is not recommended to use both probenetsid and Doripeks^®.

Doripenem does not inhibit the major cytochrome P450 isoenzymes, and therefore, probably, It does not interact with drugs, are metabolized by this enzyme system. According to the results of in vitro studies, doripenem is not capable of inducing enzyme activity.

In healthy volunteers doripenem reduces the concentration of valproic acid until subtherapeutic plasma levels (значение AUC уменьшалось на 63%), it is also consistent with the results, obtained for other carbapenems. The pharmacokinetics of doripenem are not changed. With simultaneous use of doripenem and valproic acid concentrations should be monitored and the latter to consider the possibility of appointing another treatment.

Pharmaceutically compatible

The drug should not be mixed with other drugs, except sterile water d / and, 0.9% sodium chloride solution for injection (saline solution) or 5% glucose solution.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored in its original packaging away from children, the dark place at a temperature between 15° to 30° c. Shelf life – 2 year.

The conditions of storage solution: After adding the powder doripenema sterile water d/and or 0.9% sodium chloride solution for injection (saline solution) the suspension can be stored in a bottle for 1 hours before her breeding infusion solution.

*After removal from the refrigerator recovery solution must be administered to the patient during the storage time allowed at room temperature. While the total storage time of solution in the fridge, time warming the solution to room temperature, and the time of the introduction of the solution, the patient should not exceed a total of allowable storage time in the refrigerator.