Doripenem, powder 500 mg

Pharmacotherapeutic group:

Antibiotic – carbapenem

CodeATH: J01DH04

Pharmacological properties

Pharmacodynamics

Doripenem is a synthetic carbapenem antibiotic of broad spectrum action, structurally similar to other beta-lactam antibiotics. Doripenem has pronounced in vitro activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria. Compared with imipenem and meropenem it is 2-4 times more active against Pseudomonas aeruginosa.

The mechanism of action

Doripenem has a bactericidal effect by disrupting the biosynthesis of the bacterial cell wall. It inactivates many important penicillin-binding proteins (PBPs), and this leads to disruption of bacterial cell wall synthesis and subsequent bacterial cell death. Doripenem has the greatest affinity against Staphylococcus aureus PBP.

In Escherichia coli and Pseudomonas aeruginosa cells, doripenem binds firmly to BPS, which are involved in maintaining the shape of the bacterial cell. In vitro experiments have shown that doripenem weakly inhibits the action of other antibiotics, and its action is also not inhibited by other antibiotics.

Additive activity or weak synergism with amikacin and levofloxacin against Pseudomonas aeruginosa and with daptomycin, linezolid, levofloxacin and vancomycin against gram-positive bacteria has been described.

Resistance mechanisms

The mechanisms of bacterial resistance to doripenem include its inactivation by carbapenem hydrolyzing enzymes as well as by mutant or acquired PSBs, reduction of outer membrane permeability and active release of doripenem from bacterial cells. Doripenem is resistant to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria; the exception is a relatively rare beta-lactamase capable of hydrolyzing Doripenem.

The prevalence of acquired resistance of individual species may vary in different geographic regions and at different times, and therefore information on local resistance patterns is very useful, especially when treating severe infections. If necessary, advice should be sought from microbiologists if the local resistance patterns are such that the use of a particular drug, at least for certain types of infection, is questionable.

Doripenem susceptible species

Gram-positive: Enterococcus faecalis, Staphylococcus aureus (methicillin-sensitive strains). Staphylococcus epidermidis (strains sensitive to methicillin), Staphylococcus haemolyticus (strains sensitive to methicillin). Streptococcus agalactiae (including macrolide-resistant strains4), Staphylococcus saprophytics, Streptococcus intermedius, Streptococcus conste/latus, Streptococcus pneumoniae (including strains resistant to penicillin or ceftriaxone), Streptococcus pyogenes; Streptococcus viridans (including moderately sensitive and penicillin-resistant strains).

Gram-negative aerobes: Citrobacter diversus, Citrobacter freundii (including strains insensitive to ceftazidime), Enterobacter aerogenes, Entero-bacter cloacae (including strains insensitive to ceftazidime), Haemophilus influenzae (including beta-lactamase-producing strains or ampicillin-resistant strains that do not produce beta-lactamases), Escherichia coli, including strains, resistant to levofloxacin and extended spectrum beta-lactamase (ESBL)-producing strains, Klebsiella pneumoniae (including ESBL-producing strains), Klebsiella oxytoca, Morganella morganii, Proteus mirabilis (including ESBL-producing strains), Proteus vulgaris, Providencia rettgeri, Providencia stuartii Pseudomonas aeruginosa (including ceftazidime-resistant strains), Salmonella spp., Serratia marcescens (including strains insensitive to ceftazidime), species of the genus Shigella. Anaerobes: Bacteroides fragilis, Bacteroides caccae, Bacteroides ovatus, Bacteroides uniformis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bilophila wadsworthia, species of Clostridium genus, Peptostreptococcus magnus, Peptostreptococcus micros, species of Porphyromonas genus, Prevotella species, Sutterella wadsworthenis.

Resistant microorganisms

Gram-positive aerobes: Staphylococcus aureus, resistant to methicillin; Enterococcus faecium.

Gram-negative aerobes: Stenotrophomonas maltophiNA, Legionella spp.

Acquired resistance can have: Burkholderia cepacia, Acinetobacter baumannii Acinetobacter spp., Pseudomonas aeruginosa.

Pharmacokinetics

The pharmacokinetics of doripenem (Cmax, maximum plasma concentration, and AUC, area under the concentration-time curve) are linear over the 500 mg-1 g dose range when infused intravenously for 1 or 4 h. Patients with normal renal function showed no evidence of doripenem cumulation after multiple intravenous infusions of 500 mg or 1 g every 8 h for 7-10 days.

The pharmacokinetics of doripenem are linear over a dose range of 500 mg to 2 g when administered as an intravenous infusion of 1 h and 500 mg to 1 g when administered as an intravenous infusion of 4 h. The pharmacokinetic characteristics of Doripenem when administered once [after a 4-hour infusion] in adults with cystic fibrosis are consistent with those of adults without cystic fibrosis. There have been no adequately controlled studies of the safety and efficacy of Doripenem in patients with cystic fibrosis.

Distribution: The average degree of binding of Doripenem to plasma proteins was 8.1% and was independent of its plasma concentration. The volume of distribution is approximately 16.8 liters, which is close to the volume of extracellular fluid in humans (18.2 liters). Doripenem penetrates well into a number of tissues and body fluids, such as uterine tissue, retroperitoneal fluid, prostate tissue, gallbladder tissue and urine, reaching concentrations exceeding the MIC (minimum inhibitory concentration) there.

Metabolism: Doripenem biotransformation to microbiologically inactive metabolite occurs mainly under the action of dehydropeptidase-I. In vitro metabolism of Doripenem was observed under the action of CYP450 system isoenzymes and other enzymes, both in the presence and absence of nicotinamide adenine dinucleotide phosphate (NADPH).

Elimination: Doripenem is eliminated mainly by the kidneys unchanged. In healthy young adults, the average final plasma elimination half-life of doripenem is about 1 h, and plasma clearance is approximately 15.9 L/h. Average renal clearance is 10.3 l/h. The magnitude of this figure, along with a significant decrease in elimination of doripenem when administered simultaneously with probenecid, indicates that doripenem is subject to both glomerular filtration and renal secretion. In healthy young adults who received a single dose (500 mg) of doripenem, 71% of the dose was detected in the urine as unchanged doripenem and 1 5% as an open ring metabolite, respectively. After a single dose (500 mg) of radioactively labeled doripenem in young healthy adults, less than 1% total radioactivity was detected in the feces.

Patients with renal insufficiency: After administration of a single dose (500 mg) of doripenem to patients with mild (creatinine clearance 51-79 ml/min), moderate (creatinine clearance 31-50 ml/min), and severe (creatinine clearance <30 ml/min) renal impairment, AUC increased by 1.6 times, 2.8 times, and 5.1 times, respectively, compared with AUC in healthy subjects with normal renal function (creatinine clearance >80 ml/min). The dose of Doripenem should be reduced in patients with moderate to severe renal impairment.

Patients with hepatic impairment: There are currently no data on the pharmacokinetics of doripenem in patients with hepatic impairment. Doripenem undergoes little or no metabolism in the liver, and therefore it is assumed that impaired function of this organ should not affect its pharmacokinetics.

Elderly patients: Compared with young adults, the AUC of doripenem was increased by 49% in older adults. These changes are mainly due to age-related changes in creatinine clearance. In elderly patients with normal (for their age) renal function the dose of Doripenem does not need to be reduced.

Gender differences: In women the AUC of Doripenem was 13% higher than in men. It is recommended that men and women be given the same dose of doripenem.

Raciality: There was no significant difference in doripenem clearance among diverse racial groups when doripenem was used, so no dose adjustment is recommended.

Indications

Infectious inflammatory diseases caused by doripenem-sensitive microorganisms:

– Hospital-acquired (nosocomial) pneumonia, including ventilator-associated pneumonia;

– Complicated intra-abdominal infections;

– Complicated urinary tract infections, including complicated and uncomplicated pyelonephritis and cases with concomitant bacteremia.

Active ingredient

Composition

Per 1 vial:

Active substance:

Doripenem monohydrate – 521.4 mg (in Doripenem conversion) – 500 mg.

How to take, the dosage

Intravenously.

The table below shows the recommended route of administration and doses of Doripenem.

Infections

Dose

Infusion frequency

Infusion time (h)

Length of therapy**

Hospital-acquired(nosocomial)pneumonia. including ventilator-associated pneumonia

500 mg or 1000 mg

every 8h

1 or 4h*

7-14 days**

complicated

intra-abdominal

infections/p>

500 mg

every 8h

1

5-14 days**

Complicated urinary tract infections, including pyelonephritis/p>

500 mg

every 8h

1

10 days**§

* For the treatment of patients with nosocomial pneumonia, infusions of 500 mg for 1 hour are recommended. Infusions for 4 h are recommended if there is a risk of infection with less sensitive microorganisms.

For the treatment of patients with elevated creatinine clearance (CrO) > 150 mL/min) or (and) infections caused by Gram-negative non-fermenting bacteria (e.g., Pseudomonas spp. or Acinetobacter spp.), infusions of 1000 mg for 4 h are recommended.

To treat patients with moderate renal failure, infusions of 500 mg every 8 hours are recommended; to treat patients with severe renal failure, infusions of 500 mg every 12 hours are recommended.

** The duration of therapy includes possible transition to appropriate oral therapy after at least 3 days of parenteral therapy that caused clinical improvement (fluoroquinolones, broad-spectrum penicillins in combination with clavulanic acid, and antibiotics of any pharmacotherapeutic group can be administered when transitioning to oral therapy).

§ In patients with concomitant bacteremia the duration of therapy may be up to 14 days.

The usual duration of treatment in patients with nosocomial pneumonia, including ventilator-associated pneumonia, is 7 to 14 days and should depend on the severity of the disease, the location of the infection, and the patient’s clinical response to treatment (see “Special Instructions”).

Based on the results of clinical studies, health care professionals should consider establishing a treatment duration of more than 7 days for patients with ventilator-associated pneumonia.

Patients with impaired renal function

In patients with creatinine clearance >50 ml/min, no dose adjustment is required. In patients with moderate renal impairment (creatinine clearance from >30 to <50 ml/min) the dose of Doripenem should be 250 mg every 8 hours. In patients with severe renal insufficiency (creatinine clearance from >10 to <30 ml/min) the dose should be 250 mg every 12 hours.

For patients with a recommended dose of 1000 mg every 8 hours, as a 4-hour infusion, the dose should also be adjusted: for moderate renal failure, 500 mg every 8 hours; for severe renal failure, 500 mg every 12 hours.

Patients on dialysis

Dosing information for Doripenem in patients on long-term renal replacement therapy is shown in the table.

Long-term renal replacement therapy

Renal therapy

Estimated CrCI (ml/min)

Dose

Frequency of administration

Infusion time a,b

Achieving the target (minimum

inhibitory

concentration,

MIC)

Continuous

veno-venous

hemofiltration

<30 ml/min

250 mg

every 12 h

4 h

&lt 1 m kg/ml

continuous veno-venous hemodiafiltration

< 5 ml/min

250 mg

every 12 h

4 h

< 1 m kg/ml

Continuous veno-venous hemodiafiltration

5-30 ml/min

500 mg

every 12 h

< 1 µg/mL

a – In patients with acute renal failure and on long-term renal replacement therapy, the recommended infusion time is 4 h, given the possibility of increased extrarenal clearance of carbapenems in patients with acute renal failure.

b – In patients with chronic renal impairment and who are on long-term renal replacement therapy, a 1- or 4-hour infusion is possible.

According to the FK/FD, a 4-hour infusion may be preferable in order to maximize the percentage time during the dosing interval when the plasma concentration of doripenem exceeds the minimum inhibitory concentration (%T> MIC).

Dosing recommendations at MIC >1 mg/mL have not been established for long-term renal replacement therapy due to possible accumulation of doripenem and the metabolite doripenem-M-1. Careful safety monitoring is recommended for patients on long-term renal replacement therapy because of limited clinical data and possible increased systemic exposure to the metabolite doripenem-M-1.

There is currently insufficient information to formulate recommendations for patients on other types of dialysis.

Elderly patients

In elderly patients whose renal function is appropriate for their age, no dose adjustment is required.

Patients with impaired liver function

Dose adjustment is not required in these patients.

Instructions for solution preparation and handling

Preparing a 500 mg dose of solution for infusion:

– Doripenem powder is dissolved in 10 ml of sterile water for injection or 0.9% sodium chloride solution.

– Visually check the suspension for visible foreign particles (this ready-made suspension is not used for direct injection).

– Using a syringe and needle, the ready-made suspension is added to an infusion pack (bottle) containing 100 ml of 0.9% sodium chloride solution or 5% dextrose solution and gently stirred until completely dissolved.

Preparing a dose of 250 mg infusion solution for patients with moderate to severe renal failure:

– Doripenem powder is dissolved in 10 ml of sterile water for injection or 0.9% sodium chloride solution.

– Visually check the suspension for visible foreign particles (this ready-made suspension is not used for direct injection).

– Using a syringe and needle, the ready-made suspension is added to the infusion package (bottle) containing 100 ml of 0.9% sodium chloride solution or 5% dextrose solution, and the mixture is gently mixed until completely dissolved. Take 55 ml of the solution from the infusion package (bottle) and discard it (the remaining volume of solution contains 250 mg of doripenem).

Prepared solution storage conditions: After adding sterile water for injection or 0.9% sodium chloride solution to doripenem powder, the suspension can be stored in the bottle for 1 h before diluting it with infusion solution.

The following table shows the shelf life of Doripenem after dilution with 0.9% sodium chloride solution or 5% dextrose solution when stored at room temperature or in the refrigerator.

Storage of infusion solutions prepared with 0.9% sodium chloride solution or 5% dextrose solution:

Diluent

Stability time (h)

Room temperature

2-8 °C (refrigerator)

0.9% sodium chloride solution

12

72*

5% dextrose solution**

4

24*

* After removal from the refrigerator, the infusion solution must be administered to the patient within the allowable storage time at room temperature. The cumulative storage time in the refrigerator, the time to warm the solution to room temperature, and the time to administer the solution to the patient must not exceed the total allowable refrigerator storage time.

**5% dextrose solution should not be used for infusions longer than 1h.

The prepared solution should be used immediately to maintain microbiological purity. If it is necessary to store the solution, the person preparing or storing the solution is responsible for preserving microbiological purity.

Infusion

The infusion solutions of Doripenem vary from clear and colorless to clear and slightly yellowish solution. The possible differences in color of the solution do not affect the quality of the product.

The infusion solution is visually inspected for mechanical inclusions prior to administration and discarded if any are found. Unused Doripenem solution and other wastes must be disposed of in accordance with local regulations.

Interaction

Probenecid competes with doripenem for renal tubular secretion and reduces renal clearance of doripenem. Probenecid increases the AUC of Doripenem by 75% and the plasma elimination half-life by 53%. Therefore, it is not recommended to use probenecid and doripenem concomitantly.

Doripenem does not inhibit the main isoenzymes of the cytochrome P450 system, and therefore probably does not interact with drugs that are metabolized by these enzymes. Doripenem, judging by the results of in vitro studies, has no ability to induce enzyme activity.

In healthy volunteers, doripenem reduced plasma concentrations of valproic acid to subtherapeutic levels (AUC of valproic acid decreased rapidly by 63%), which is also consistent with results obtained for other carbapenems.

The pharmacokinetics of doripenem did not change. If doripenem and valproic acid or valproate seminatrium are taken concomitantly, concentrations of the latter should be monitored and other treatment should be considered.

The drug should not be mixed with other drugs and solutions, except for 0.9% sodium chloride solution, 5% dextrose solution and water for injection.

Special Instructions

Patients receiving beta-lactam antibiotics can have serious and sometimes fatal hypersensitivity reactions (anaphylactic reactions). Before starting treatment with Doripenem, patients should be carefully asked whether they have previously had hypersensitivity reactions to other carbapenems or to beta-lactam antibiotics.

If a hypersensitivity reaction has occurred to doripenem, it should be stopped immediately and treated appropriately.

Serious hypersensitivity reactions (anaphylactic shock) require emergency therapy, including glucocorticosteroid and pressor amine (epinephrine) administration, as well as other measures including oxygen therapy, IV fluids and, if necessary, antihistamines, and airway support.

Cases of seizures have been reported during therapy with caroapenems, including doripenem (see section “Side effects”). In clinical trials of Doripenem, seizures were more frequently observed in patients with underlying central nervous system disorders (e.g., stroke, history of seizures), impaired renal function and when using doses in excess of 500 mg.

Pseudomembranous colitis caused by Clostridium difficile may appear both with long-term use and 2-3 weeks after discontinuation of treatment; it is manifested with diarrhea, leukocytosis, fever, and abdominal pain (sometimes accompanied with excretion of blood and mucus in the feces).

In the occurrence of these phenomena in mild cases withdrawal of treatment and use of ion exchange resins (colestiramine, colestipol) is sufficient, in severe cases compensation of loss of fluid, electrolytes and protein, the prescription of oral vancomycin or metronidazole is indicated. Do not use drugs that inhibit intestinal peristalsis.

Long-term treatment with Doripenem should be avoided to prevent overgrowth of resistant microorganisms. Bacteriological testing is recommended before using the drug.

An appropriate sample should be taken for bacteriological examination in order to isolate the pathogens, identify them and determine their sensitivity to doripenem. In the absence of such data, empirical drug selection should be based on local epidemiological data and local microbial sensitivity patterns.

Long-term renal replacement therapy

The metabolite metabolite excretion of doripenem-M-1 in patients on long-term renal replacement therapy may be reduced to levels for which there are no in vivo safety data.

This metabolite has no microbiological activity, and other possible pharmacological effects are unknown. Therefore, close monitoring of side effects is recommended for patients on long-term renal replacement therapy.

In a clinical trial in patients with ventilator-associated pneumonia, a 7-day course of doripenem (1 g as a 4-hour infusion every 8 hours) showed no efficacy compared with a 10-day course of imipenem-cylastatin (1 g as a 1-hour infusion every 8 hours). The usual duration of treatment for patients with nosocomial pneumonia, including ventilator-associated pneumonia, is 7 to 14 days and should depend on the severity of the disease, the localization of the infection, and the patient’s clinical response to treatment.

Influence on driving and operating ability

There have been no studies of the effect of Doripenem on driving and other potentially dangerous activities requiring increased concentration and quick psychomotor reactions, but due to the safety profile of the drug and the presence of adverse effects on the nervous system, attention must be paid to the possible effect of the drug on the above functions.

Contraindications

Side effects

The frequency of adverse effects was classified as follows: very frequently >1/10; frequently >1/100-<1/10; infrequently >1/1000-<1/100; rarely >1/10,000-<1/1000; very rarely >1/100,000-<1/10,000. The following undesirable effects have been noted:

Nervous system effects:

very common: headache

frequency unknown: seizures

Cardiovascular system:

often: phlebitis

Gastrointestinal tract:

often: nausea, diarrhea;

infrequently: Pseudomembranous colitis

Skin and subcutaneous tissue: often: itching, rash

Allergic reactions:

infrequent: hypersensitivity reactions (anaphylactic reactions);

very rare: toxic epidermal necrolysis, Stevens-Johnson syndrome

Hepatobiliary system disorders:

often: increased activity of “liver” enzymes

Blood and lymphatic system disorders:

Infrequent: neutropenia, thrombocytopenia

Other:

often: oral mucosal candidiasis, vaginal candidiasis.

Overdose

Papulo-erythematous rash has been observed when doripenem is administered by intravenous drip in a dose of 2 g every 8 hours for 10 to 14 days. The papulo-erythematous rash resolved within 10 days after discontinuation of doripenem.

In case of overdose, doripenem should be discontinued and maintenance therapy should be carried out until it is completely eliminated from the body by the kidneys. Treatment of overdose consists of general supportive symptomatic therapy including monitoring of basic physiological parameters and observation of the clinical condition of the patient.

Doripenem is eliminated from the body with hemodialysis or long-term renal replacement therapy, but there is currently insufficient information on the use of hemodialysis or long-term renal replacement therapy for doripenem overdose.

Pregnancy use

Pregnancy

There are limited clinical data on the use of Doripenem in pregnant women. The potential risk to the fetus is unknown. In pregnancy, use only if the estimated benefit to the mother is greater than the potential risk to the fetus.

Lactation

Breastfeeding must be stopped if doripenem needs to be used during lactation.