Doripenem powder solution for infusion 500mg, 1pc

Composition

Active ingredient:  doripenem monohydrate – 521.4 mg (equivalent to doripenem-500.0 mg).

Pharmacological action

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

Mechanism of action

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

In Escherichia coli and Pseudomonas aeruginosa cells, doripenem binds strongly to PSBs, 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 also its action is not inhibited by other antibiotics.

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

Mechanisms of resistance

Mechanisms of bacterial resistance to doripenem include its inactivation by carbapenem hydrolyzing enzymes, as well as mutant or acquired PSBs, decreased permeability of the outer membrane, and active release of doripenem from bacterial cells.

Doripenem is resistant to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases, which are produced by gram-positive and gram-negative bacteria; the exception is relatively rare beta-lactamases that can hydrolyze doripenem.

The prevalence of acquired resistance of individual species can vary in different geographical regions and at different times, and therefore information on the structure of local resistance is very useful, especially in the treatment of severe infections.

If necessary, consult a microbiologist if the structure of local resistance is such that the use of a particular drug, at least in some types of infection, is questionable.

They are sensitive to doripenem:

Usually sensitive species

Gram-positive:  Enterococcus faecalis, Staphylococcus aureus (methicillin-sensitive strains). Staphylococcus epidermidis (methicillin-sensitive strains), Staphylococcus haemolyticus (methicillin-sensitive strains). Streptococcus agalactiae (including strains 4 resistant to macrolides), Staphylococcus saprophytics, Streptococcus intermedius, Streptococcus conste/latus, Streptococcus pneumoniae (including strains resistant to penicillin or ceftriaxone), Streptococcus pyogenes; Streptococcus viridans (including strains that are moderately sensitive and resistant to penicillin).

Gram-negative aerobes:  Citrobacter diversus, Citrobacter freundii (including ceftazidime-insensitive strains), Enterobacter aerogenes, Enterobacter cloacae (including ceftazidime-insensitive strains), Haemophilus influenzae (including beta-lactamase-producing or ampicillin-resistant strains that do not produce beta-lactamase). lactamases), Escherichia coli, including levofloxacin-resistant strains 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 ceftazidime-insensitive strains), species of the genus Shigella. Anaerobes:  Bacteroides fragilis, Bacteroides caccae, Bacteroides ovatus, Bacteroides uniformis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bilophila wadsworthia, Kinds of genus Clostridium, Peptostreptococcus magnus, Peptostreptococcus micros, Kinds of genus Porphyromonas, species of the genus Prevotella, Sutterella wadsworthenis.

Resistant microorganisms

Gram-positive aerobes: Methicillin-resistant staphylococci; Enterococcus faecium.

Gram-negative aerobes:  Stenotrophomonas maltophilia, Legionella spp.

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

Pharmacokinetics

Plasma concentrations of doripenem: The average plasma concentrations (mg/L) of doripenem after one 1-hour and 4-hour intravenous infusion of 500 mg and one 4-hour infusion of 1 g are shown in the table below.

Mean plasma concentrations of doripenem after single dose use

doripenem Pharmacokinetics (Cmax – the maximum plasma concentration and AUC – area under the curve “concentration-time”) is linear in the dose range of 500 mg-1 g intravenous infusion for 1 or 4 h. Patients with normal renal function showed no signs of doripenem accumulation after repeated intravenous infusions of 500 mg or 1 g every 8 hours for 7-10 days.

Doripenem pharmacokinetics is linear in the dose range of 500 mg to 2 g when administered in an intravenous infusion duration of 1 h and 500 mg – 1 g intravenous infusion duration of 4 h.

the Pharmacokinetic characteristics doripenem after a single dose [after a 4-hour infusion] in adults with cystic fibrosis are the same for adults without cystic fibrosis. There have been no adequate, well-controlled studies on 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 did not depend on its concentration in blood plasma. 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 MIC (minimum inhibitory concentration).

Metabolism: Biotransformation of doripenem into a microbiologically inactive metabolite occurs mainly under the action of dehydropeptidase-I. In vitro metabolism of doripenem was observed under the action of CYP450 isoenzymes and other enzymes, both in the presence and in the absence of nicotinamide adenine dinucleotide phosphate (NADP).

Elimination: Doripenem is eliminated mainly by the kidneys in unchanged form. In healthy young adults, the average terminal plasma half-life of doripenem is approximately 1 hour, and the plasma clearance is approximately 15.9 l/h.The average renal clearance is 10.3 l/h.

The value of this indicator, along with a significant decrease in the elimination of doripenem when it is administered simultaneously with probenecid, indicates that doripenem undergoes both glomerular filtration and renal secretion.

In healthy young adults who received a single dose (500 mg) of doripenem,71% of the dose was found in the urine as unchanged doripenem and 1.5% as an open-ring metabolite, respectively. After use of a single dose (500 mg) of radiolabeled doripenem to young healthy adults, less than 1% of total radioactivity was detected in the stool.

Patients with renal insufficiency: After use 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 insufficiency, AUC increased 1.6-fold,2.8-fold, and 5.1-fold, respectively, compared to 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 insufficiency.

Patients with impaired liver function: Currently, there are no data on the pharmacokinetics of doripenem in patients with impaired liver function. Doripenem is practically not metabolized in the liver, and therefore it is assumed that impaired function of this organ should not affect its pharmacokinetics.

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

Gender differences: In women, the AUC of doripenem was 13% higher than in men. Men and women are advised to administer the same doses of doripenem.

Race: When using doripenem among various racial groups, there was no significant discrepancy in the clearance of doripenem, so it is not recommended to adjust the dose.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to doripenem:

• Nosocomial pneumonia, including pneumonia associated with mechanical ventilation (IVL).
• Complicated intra-abdominal infections.
• Complicated urinary tract infections, including complicated and uncomplicated pyelonephritis and cases with concomitant bacteremia.

Use during pregnancy and lactation

Pregnancy

There are limited clinical data on the use of doripenem in pregnant women. The potential risk to the fetus is unknown. During pregnancy, it is used only if the intended benefit to the mother exceeds the potential risk to the fetus.

Lactation

If it is necessary to use doripenem during lactation, it is necessary to stop breastfeeding.

Contraindications

• Hypersensitivity to doripenem or other carbapenems. and also to beta-lactam antibiotics.
• Children under 18 years of age.

Adverse effects

the adverse effects were classified as follows: very common >1/10; often >1/100-<1/10; uncommon > 1/1000 – <1/100; rare >1/10 000-<1/1000; very rare > 1/100 000 -<1/10 000. Was marked with the following undesirable effects:

Nervous system disorders:

very common: headache

frequency unknown: seizures

From the cardiovascular system:

common: phlebitis

From the gastrointestinal tract:

common: nausea, diarrhea;

uncommon: pseudomembranous colitis

Skin and subcutaneous tissue disorders: common: itching, rash

Allergic reactions:

infrequently: hypersensitivity reactions (anaphylactic reactions);

very rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome

From the side of the hepatobiliary system:

often: increased activity of “liver” enzymes

From the circulatory and lymphatic system:

Infrequently – neutropenia, thrombocytopenia

Other services:

common: candidiasis of the oral mucosa, vaginal candidiasis.

Interaction

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

Doripenem does not inhibit the main cytochrome P450 isoenzymes, and therefore, most likely, does not interact with drugs that are metabolized by these enzymes. Doripenem, according to the results of in vitro studies, does not have the ability to induce the activity of enzymes.

In healthy volunteers, doripenem reduced the plasma valproic acid concentration to a sub-therapeutic value (valproic acid AUC rapidly decreased by 63%), which is also consistent with the results obtained for other carbapenems.

The pharmacokinetics of doripenem did not change. When taking doripenem and valproic acid or seminodium valproate at the same time, the concentration of the latter should be monitored and the possibility of prescribing other treatment should be considered.

The drug should not be mixed with other medicines and solutions, with the exception of 0.9% sodium chloride solution,5% dextrose solution and water for injection.

How to take, course of use and dosage

Intravenously.

The table below shows the recommended dosage and use of Doripenem.

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

For the treatment of patients with elevated creatinine clearance (CrO) > 150 ml / min) or (and) infections caused by gram-negative non-fermentable bacteria (eg. Pseudomonas spp. or Acinetobacter spp. ) infusions with a dosage of 1000 mg for 4 hours are recommended.

For patients with moderate renal insufficiency is recommended infusion at a dosage of 500 mg every 8 h, for the treatment of patients with severe renal failure are recommended infusion at a dosage of 500 mg every 12 h

** Duration of therapy includes a transition to an appropriate oral therapy, after at least a 3-day parenteral therapy, caused clinical improvement (during the transition to oral therapy, you can assign fluoroquinolones, penicillins a wide spectrum of action in combination with clavulanic acid, and antibiotics any pharmacotherapeutic group).

§ In patients with concomitant bacteremia, the duration of therapy can reach 14 days.

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

Based on the results of clinical trials, healthcare professionals should consider setting the duration of treatment for patients with ventilator-associated pneumonia for more than 7 days.

Patients with impaired renal function

No dose adjustment is required in patients with creatinine clearance >50 ml / min. In patients with moderate renal insufficiency (creatinine clearance of >30 and <50 ml/min) dose 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 h

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

Patients undergoing dialysis

Information on the dosage of Doripenem in patients undergoing long-term renal replacement therapy is given in the table.

a-In patients with acute renal failure and on long-term renal replacement therapy, the recommended infusion time is 4 hours, taking into account the possibility of increasing the 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 FC/FD data, 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).

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

Currently, there is insufficient information to formulate recommendations for patients undergoing other types of dialysis.

Elderly patients

No dose adjustment is required in elderly patients with age-appropriate renal function.

Patients with impaired liver function

No dose adjustment is required in these patients.

Instructions for preparing and handling the solution

Preparation of a 500 mg infusion solution:

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

* Visually check the suspension for the presence of visible foreign particles (this finished suspension is not used for direct use).

* The finished suspension is added using a syringe and needle to an infusion bag (bottle) containing 100 ml of 0.9% sodium chloride solution or 5% dextrose solution, and gently mixed until completely dissolved.

Preparation of a 250 mg infusion solution for patients with moderate to severe renal insufficiency:

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

* Visually check the suspension for the presence of visible foreign particles (this finished suspension is not used for direct use).

* The finished suspension is added using a syringe and needle to an infusion bag (bottle) containing 100 ml of 0.9% sodium chloride solution or 5% dextrose solution, and gently mixed until completely dissolved. 55 ml of the solution is taken from the infusion bag (bottle) and discarded (the remaining volume of the solution contains 250 mg of doripenem).

Storage conditions of the finished solution: After adding sterile water for injection or 0.9% sodium chloride solution to doripenem powder, the suspension can be stored in a vial for 1 hour before diluting it with an infusion solution.

The table below shows the shelf life of doripenem after dilution with 0.9% sodium chloride solution or 5% dextrose solution under storage conditions at room temperature or in the refrigerator.

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

* After being removed from the refrigerator, the infusion solution should be administered to the patient within the permitted storage time at room temperature. At the same time, the total time of storage of the solution in the refrigerator, the time of warming the solution to room temperature and the time of use of the solution to the patient should not exceed the total permissible storage time in the refrigerator.

* * 5% dextrose solution should not be used for infusions lasting more than 1 hour.

To preserve the microbiological purity of the prepared solution, it should be used immediately. If it is necessary to store the solution, it is the responsibility of the person preparing or storing the solution to preserve the microbiological information.

Infusion

Infusion solutions of Doripenem range from clear and colorless to clear and slightly yellowish solutions. Possible differences in the color of the solution do not affect the quality of the product.

Before use, the infusion solution is visually checked for the absence of mechanical inclusions, and if the latter are detected, it is rejected. Unused doripenem solution and other waste must be disposed of in accordance with local regulations.

Overdose

There were cases of papulo-erythematous rash when doripenem was administered intravenously at a dose of 2 g every 8 hours for 10-14 days. Papulo-erythematous rash resolved within 10 days after discontinuation of doripenem.

In case of overdose, the use of 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 the main physiological parameters and monitoring the patient’s clinical condition.

Doripenem is removed from the body by hemodialysis or long-term renal replacement therapy, however, there is currently insufficient information about the use of hemodialysis or long-term renal replacement therapy for overdose of doripenem.

Special instructions

Patients receiving beta-lactam antibiotics may experience severe and sometimes fatal hypersensitivity reactions (anaphylactic reactions). Before starting treatment with doripenem, the patient should be carefully asked if they have previously experienced hypersensitivity reactions to other carbapenems or to beta-lactam antibiotics.

If a hypersensitivity reaction to doripenem occurs, it should be immediately discontinued and appropriate treatment should be carried out.

Serious hypersensitivity reactions (anaphylactic shock) require emergency therapy, including use of glucocorticoids and pressor amines (epinephrine), as well as other measures, including oxygen therapy, intravenous fluids, as well as, if necessary, antihistamines, and maintenance of airway patency.

Seizures have been reported during treatment 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 diseases (e. g., stroke, a history of seizures), impaired renal function, and when using doses greater than 500 mg.

Pseudomembranous colitis caused by Clostridium difficile can worsen both with prolonged use and 2-3 weeks after discontinuation of treatment; it is manifested by diarrhea, leukocytosis, fever, abdominal pain (sometimes accompanied by the release of blood and mucus with feces).

If these phenomena occur in mild cases, it is sufficient to cancel treatment and use ion exchange resins (colestyramine, colestipol), in severe cases, compensation for the loss of fluid, electrolytes and protein, the appointment of vancomycin inside or metronidazole is indicated. Do not use medications that inhibit intestinal motility.

Long-term treatment with doripenem should be avoided to prevent excessive proliferation of resistant microorganisms. Before using the drug, it is recommended to conduct a bacteriological study.

Appropriate samples should be selected for bacteriological testing to isolate 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 escposition of the doripenem-M-1 metabolite in patients undergoing long-term renal replacement therapy may be reduced to a level for which there are no data on the safety of the drug in vivo.

This metabolite does not show microbiological activity, and other possible pharmacological effects are unknown. Therefore, careful monitoring of side effects is recommended for patients undergoing long-term renal replacement therapy.

According to a clinical study in patients with pneumonia associated with artificial ventilation, a 7-day course of doripenem (1 g in the form of 4-hour infusions every 8 hours) It did not show efficacy compared to 10-day courses of imipenem-cilastatin (1 g in 1-hour infusions every 8 hours). The usual duration of treatment for patients with nosocomial pneumonia, including ventilator-related pneumonia, is 7 to 14 days, and should depend on the severity of the disease, the location of infection, and the patient’s clinical response to treatment.

Influence on the ability to drive vehicles and mechanisms

Studies on the effect of doripenem on the ability to drive vehicles and engage in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions have not been conducted, but given the safety profile of the drug and the presence of side effects from the nervous system, attention should be paid to the possible effect of the drug on the above functions.

Storage conditions

In a dark place at a temperature not exceeding 25 °C. Keep out of reach of children.

Shelf

life is 3 years.

Active ingredient

Doripenem

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution