Doripenem-Belpharm 500 mg

Trade name of the drug: Doripenem-Belpharm
Active ingredient (INN): Doripenem.
Dosage form: powder for the preparation of infusion solution 500 mg
Composition for 1 bottle:
Doripenem (as doripenem monohydrate) – 500 mg
Description: white to almost white powder

Pharmacotherapeutic group: Antibiotic of the carbapenem group
ATX code: J01DH04

Pharmacological properties
Pharmacodynamics
Doripenem is a synthetic antibiotic of the carbapenem group with a broad spectrum of activity, structurally similar to other beta-lactam antibiotics. Doripenem inhibits the synthesis of bacterial cell walls and has a bactericidal effect against anaerobic and aerobic gram-positive and gram-negative bacteria. Compared with imipenem and meropenem, doripenem is 2-4 times more active against Pseudomonas aeruginosa. The powerful bactericidal effect of the drug is explained by its resistance to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases, and the ability to inactivate many important penicillin-binding proteins (PBPs), which leads to disruption of cell wall synthesis and subsequent death of bacterial cells. Doripenem has the highest affinity against Staphylococcus aureus PSB. In Escherichia coli and Pseudomonas aeruginosa cells, doripenem binds tightly to PBPs, which are involved in maintaining the shape of the bacterial cell.
In vitro experiments have shown that the drug weakly inhibits the action of other antibiotics, and its action is not inhibited by other antibiotics.
Cases of weak synergism with amikacin and levofloxacin against Pseudomonas aeruginosa, as well as with daptomycin, linezolid, levofloxacin and vancomycin against gram-positive bacteria have been described.
Doripenem is active against gram-positive aerobic bacteria: Enterococcus faecalis, Staphylococcus saprophyticus, Staphylococcus aureus (only sensitive to methicillin), Staphylococcus epidermalis (sensitive to methicillin), Streptococcus intermedius, Streptococcus constellatus, Streptococcus agalactiae, Streptococcus pneumonia (including strains resistant to penicillin and ceftriaxone), Streptococcus pyogenes, Streptococcus viridians (including strains moderately sensitive and resistant to penicillin); Gram-negative aerobic bacteria: Citrobacter diversus, Citrobacter freundii (including strains that are not susceptible to ceftazidime), Haemophilus influenza (including strains that produce beta-lactamases or ampicillin-resistant strains that do not produce beta-lactamases), Escherichia coli (including strains that are resistant to to levofloxacin and strains producing extended-spectrum beta-lactamases), Enterobacter cloacae (including strains insensitive to ceftazidime), Enterobacter aerogenes, Klebsiella pneumonia, Klebsiella oxytoca, Morganella morganii, Proteus mirabilis (including strains producing extended-spectrum beta-lactamases), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Salmonella species, Shigella species, Serratia marcescens (including strains insensitive to ceftazidime); anaerobic bacteria: Bacteroides fragilis, Bacteroides caccae, Bacteroides uniformis, Bacteroides thetaiotaomicron, Bacteroides vulgates, Bacteroides ovatus, Bilophila wadsworthia, Peptostreptococcus magnus, Peptostreptococcus micros, species of the genus Prevotella, species of the genus Porphyromonas, Sutterella wadswo thenis.
Doripenem is resistant to methicillin-resistant staphylococci, Enterococcus faecium, Stenotrophomonas maltophila, Legionella spp. The following may have acquired resistance: Acinetobacter baumannii, Acinetobacter spp., Burkholderia cepacia, Pseudomonas aeruginosa (including strains resistant to ceftazidime).

Pharmacokinetics
Mean C_max and AUC0-∞ of doripenem in healthy volunteers in studies after administration of a dose of 500 mg over 1 hour were approximately 23 µg/ml and 36 µg×h/ml, respectively.
Mean C_max and AUC0-∞ values of doripenem in healthy volunteers in studies after administration of a dose of 500 mg and 1 g over 4 hours were approximately 8 μg/ml and 17 μg/ml.
and 34 μg×h/ml and 68 μg×h/ml. In patients with normal renal function, there was no evidence of accumulation of doripenem after repeated intravenous infusions of 500 mg or 1 g every 8 hours for 7-10 days.

Distribution
On average, the degree of binding of doripenem to plasma proteins is 8.1% and does not depend on its concentration in the blood plasma. The volume of distribution is approximately 16.8 L, which is close to the volume of extracellular fluid in humans (18.2 L). Doripenem penetrates well into a number of tissues and biological fluids, for example, into uterine tissue, retroperitoneal fluid, prostate tissue, gallbladder tissue and urine, reaching concentrations there that exceed the minimum inhibitory concentration (MIC).

Metabolism and excretion
The biotransformation of doripenem into a microbiologically inactive metabolite occurs predominantly under the action of dehydropeptidase-l. Doripenem is virtually free of CYP450-mediated metabolism and does not inhibit or induce the activity of CYP isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 or 3A4, as demonstrated by in vitro studies.
Doripenem is eliminated mainly unchanged by the kidneys. In healthy young adults, the mean terminal plasma half-life of doripenem was approximately 1 hour and plasma clearance was approximately 15.9 L/hour. Average renal clearance was 10.3 l/h. The magnitude of this indicator, along with a significant decrease in the elimination of doripenem when administered simultaneously with probenecid, indicates that doripenem undergoes both glomerular filtration and renal secretion. In healthy young adults receiving a single dose (500 mg) of doripenem, 71% of dose was found in urine as unchanged doripenem and 15% as the metabolite at 48 hours. Following administration of a single dose (500 mg) of radiolabeled doripenem to young healthy adults, less than 1% of total radioactivity was detected in the stool after one week. Pharmacokinetics of doripenem is linear when administered intravenously over 1 hour for doses from 500 mg to 2 g and when administered intravenously over 4 hours for doses from 500 mg to 1 g.


Patients with renal failure
After administration of one 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) degree of renal failure AUC increased by 1.6 times, 2.8 times and 5, respectively. 1 time compared to AUC in healthy people with normal renal function (creatinine clearance ≥ 80 ml/min). Therefore, the dose of doripenem should be reduced in patients with moderate to severe renal impairment.

Patients with liver dysfunction
There are currently 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 dysfunction of this organ should not affect the pharmacokinetics of the drug.

Elderly patients
Compared with younger adults, doripenem AUC increased by 49% in older adults. These changes are explained mainly by age-related changes in creatinine clearance. In elderly patients with normal renal function, there is no need to reduce the dose of doripenem.

Sex differences
The C_max and AUC of doripenem are similar in men and women. No dose adjustment is required depending on gender.

Indications for use
Complicated intra-abdominal infections; complicated urinary system infections; nosocomial pneumonia, including pneumonia associated with artificial ventilation (ALV).

Directions for use and dosage
Doripenem-Belpharm is used intravenously only! Dosage regimen and duration of therapy are determined depending on the type and severity of the infection, the sensitivity of the pathogenic microorganism and the patient's condition.

Table below shows the recommended doses of Doripenem-Belpharm for IV infusion depending on the type of infection.

* Dosage regimen may be used in patients with creatinine clearance ≥ 150 ml/min and in infections caused by non-fermentative gram-negative microorganisms (such as Pseudomonas spp. and Acinetobacter spp.). 4-hour infusions can be used
1 g every 8 hours. This dosage regimen is based on pharmacodynamics and pharmacokinetics data.
** A 4-hour infusion may be more appropriate for infections caused by less susceptible pathogens or for particularly severe infections.
Average duration of therapy is 5-14 days. In patients with nosocomial pneumonia, including ventilator-associated pneumonia, the duration of therapy is 10-14 days. The safety of longer-term use has not been established.

Dosing recommendations for Doripenem-Belpharm for patients with impaired renal function:

In patients with severe renal impairment, Doripenem-Belpharm should be administered with caution due to limited clinical data and the predicted longer circulation of doripenem and its metabolite in the body.
Dosing recommendations for Doripenem-Belpharm for patients on dialysis

¹ In patients with acute renal failure and on long-term renal replacement therapy, the recommended infusion time is 4 hours, and the possibility of increased extrarenal clearance of carbapenems must be taken into account.
² In patients with chronic renal impairment and those on long-term replacement therapy, a 1- or 4-hour infusion is possible. Based on studies, an infusion over 4 hours may be preferable to maximize the percentage of time during the dosing interval that doripenem plasma concentrations exceed the minimum inhibitory concentration (%T > MIC). Dosing recommendations for MICs > 1 mg/mL have not been established for long-term renal replacement therapy due to possible accumulation of doripenem and the doripenem metabolite-M-1. Close 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.
There is currently insufficient information to formulate recommendations for patients on other types of dialysis.
In patients with impaired liver function and elderly patients with normal renal function, no dose adjustment is required.

Rules for preparing and administering the solution
Doripenem-Belpharm should be administered intravenously as an infusion!
The drug does not contain preservatives, therefore, when preparing a solution for infusion, it is necessary to follow standard aseptic rules.
To prepare a solution for infusion, the contents of the Doripenem-Belpharm vial are dissolved in 10 ml of water for injection or 0.9% sodium chloride solution, shaken gently until a homogeneous suspension is formed.
Resulting suspension cannot be used for direct administration!
Resulting suspension is transferred using a syringe into an infusion container containing 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The resulting solution is thoroughly mixed until a clear liquid forms.
Preparation of drug solutions should be carried out immediately before administration. Unused solution must be disposed of in accordance with local regulations.
To avoid administering a dose less than the required one, the prepared suspension must be carefully removed from the vial! Doripenem-Belpharm suspension and infusion solution cannot be frozen!

Side effects
From the nervous system: very often: headache; uncommon: seizures.
From the cardiovascular system: often: phlebitis.
From the digestive system: often: nausea, diarrhea; uncommon: pseudomembranous colitis.
From the skin and subcutaneous tissue: often: itching, rash; frequency unknown: toxic epidermal necrolysis, Stevens-Johnson syndrome.
From the immune system: uncommon: hypersensitivity reactions; frequency unknown: anaphylactic reactions.
From the hepatobiliary system: often: increased activity of liver enzymes.
From the circulatory and lymphatic system: uncommon: neutropenia, thrombocytopenia; frequency unknown: leukopenia
From the respiratory system: frequency unknown: interstitial pneumonia.
Other: often: candidiasis of the oral mucosa, vaginal candidiasis.
If any adverse reactions occur, you should consult a doctor immediately.

Contraindications
Hypersensitivity to doripenem or other carbapenems; severe hypersensitivity reactions (eg. anaphylactic reactions, severe skin reactions) to other beta-lactam antibiotics. Children under 18 years of age.

Drug interactions
Doripenem reduces plasma concentrations of valproic acid to below therapeutic levels, leading to inadequate control of epileptic seizures. This is consistent with results obtained for other carbapenems. In such cases, alternative antibacterial or anticonvulsant treatment should be considered.
Probenecid competes with doripenem for renal tubular secretion and reduces the renal clearance of doripenem. Co-administration of probenecid and Doripenem-Belpharm is not recommended. Interaction with other drugs eliminated by renal tubular excretion is possible.

Special instructions
Use during pregnancy and breastfeeding
The clinical safety of doripenem during pregnancy has not been established. Therefore, Doripenem-Belpharm should not be used during pregnancy, unless the potential benefit from its use justifies the possible risk to the fetus. In each case, the drug must be used under the direct supervision of a physician.
If it is necessary to use the drug during lactation, breastfeeding should be stopped.

Children and adolescents
Doripenem-Belpharm should not be used in children or adolescents under 18 years of age due to insufficient data on its effectiveness and safety in children and adolescents.

Special instructions
In patients receiving beta-lactam antibiotics, incl. carbapenems, cases of serious anaphylactic reactions have been reported, and the risk of such reactions is higher in patients with a history of hypersensitivity reactions. If an allergic reaction occurs, it is necessary to discontinue the drug and prescribe symptomatic therapy. Serious hypersensitivity reactions (anaphylactic shock) require emergency treatment, including the administration of corticosteroids and pressor amines (epinephrine), as well as other measures such as oxygen therapy, intravenous fluids and, if necessary, antihistamines, and airway management. ways.
When selecting doripenem for the treatment of an individual patient, the appropriateness of using a carbapenem antibacterial should be considered based on the severity of the infection, the prevalence of resistance to other appropriate antibacterial drugs, and the risk of selecting treatment for carbapenem-resistant organisms.
When treating patients with late onset of ventilator-associated pneumonia (more than 5 days of hospitalization), as well as in other cases of nosocomial pneumonia, when infection with pathogens with reduced sensitivity, such as Pseudomonas spp. and Acinetobacter spp., special attention should be paid to the choice of antibiotic and the dose taken. If Pseudomonas aeruginosa infections are suspected or confirmed, aminoglycosides may be prescribed concomitantly with doripenem for approved indications.
The development of convulsive seizures has been reported, which was observed more often in patients with underlying diseases of the central nervous system (for example, a history of stroke or seizures), impaired renal function and when using doses exceeding 500 mg.
In patients with impaired renal function, it is necessary to monitor renal function and, if necessary, adjust the dose of doripenem.
Simultaneous use of doripenem and valproic acid is not recommended.
Doripenem-Belpharm should not be used by inhalation, as there is a risk of developing pneumonitis.
Pseudomembranous colitis caused by Clostridium difficile may occur during treatment with almost all antibacterial drugs. If diarrhea occurs during treatment with Doripenem-Belpharm, the possibility of developing pseudomembranous colitis should be considered.
Long-term treatment with Doripenem-Belpharm should be avoided, as with other antibiotics, as overgrowth of insensitive microorganisms may occur. Patients must be carefully monitored during treatment.
Before using the drug, it is recommended to conduct a bacteriological study. In this case, it is necessary to select appropriate samples for bacteriological testing in order to isolate pathogens, their identification and determination of sensitivity to doripenem. In the absence of such data, empirical drug selection should be based on local epidemiological data and local susceptibility patterns of microorganisms.
During long-term renal replacement therapy, exposure to the doripenem metabolite may be increased to levels for which in vivo safety data are not available. This metabolite does not exhibit microbiological activity, and other possible pharmacological effects are currently unknown. Patients on long-term renal replacement therapy should be closely monitored for side effects.
The effect on the ability to drive vehicles and operate machinery has not yet been established.

Overdose
There have been cases of papulo-erythematous rash when doripenem was administered intravenously at a dose of 2 g every 8 hours for 10-14 days. The papuloerythematous rash resolved within 10 days after discontinuation of doripenem.
In case of overdose, you should stop administering the drug and carry out symptomatic therapy until doripenem is completely eliminated by the kidneys. In this case, the clinical condition of the patient should be monitored. Doripenem is eliminated from the body by hemodialysis, but there are currently no cases of hemodialysis described in cases of doripenem overdose.

Release form
500 mg in 10 ml glass injection bottles.
1 or 5 bottles along with instructions for medical use in a cardboard pack.
For hospitals: 36 bottles each with the appropriate number of instructions for medical use in cardboard boxes for hospitals.

Storage conditions
Store in a place protected from moisture and light at a temperature not exceeding 25 °C.
Keep out of the reach of children.

Expiration date
Expiration date: 2 years.
Do not use after the expiration date stated on the packaging.

Release conditions
On prescription.

Manufacturer / name and address of the organization accepting claims (suggestions) regarding the quality of the medicinal product in the territory of the Republic of Uzbekistan
FE LLC "BELPHARM", Republic of Uzbekistan, Tashkent city, st. Kichik khalka yuli and Badamzar, 37
www.belpharm.uz