Doripenem, powder 500 mg

Infectious inflammatory diseases caused by doripenem-sensitive microorganisms:

• Inpatient (nosocomial) pneumonia, including ventilator-associated pneumonia.
• Complicated intra-abdominal infections.
• complicated urinary tract infections, including complicated and uncomplicated pyelonephritis and cases with associated bacteremia.

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Active ingredient

Composition

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

500 mg

every 8h

10 days**§

* For the treatment of patients with nosocomial pneumonia, infusions of 500 mg for 1 hour are recommended. Infusions for 4 hours 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 with a dose of 1000 mg for 4 h are recommended.

Infusions with a dose of 500 mg every 8 hours are recommended to treat patients with moderate renal impairment; infusions with a dose of 500 mg every 12 hours are recommended to treat patients with severe renal impairment.

** 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 of patients with nosocomial pneumonia, including ventilator-associated pneumonia, is 7 to 14 days and should depend on the severity of the disease, localization of infection, and the patient’s clinical response to treatment (see section “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 h. For patients with a recommended dose of 1000 mg every 8 hours, as a 4-hour infusion, the dose should also be adjusted: in moderate renal failure – 500 mg every 8 hours, in 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

/p>

500 mg

every 12 h

4 h

/p>

< 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 dysfunction and 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-to-use 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 table below shows storage times for Doripenem after dilution with 0.9% sodium chloride solution or 5% dextrose solution 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

Doripenem infusion solutions range from clear and colorless to clear and slightly yellowish solution. The possible differences in coloration of the solution do not affect the quality of the product. The infusion solution is visually checked for the absence of mechanical inclusions before injection, and if detected, it is rejected. 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 simultaneously. 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, according to the results of in vitro studies, does not have the ability to induce enzyme activity. In healthy volunteers doripenem reduced the plasma concentration of valproic acid to a subtherapeutic value (AUC of valproic acid decreased rapidly by 63%), which is also consistent with the results obtained for other carbapenems. The pharmacokinetics of Dori-penem 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 treatment with Doripenem, patients should be carefully asked whether they have had hypersensitivity reactions to other carbapenems or beta-lactam antibiotics before. If a hypersensitivity reaction has occurred to doripenem, it should be discontinued immediately and treated accordingly. Serious hypersensitivity reactions (anaphylactic shock) require emergency therapy, including glucocorticosteroid and pressor amines (epinephrine) administration, as well as other measures, including oxygen therapy, intravenous 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 during long-term use and 2-3 weeks after discontinuation of treatment; it is manifested with diarrhea, leukocytosis, fever, abdominal pain (sometimes accompanied with excretion of blood and mucus with feces). If these phenomena occur, 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, 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. It is necessary to take appropriate samples for bacteriological study in order 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 metabolite metabolite 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 indices and observation of the clinical condition of the patient. Doripenem is eliminated from the body with hemodialysis or long-term renal replacement therapy, however, currently there is not enough information about 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.