Doripenem

Description

Fine crystalline powder, white or white yellowish.
Pharmacotherapeutic group: carbapenem antibiotic.
ATC Code: J01DН04

Pharmacological properties
Pharmacodynamics
Doripenem is a synthetic broad-spectrum carbapenem antibiotic that is structurally similar to other beta-lactam antibiotics.
Doripenem has a significant 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.

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), which leads to disruption of the synthesis of the bacterial cell wall and the subsequent death of bacterial cells. Doripenem has the highest affinity for the PBPs of Staphylococcus aureus. In Escherichia coli and Pseudomonas aeruginosa cells, doripenem strongly binds to PBPs, which are involved in maintaining the shape of the bacterial cell

Experiments in vitro 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.

Mechanism of resistance
The mechanisms of bacterial resistance to doripenem include its inactivation by enzymes that hydrolyze carbapenems, as well as mutant or acquired PBPs, a decrease in the permeability of the outer membrane, and an 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 capable of hydrolyzing doripenem.

The prevalence of acquired resistance in individual species may vary in different geographic regions and at different times, and therefore information on the structure of local resistance is very useful, especially in the treatment of severe infections. Circumstances require, it is necessary to seek advice from microbiologists: for example, if the structure of local resistance is such that the use of a particular drug, at least for some types of infection, is questionable.

The following are sensitive to doripenem:
Usually sensitive species
Gram-positive aerobes: 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 ceftriaxone), Streptococcus pyogenes, Streptococcus viridans (including strains moderately sensitive and resistant to penicillin).

Gram-negative aerobes: Citrobacter diversus, Citrobacter freundii (including strains insensitive to ceftazidime), Enterobacter aerogenes, Enterobacter cloacae (including strains insensitive to ceftazidime), Haemophilus influenzae (including strains that produce beta-lactamases or ampicillin-resistant strains that do not produce beta-lactamases), Escherichia coli (including strains resistant to levofloxacin and strains producing extended spectrum beta-lactamases (ESBL)), Klebsiella pneumoniae* (including strains producing ESBL), Klebsiella oxytoca, Morganella morganii, Proteus mirabilis (including strains producing ESBL), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa* (including strains resistant to ceftazidime), Salmonella spp., Serratia marcescens (including strains insensitive to ceftazidime), Shigella genus species.

Anaerobes: Bacteroides fragilis, Bacteroides сассае, Bacteroides ovatus, Bacteroides uniformis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bilophila wadsworthia, Clostridium genus species, Peptostreptococcus magnus. Peptostreptococcus micros, Porphyromonas genus species, Prevotella genus species, Sutterella wadsworthenis.

Resistant microorganisms
Gram-positive aerobes: methicillin resistant Staphylococcus;

Enterococcus faecium.
Gram-negative aerobes:
Stenotrophomonas maltophilia, Legionella spp.

The following species can have acquired resistance:
Burkholderia cepacia, Acinetobacter baumannii, Acinetobacter spp., Pseudomonas aеruginosa.
*Species for which doripenem has been active in clinical trials.

Pharmacokinetics
Doripenem concentrations in plasma: mean 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

The pharmacokinetics of doripenem (Cmax — maximum plasma concentration and AUC — area under the concentration-time curve) is linear in the dose range of 500 mg – 1 g with intravenous infusion over 1 or 4 hours. In patients with normal renal function, no signs of cumulation of doripenem after multiple intravenous infusions of 500 mg or 1 g every 8 hours for 7-10 days was found. The pharmacokinetics of doripenem is linear in the dose range of 500 mg – 2 g when administered as an intravenous infusion for 1 hour and 500 mg – 1 g for intravenous infusion for 4 hours.

The pharmacokinetic characteristics of doripenem after a single administration (after a 4-hour infusion) in adults with cystic fibrosis are similar to those for adults without cystic fibrosis. There have been no well-controlled studies of the safety and efficacy of doripenem in patients with cystic fibrosis.

Distribution: the average degree of binding of doripenem with 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 biological fluids, for example, in uterine tissue, retroperitoneal fluid, prostate tissue, gallbladder tissue and urine, reaching concentrations exceeding the MIC (minimum inhibitory concentration) there.

Metabolism: biotransformation of doripenem into a microbiologically inactive metabolite occurs mainly under the action of dehydropeptidase-1. In vitro metabolism of doripenem was observed under the influence of CYP450 system isoenzymes and other enzymes, both in the presence and in the absence of nicotinamide adenine dinucleotide phosphate (NADP).

Excretion: doripenem is eliminated mainly by the kidneys unchanged. In healthy young adults, the mean terminal plasma half-life of doripenem is about 1 hour and plasma clearance is about 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 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 urine as unchanged doripenem and 15% as an open-ring metabolite, respectively. After administration of a single dose (500 mg) of radioactively labeled doripenem to young healthy adults, less than 1% of the total radioactivity was found 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) the degree of renal failure, the AUC increased by 1.6 times, 2.8 times and 5.1 times, respectively, compared with the AUC in healthy people 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 compromised liver function: there is currently no data on the pharmacokinetics of doripenem in patients with compromised liver function. Doripenem is almost not metabolized in the liver, and therefore it is assumed that dysfunction of this organ should not affect its pharmacokinetics.

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

Sex differences: the AUC of doripenem was 13% higher in women than in men Men and women are advised to administer the same dose of doripenem.

Race: no significant difference in clearance of doripenem was observed with this drug among various racial groups, so dose adjustments are not recommended.

Indications
Infectious and inflammatory diseases caused by microorganisms sensitive to doripenem:
– hospital-acquired (nosocomial) pneumonia, including pneumonia associated with mechanical ventilation (MV);
– complicated intra-abdominal infections;
– complicated infections of the urinary system, including complicated and uncomplicated pyelonephritis and cases with concomitant bacteremia.

Contraindications
Hypersensitivity to doripenem or other carbapenems, as well as beta-lactam antibiotics.
Infancy under 18.

Use during pregnancy and breastfeeding
Pregnancy
There are limited clinical data on the use of doripenem in pregnant women. The potential risk to the fetus is unknown. During pregnancy, use only if the intended benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding
If it is necessary to use doripenem during lactation, it is necessary to stop breastfeeding.

Dosage and administration
Intravenous.
The table below shows the recommended route of administration and dosage of Doripenem.

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

For the treatment of patients with increased creatinine clearance (CrCl) ≥ 150 mL/min) or(and) with infections caused by gram-negative non-fermenting bacteria (for example, Pseudomonas spp. or Acinetobacter spp.), infusions with a dosage of 1000 mg within 4 hours are recommended.

For the treatment of patients with moderate renal impairment, infusions with a dosage of 500 mg every 8 hours are recommended, for the treatment of patients with severe renal impairment, infusions with a dosage of 500 mg every 12 hours are recommended.

**The duration of therapy includes a possible transition to the appropriate oral therapy after at least 3 days of parenteral therapy, which caused clinical improvement (when switching to oral therapy, fluoroquinolones, broad-spectrum penicillins in combination with clavulanic acid, as well as antibiotics of any pharmacotherapeutic group can be prescribed).

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

The usual duration of treatment of patients with nosocomial pneumonia, including pneumonia associated with MV, 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. 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 impairment (creatinine clearance ≥ 30 to ≤ 50 mL/min), the dose of doripenem should be 250 mg every 8 hours. In patients with severe renal impairment (creatinine clearance > 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, in the form of a 4-hour infusion, the dose should also be adjusted: with moderate renal failure – 500 mg every 8 hours, with severe renal impairment – 500 mg every 12 hours.

Dialysis patients
Dosing recommendations for Doripenem in patients on long-term substitutive renal therapy are given in the table:

a In patients with acute renal impairment and those on long-term substitutive renal therapy, the recommended infusion time is 4 hours, given the possibility of increasing the extrarenal clearance of carbapenems in patients with acute renal impairment.

b In patients with chronic renal impairment and who are on long-term substitutive renal therapy, a 1- or 4-hour infusion may be performed. According to pharmacokinetic/pharmacodynamic data, infusion over 4 hours may be preferred in order to maximize the percentage of time during the dosing interval when the plasma concentration of doripenem exceeds the minimum inhibitory concentration (% T > MIC). Dosing recommendations for MIC> 1 mg/mL have not been established for long-term renal replacement therapy due to the possible accumulation of doripenem and the doripenem-M-1 metabolite. Careful monitoring of safety is recommended for patients on long-term substitutive renal therapy due to limited clinical data and a possible increase in systemic exposure to the doripenem-M-1 metabolite. Currently, there is not enough information to give recommendations for patients on other types of dialysis.

Elderly patients
In elderly patients, whose renal function is appropriate for their age, dose adjustment is not required.

Patients with hepatic impairment
In such patients, dose adjustment is not required.

Solution preparation and handling instructions
Preparation of a 500 mg dose solution for infusion (using vials containing 500 mg of doripenem):
• Dissolve doripenem powder 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 ready-made suspension is not used for direct administration).
• The ready suspension is added with a syringe and needle to an infusion bag (bottle) containing 100 ml of 0.9% sodium chloride solution or 5% dextrose solution, and gently mix until completely dissolved.
Preparation of a dose of 250 mg solution for infusion for patients with moderate to severe renal impairment (using vials containing 500 mg of doripenem):
• Dissolve doripenem powder 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 ready-made suspension is not used for direct administration).
• The ready suspension is added with a syringe and needle to an infusion bag (bottle) containing 100 ml of 0.9% sodium chloride solution or 5% dextrose solution, and gently mix until completely dissolved. Take 55 ml of the solution from the infusion bag or bottle and discard (the remaining volume of the solution contains 250 mg of doripenem).
Preparation of a dose of 250 mg solution for infusion for patients with moderate to severe renal impairment (using vials containing 250 mg of doripenem):
• Dissolve doripenem powder in 5 ml of sterile water for injection or 0.9% sodium chloride solution.
• Visually check the suspension for the presence of visible foreign particles (this ready-made suspension is not used for direct administration).
• The ready suspension is added with a syringe and needle to an infusion bag (bottle) containing 50 ml of 0.9% sodium chloride solution or 5% dextrose solution, and gently mix until completely dissolved.

Storage conditions for the finished solution: after adding sterile water for injection or 0.9% sodium chloride solution to the 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 when stored at room temperature or in a refrigerator.
Storage of infusion solutions prepared in 0.9% sodium chloride solution or 5% dextrose solution:

* Once removed from the refrigerator, the infusion solution must be administered to the patient within the permitted storage time at room temperature. In this case, the total storage time of the solution in the refrigerator, the time of warming the solution to room temperature and the time of administration of the solution to the patient should not exceed the total allowable storage time in the refrigerator.

* 5% dextrose solution should not be used for infusions longer 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, the responsibility for maintaining the microbiological purity lies with the person preparing or storing the solution.

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

Before administration, the infusion solution is visually checked for the absence of mechanical impurities, and if the latter are found, they are discarded.
Unused doripenem solution and other waste must be disposed of in accordance with local regulations.

Adverse effects
The frequency of undesirable effects was classified as follows:
very common ≥ 1/10);
common ≥1/100 – < 1/10;
uncommon ≥ 1/1000 – <1/100;
rare ≥1/10 000 – <1/1 000);
very rare ≥ 1/100 000 – < 1/10 000.

The following undesirable effects have been noted:
Nervous system disorders:
very common: headache;
unknown frequency*: cramps.
Cardiovascular system disorders:
common: phlebitis.
Gastrointestinal disorders:
common: nausea, diarrhea;
uncommon: pseudomembranous colitis.
Skin and subcutaneous tissue:
common: itching, rash.
Allergic reactions:
uncommon: hypersensitivity reactions (anaphylactic reactions);
very rare: toxic epidermal necrolysis, Stevens–Johnson syndrome.
Hepatobiliary disorders:
common: increased activity of liver enzymes.
Blood and lymphatic system:
uncommon: neutropenia, thrombocytopenia.
Other:
common: candidiasis of the oral mucosa, vaginal candidiasis.
* These reactions were reported voluntarily by physicians, without indicating the number of patients receiving doripenem, and therefore it is impossible to establish their relative frequency.

Overdose
Cases of papulo-erythematous rash were observed when doripenem was administered intravenously at a dose of 2 g every 8 hours for 10-14 days. The papulo-erythematous rash resolved within 10 days after discontinuation of doripenem.
In case of an overdose, the administration of doripenem should be discontinued and maintenance therapy should be carried out until it is completely eliminated from the organism by the kidneys. Overdose treatment consists in carrying out general supportive symptomatic therapy, including monitoring of basic physiological parameters and monitoring the clinical condition of the patient. Doripenem is removed from the body by hemodialysis or long-term substitutive renal therapy, however, there is currently insufficient information on the use of hemodialysis or long-term renal replacement therapy for doripenem overdose.

Interactions with other drugs
Probenecid competes with doripenem for renal tubular secretion and decreases 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 at the same time.
Doripenem does not inhibit the main isozymes of the cytochrome P450 system, and therefore, most likely, does not interact with drugs that are metabolized by these enzymes. Doripenem, judging by the results of in vitro studies, does not have the ability to induce enzyme activity.
In healthy volunteers, doripenem reduced the plasma valproic acid concentration to a subtherapeutic 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. With the simultaneous administration of doripenem and valproic acid or valproate seminatrium, the concentration of the latter should be monitored and the possibility of prescribing another treatment should be considered.
The drug should not be mixed with other drugs and solutions, with the exception of 0.9% sodium chloride solution, 5% dextrose solution and water for injection.

Special instructions
Serious and sometimes fatal hypersensitivity reactions (anaphylactic reactions) can occur in patients receiving beta-lactam antibiotics. Before starting treatment with doripenem, the patient should be carefully asked about whether he has had previous hypersensitivity reactions to other carbapenems or to beta-lactam antibiotics. In the event of a hypersensitivity reaction to doripenem, it must be immediately canceled and appropriate treatment carried out. Serious hypersensitivity reactions (anaphylactic shock) require emergency treatment, including the administration of glucocorticosteroids and pressor amines (epinephrine), as well as other measures, including oxygen therapy, intravenous fluids, and, if necessary, antihistamines, and airway maintenance.
During therapy with carbapenems, including doripenem, cases of seizures have been reported (see section “Side Effects”). In clinical studies of doripenem, seizures were more often observed in patients with underlying diseases of the central nervous system (CNS) (for example, stroke or seizures in history), impaired renal function and when using doses exceeding 500 mg.
Pseudomembranous colitis caused by Clostridium difficile. can appear both against the background of prolonged use, and 2-3 weeks after stopping treatment; 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 discontinue treatment and use ion-exchange resins (colestyramine, colestipol), in severe cases, compensation for the loss of fluid, electrolytes and protein is indicated, the appointment of vancomycin by mouth or metronidazole. Do not use drugs that inhibit intestinal motility.
Long-term treatment with doripenem should be avoided to prevent excessive reproduction of microorganisms resistant to it.
Before use, it is recommended to conduct a bacteriological study. It is necessary to select appropriate samples for bacteriological research in order to isolate pathogens, identify them and determine their sensitivity to doripenem. In the absence of such data, empirical selection of drugs should be based on local epidemiological data and local microbial susceptibility patterns.

Long-term substitutive renal therapy
The exposure of the metabolite doripenem-M-1 in patients undergoing long-term substitutive renal therapy can be reduced to a level for which there is no data on the safety of the drug in vivo. This metabolite does not demonstrate microbiological activity, and other possible pharmacological effects are unknown. Therefore, careful monitoring of side effects is recommended for patients on long-term substitutive renal therapy.

Ventilator-associated pneumonia
A study involving patients hospitalized for at least 5 days and diagnosed with ventilator-associated pneumonia did not confirm the efficacy of 7-day courses of doripenem (1 g as 4-hour infusions every 8 hours) compared with 10-day courses of imipenem/cilastatin (1 g as 1-hour infusion every 8 hours). The usual duration of treatment for patients with nosocomial pneumonia, including ventilator-associated pneumonia, is 7-14 days and is determined by the severity of the disease, the location of the infection and the patient’s clinical response to treatment (see section Dosage and Administration).

Effects on the ability to drive and use machines
Studies concerning the effect of doripenem on the ability to drive vehicles and engaging in other potentially hazardous activities that require increased concentration of attention 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 the drug for the above functions.

Presentation
Powder for solution for infusion, 250 mg, 500 mg.
The drug quantity containing 250 or 500 mg of the active substance is placed in transparent glass vials of the 1st hydrolytic class with a capacity of 10 or 20 ml, hermetically sealed with rubber stoppers, crimped with aluminum caps or combined caps (aluminum caps with safety plastic caps).
1 vial with the drug and instructions for medical use are placed in a cardboard box.

For in-patient facilities:
from 10 to 50 vials with the drug with an equal number of instructions for medical use are placed in a cardboard box.

Storage conditions
In a dark place at a temperature below 25 °C.
Keep out of the reach of children.

Shelf life
3 years.
Do not use after expiration date.

Prescription status
Rx only.