Doriprex^® (Powder) Instructions for Use

Marketing Authorization Holder

Shionogi & Co., Ltd. (Japan)

Manufactured By

Shionogi & Co., Ltd. (Japan)

Secondary Packaging

PHARMA PACKAGING SOLUTIONS (USA)

ATC Code

J01DH04 (Doripenem)

Active Substance

Doripenem (Rec.INN registered by WHO)

Dosage Form

Doriprex®

Powder for solution for infusion 500 mg: vial 1 or 10 pcs.

Dosage Form, Packaging, and Composition

Powder for solution for infusion from white or almost white to slightly yellowish, crystalline; reconstituted solution: when the drug is added to 10 ml of water for injections, a homogeneous suspension of white or almost white color is formed, which freely passes into the syringe through needle No. 0840.

Vials made of colorless transparent type I glass with a capacity of 20 ml (1) – cardboard boxes.
Vials made of colorless transparent type I glass with a capacity of 20 ml (10) – cardboard boxes.

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Antibiotic-carbapenem

Pharmacological Action

Synthetic broad-spectrum antibiotic from the carbapenem group, structurally similar to other beta-lactam antibiotics. Doripenem is active 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.

Doripenem exerts a bactericidal effect by disrupting bacterial cell wall biosynthesis. It inactivates a large number of important penicillin-binding proteins (PBPs), leading to disruption of bacterial cell wall synthesis and subsequent death of bacterial cells. Doripenem has the highest affinity for Staphylococcus aureus PBPs. In Escherichia coli and Pseudomonas aeruginosa cells, Doripenem binds firmly to the PBP involved in maintaining the shape of the bacterial cell.

In vitro experiments have shown that Doripenem slightly reduces the activity of other antibiotics; other antibiotics do not reduce the activity of doripenem. Additive activity or weak synergy with amikacin and levofloxacin against Pseudomonas aeruginosa, as well as with daptomycin, linezolid, levofloxacin and vancomycin against gram-positive bacteria, has been described.

Mechanisms of resistance to doripenem include inactivation of the drug by mutant or acquired carbapenem-hydrolyzing enzymes (PBPs), reduced outer membrane permeability, and active efflux 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; an exception is the relatively rare β-lactamases capable of hydrolyzing Doripenem.

The prevalence of acquired resistance of individual species may vary in different geographical regions and at different times, so it is very important to have information on the structure of local resistance, especially when treating severe infections. If necessary, consultation with microbiologists should be sought if the local resistance structure is such that the advisability of using a particular drug, at least for some types of infection, is in doubt.

The drug is active against aerobic gram-positive bacteria Enterococcus faecalis, Staphylococcus aureus (methicillin-susceptible strains), Staphylococcus epidermidis (methicillin-susceptible strains), Staphylococcus haemolyticus (methicillin-susceptible strains), Streptococcus agalactiae (including macrolide-resistant strains), Staphylococcus saprophyticus, Streptococcus intermedius, Streptococcus constellatus, Streptococcus pneumoniae (including penicillin- or ceftriaxone-resistant strains), Streptococcus pyogenes, Streptococcus viridans (including penicillin-intermediate and resistant strains); aerobic gram-negative bacteria Acinetobacter baumannii, Acinetobacter calcoaceticus, Aeromonas hydrophila, Citrobacter diversus, Citrobacter freundii (including ceftazidime-resistant strains), Enterobacter aerogenes, Enterobacter cloacae (including ceftazidime-resistant strains), Haemophilus influenzae (including β-lactamase-producing strains, or ampicillin-resistant strains that do not produce β-lactamases), Escherichia coli (including levofloxacin-resistant strains and extended-spectrum β-lactamase-producing strains), Klebsiella pneumonia* (including β-lactamase-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-resistant strains), Shigella spp.; anaerobic bacteria : Bacteroides fragilis, Bacteroides caccae, Bacteroides ovatus, Bacteroides uniformis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bilophora wadsworthia, Clostridium spp., Peptostreptococcus magnus, Peptostreptococcus micros, Porphyromonas spp., Prevotella spp., Suterella wadsworthia.

The following are resistant to the drug: aerobic gram-positive bacteria methicillin-resistant staphylococci, Enterococcus faecium; aerobic gram-negative bacteria Stenotrophomonas maltophila; Burkholderia cepacia may also have acquired resistance.

*species against which Doripenem was active in clinical studies.

Pharmacokinetics

Distribution

C_max and AUC change linearly in the dose range from 500 mg to 1 g with IV infusion over 1 or 4 hours. The mean plasma concentrations (mg/L) of doripenem after a single 1-hour and 4-hour IV infusion of 500 mg and a single 4-hour infusion of 1 g are shown in the table below.

Mean plasma concentrations of doripenem after a single dose administration

In patients with normal renal function, no signs of doripenem accumulation were found after multiple IV infusions of 500 mg or 1 g every 8 hours for 7-10 days.

The binding of doripenem to plasma proteins averages 8.1% and does not depend on its concentration in blood plasma. V_d is approximately 16.8 L, which is close to the volume of extracellular fluid in humans (18.2 L). Doripenem penetrates well into the tissues of the uterus, prostate gland, gallbladder and urine, as well as retroperitoneal fluid, reaching concentrations there that exceed the MIC.

Metabolism

The active substance is biotransformed into a microbiologically inactive metabolite 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 NADPH.

Excretion

Doripenem is excreted primarily by the kidneys unchanged. In healthy young adults, the terminal T_1/2 of doripenem is about 1 h, and plasma clearance is approximately 15.9 L/h. The mean 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, after a single dose of doripenem 500 mg, 71% of the dose was found in the urine as unchanged doripenem and 15% as the ring-opened metabolite, respectively. After administration of a single dose (500 mg) of radioactively labeled doripenem to healthy young adults, less than 1% of the total radioactivity was found in the stool.

Pharmacokinetics in special clinical cases

After administration of a single dose of doripenem 500 mg to patients with impaired renal function, the AUC increases compared to the AUC in healthy people with normal renal function (CrCl ≥80 ml/min)

The dose of doripenem should be reduced in patients with moderate and severe renal impairment.

Currently, there are no data on the pharmacokinetics of doripenem in patients with impaired liver function. Doripenem is practically not metabolized in the liver, so it is assumed that liver disease does not affect its pharmacokinetics.

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

In women, the AUC of doripenem was 13% greater than in men. The same doses of doripenem are recommended for men and women.

When using this drug among diverse racial groups, no significant divergence in doripenem clearance was observed, so dose adjustment is not recommended.

Indications

• Hospital-acquired (nosocomial) pneumonia, including ventilator-associated pneumonia;
• Complicated intra-abdominal infections;
• Complicated urinary tract infections, including complicated and uncomplicated pyelonephritis, including with concomitant bacteremia.

ICD codes

Dosage Regimen

The drug is administered intravenously.

Recommended method of administration and doses of doripenem for adults

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

**the duration of therapy includes a possible switch to appropriate oral therapy after at least 3 days of parenteral therapy that has 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).

¹ in patients with concomitant bacteremia, the duration of therapy can be up to 14 days.

In patients with impaired renal function with CrCl >50 ml/min, no dose adjustment is required. In patients with moderate renal impairment (CrCl from ≥30 to ≤50 ml/min), the drug is administered at a dose of 250 mg every 8 hours. In patients with severe renal impairment (CrCl from >10 to <30 ml/min), the drug is administered at a dose of 250 mg every 12 hours.

Doripenem is removed from the blood by hemodialysis; currently there is not enough information to formulate recommendations for patients on dialysis.

In elderly patients whose renal function corresponds to their age, no dose adjustment is required.

In patients with hepatic insufficiency, there is no need for dose adjustment.

Rules for preparation and administration of the solution

To prepare a solution for infusion containing 500 mg of doripenem, the doripenem powder is dissolved in 10 ml of sterile water for injections or 0.9% sodium chloride solution (saline). The suspension is visually checked for the presence of mechanical inclusions (this ready-made suspension is not used for direct administration). The ready-made suspension is added by syringe injection to an infusion bag containing 100 ml of saline or 5% glucose solution, and gently mixed until completely dissolved.

To prepare a solution for infusion containing 250 mg of doripenem for patients with moderate or severe renal impairment**, the doripenem powder is dissolved in 10 ml of sterile water for injections or 0.9% sodium chloride solution (saline). The suspension is visually checked for the presence of mechanical inclusions (this ready-made suspension is not used for direct administration). The ready-made suspension is added by syringe injection to an infusion bag containing 100 ml of saline or 5% glucose solution, and gently mixed until completely dissolved. 55 ml of the solution is withdrawn from the infusion bag and discarded (the remaining volume of solution contains 250 mg of doripenem).

Infusion solutions of the drug Doriprex^® vary from clear and colorless to clear and slightly yellowish solution. Possible differences in the color of the solution do not affect the quality of the product. The infusion solution is visually checked for the absence of mechanical inclusions before administration and discarded if any are found.

Adverse Reactions

The most common adverse effects were headache (10%), diarrhea (9%) and nausea (8%).

Definition of adverse reaction frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (≥1/100 000, <1/10 000).

From the CNS : very common – headache.

From the cardiovascular system: common – phlebitis.

From the digestive system: common – nausea, diarrhea, increased activity of liver enzymes; uncommon – Clostridium difficile-induced colitis.

Dermatological reactions common – itching, rash.

Allergic reactions uncommon – anaphylactic shock.

Other: common – oral candidiasis, vaginal candidiasis.

During post-registration use

From the hematopoietic system : uncommon – neutropenia, thrombocytopenia.

Allergic reactions: very rare – toxic epidermal necrolysis, Stevens-Johnson syndrome.

It is impossible to establish the relative frequency of these reactions because doctors, when reporting these side effects, did not indicate the number of patients receiving Doripenem.

Contraindications

• Age under 18 years;
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other drugs of the carbapenem group, as well as to beta-lactam antibiotics.

Use in Pregnancy and Lactation

Data regarding the use of doripenem in a small number of pregnant women indicate that the drug does not have a negative effect on pregnancy, as well as on the health of the fetus and newborn. Caution is required when treating pregnant women with Doriprex^®.

If it is necessary to use Doriprex^® during lactation, breastfeeding should be discontinued.

Pediatric Use

The drug is contraindicated in children under 18 years of age.

Geriatric Use

In elderly patients whose renal function corresponds to their age, no dose adjustment is required.

Special Precautions

In patients receiving beta-lactam antibiotics, serious, sometimes fatal, hypersensitivity reactions (anaphylactic reactions) may occur. Before starting treatment with doripenem, the patient should be questioned in detail about whether he has previously had hypersensitivity reactions to other carbapenems or to beta-lactam antibiotics. If a hypersensitivity reaction to Doripenem occurs, it should be discontinued immediately and appropriate treatment should be carried out. Serious hypersensitivity reactions (anaphylactic shock) require emergency therapy, including the administration of corticosteroids and pressor amines (adrenaline), as well as other measures, including oxygen therapy, IV fluids, and, if necessary, the administration of antihistamines and maintaining airway patency.

Pseudomembranous colitis caused by Clostridium difficile can occur with treatment with almost all antibacterial drugs and can range from mild to life-threatening. Therefore, it is necessary to remember this complication if a patient receiving Doripenem develops diarrhea.

Prolonged use of doripenem should be avoided to prevent the overgrowth of microorganisms resistant to it.

Before using the drug, it is recommended to conduct a bacteriological study. In this case, appropriate samples should be collected for bacteriological testing to isolate pathogens, identify them, and determine their sensitivity to doripenem. In the absence of such data, the empirical choice of drugs should be based on local epidemiological data and the local susceptibility profile of microorganisms.

Influence on the Ability to Drive Vehicles and Operate Machinery

Studies evaluating the effect of doripenem on these functions have not been conducted. It is assumed that Doripenem is unlikely to affect the ability to drive a car or operate machinery.

Overdose

Cases of doripenem overdose have not been described. In case of overdose, the administration of the drug should be discontinued and symptomatic therapy should be carried out until doripenem is completely eliminated by the kidneys. The patient’s clinical condition should be monitored.

Doripenem is removed from the body by hemodialysis; however, no cases of using hemodialysis for doripenem overdose have been described to date.

Drug Interactions

Probenecid competes with doripenem for renal tubular secretion and reduces the renal clearance of doripenem. Probenecid increases the AUC of doripenem by 75% and the plasma T_1/2 by 53%. Therefore, the concomitant use of probenecid and Doriprex^® is not recommended.

Doripenem does not inhibit the major isoenzymes of the cytochrome P450 system and is therefore unlikely to interact with drugs that are metabolized by this enzyme system. According to in vitro studies, Doripenem does not have the ability to induce enzyme activity.

In healthy volunteers, Doripenem reduced the plasma concentration of valproic acid to a subtherapeutic level (the AUC value decreased by 63%), which is also consistent with the results obtained for other carbapenems. The pharmacokinetics of doripenem did not change. When doripenem and valproic acid or sodium valproate are used concomitantly, their concentration should be monitored and the possibility of prescribing another treatment should be considered.

Pharmaceutical Compatibility

The drug should not be mixed with other medicinal products, except for sterile water for injections, 0.9% sodium chloride solution for injections (saline) or 5% glucose solution.

Storage Conditions

The drug should be stored in the original packaging, out of the reach of children, protected from light, at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 2 years.

Storage Conditions of the Prepared Solution : after adding sterile water for injections or 0.9% sodium chloride solution for injections (saline) to the doripenem powder, the suspension can be stored in the vial for 1 hour before its dilution with an infusion solution.

*After removal from the refrigerator, the infusion solution must be administered to the patient within the allowed storage time at room temperature. In this case, the total storage time of the solution in the refrigerator, the time for warming the solution to room temperature, and the time for administering the solution to the patient should not exceed the total allowable storage time in the refrigerator.

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

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.