Dorifarm (Powder) Instructions for Use

Marketing Authorization Holder

Kraspharma, PJSC (Russia)

ATC Code

J01DH04 (Doripenem)

Active Substance

Doripenem (Rec.INN registered by WHO)

Dosage Forms

	Dorifarm	Powder for solution for infusion 250 mg
		Powder for solution for infusion 500 mg

Dosage Form, Packaging, and Composition

Powder for solution for infusion

250 mg – vials – carton packs – By prescription
250 mg – vials (10 pcs.) – carton boxes – By prescription
250 mg – vials (50 pcs.) – carton boxes – for hospitals

Powder for solution for infusion

500 mg – vials – carton packs – By prescription
500 mg – vials (10 pcs.) – carton boxes – By prescription
500 mg – vials (50 pcs.) – carton boxes – for hospitals

Clinical-Pharmacological Group

Antibiotic of the carbapenem group

Pharmacotherapeutic Group

Systemic antibacterial agents; other beta-lactam antibacterial agents; carbapenems

Pharmacological Action

Doripenem is a 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 the PBPs of Staphylococcus aureus. 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 permeability of the outer membrane, 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 questionable.

Active against aerobic gram-positive bacteriaEnterococcus 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 strains moderately susceptible and resistant to penicillin); aerobic gram-negative bacteriaAcinetobacter baumannii, Acinetobacter calcoaceticus, Aeromonas hydrophila, Citrobacter diversus, Citrobacter freundii (including ceftazidime-resistant strains), Enterobacter aerogenes, Enterobacter cloacae (including ceftazidime-resistant strains), Haemophilus influenzae (including beta-lactamase-producing strains, or ampicillin-resistant strains that do not produce beta-lactamases), Escherichia coli (including levofloxacin-resistant strains and extended-spectrum beta-lactamase-producing strains), Klebsiella pneumonia (including beta-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, Bilophila wadsworthia, Clostridium spp., Peptostreptococcus magnus, Peptostreptococcus micros, Porphyromonas spp., Prevotella spp., Suterella wadsworthia.

Resistant aerobic gram-positive bacteria methicillin-resistant staphylococci, Enterococcus faecium; aerobic gram-negative bacteriaStenotrophomonas maltophila; Burkholderia cepacia may also have acquired resistance.

Pharmacokinetics

In the dose range from 500 mg to 1 g with IV infusion over 1 or 4 hours, C_max and AUC change linearly.

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.

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.

Doripenem is excreted primarily by the kidneys unchanged. In healthy young adults, the terminal T_1/2 of doripenem is about 1 hour, 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.

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

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.

Indications

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

ICD codes

Dosage Regimen

Administered IV as an infusion. Single dose – 500 mg. Interval between administrations – 8 hours. Duration of therapy is 5-14 days.

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.

Adverse Reactions

Most common headache (10%), diarrhea (9%) and nausea (8%).

From the CNS : very common – headache.

From the cardiovascular system: common – phlebitis.

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

Dermatological reactions common – itching, rash.

Allergic reactions sometimes – anaphylactic shock; very rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome.

From the hematopoietic system : sometimes – neutropenia, thrombocytopenia.

Other: common – oral candidiasis, vaginal candidiasis.

Contraindications

Childhood and adolescence under 18 years; hypersensitivity to doripenem; hypersensitivity to other drugs of the carbapenem group, as well as to beta-lactam antibiotics.

Use in Pregnancy and Lactation

When using doripenem in a small number of pregnant women, no negative effects on pregnancy, as well as on the health of the fetus and newborn, were observed. If use during pregnancy is necessary, caution is required, as well as an assessment of the ratio of the expected benefit of therapy for the mother and the potential risk to the fetus.

If it is necessary to use doripenem during lactation, breastfeeding should be discontinued.

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 (epinephrine), 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. This is why it is necessary to remember this complication if a patient receiving Doripenem develops diarrhea.

Long-term use of doripenem should be avoided to prevent overgrowth of microorganisms resistant to it.

Before using doripenem, it is recommended to conduct a bacteriological study. In this case, appropriate samples should be taken for bacteriological testing in order 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 structure of microorganism sensitivity.

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%. This combination is not recommended.

In healthy volunteers, Doripenem reduced the plasma concentration of valproic acid to a subtherapeutic level (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 valproate semisodium are used simultaneously, the concentration of the latter should be monitored and the possibility of prescribing another treatment should be considered.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.