Composition, form of production and packaging
Powder for solution for infusions from white or almost white to slightly yellowish color, crystalline; reconstituted solution: when the preparation is added to 10 ml of water, a uniform suspension of white or almost white color is formed, freely passing into the syringe through needle No. 0840.
Doripenema monohydrate 521.4 mg,
is equivalent to Doripenem 500 mg
Vials of colorless transparent glass of type I with a capacity of 20 ml (1) - packs of cardboard.
Vials of colorless transparent glass of type I with a capacity of 20 ml (10) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
A synthetic antibiotic from the broad-spectrum carbapenem group, similar in structure to other beta-lactam antibiotics. Doripenem in vitro is active 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.
Doripenem has a bactericidal effect due to disruption of the bacterial cell wall biosynthesis. It inactivates a large number of important penicillin-binding proteins (PSB), which leads to a disruption in the synthesis of the bacterial cell wall and the subsequent death of bacterial cells. Doripenem has the greatest affinity for PSB Staphylococcus aureus. In the cells of Escherichia coli and Pseudomonas aeruginosa, Doripenem strongly binds to the PSB, which participates in maintaining the shape of the bacterial cell.
Experiments in vitro have shown that doripenem reduces the activity of other antibiotics slightly, other antibiotics do not reduce the activity of Doripenem. 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.
Mechanisms of bacterial resistance to Doripenem include the inactivation of the preparation by mutant or acquired (PSB) enzymes that hydrolyze carbapenems, reduce the permeability of the outer membrane, and actively release Doripenem from bacterial cells. Doripenem is resistant to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases, which produce gram-positive and gram-negative bacteria; The exception is relatively rare ОІ-lactamases, which can hydrolyse Doripenem.
The prevalence of acquired resistance of individual species can vary in different geographic regions and at different times, so it is very important to have information about the structure of local resistance, especially when treating severe infections. If necessary, consult a microbiologist if the structure of local resistance is such that the advisability of using a particular drug, at least for some types of infection, raises doubts.
The drug is active against aerobic Gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus (strains sensitive to methicillin), Staphylococcus epidermidis (strains sensitive to methicillin), Staphylococcus haemolyticus (strains sensitive to methicillin), Streptococcus agalactiae (including macrolide-resistant strains ), 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); aerobic gram-negative bacteria:Acinetobacter baumannii, Acinetobacter calcoaceticus, Aeromonas hydrophila, Citrobacter diversus, Citrobacter freundii (including strains resistant to ceftazidime), Enterobacter aerogenes, Enterobacter cloacae (including strains resistant to ceftazidime), Haemophilus influenzae (including strains producing ОІ- lactamase, or ampicillin resistant strains that do not produce ОІ-lactamase), Escherichia coli (including strains resistant to levofloxacin and strains producing ОІ-lactamases of the spread spectrum), Klebsiella pneumonia * (including strains producing ОІ-lactamases), Klebsiella oxytoca, Morganella morganii, Prot eus mirabilis (including strains producing ESBL), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa * (including strains resistant to ceftazidime), Salmonella spp., Serratia marcescens (including strains resistant to ceftazidime), 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 drug is resistant to aerobic Gram-positive bacteria: Staphylococcus, resistant to methicillin, Enterococcus faecium; aerobic gram-negative bacteria:Stenotrophomonas maltophila; Acquired resistance may have Burkholderia cepacia.
* Species in respect of which Doripenem was active in clinical studies.
Cmax and AUC change linearly in the dose range from 500 mg to 1 g with iv infusion for 1 or 4 hours. Average plasma concentrations (mg / l) of Doripenem after one 1-hour and 4-hour IV infusion 500 mg and one 4-hour infusion of 1 g are shown in the table below.
The average concentration of Doripenem in plasma after the administration of a single dose:
Dose and duration of infusion
500 mg for 1 hour 500 mg for 4 hours 1 g for 4 hours
Time from the onset of infusion (h) Average plasma concentration (mg / L)
0.5 20.2 4.01 7.80
1 20.9 5.70 11.6
2 6.13 7.26 15.1
3 2.69 8.12 16.9
4 1.41 8.53 18.3
6 0.45 1.43 2.98
7 - 0.78 1.66
8 0.13 - -
9 - 0.28 0.55
Patients with normal renal function showed no signs of cumulation of Doripenem 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 the blood plasma. V d is approximately 16.8 liters, which is close to the volume of extracellular fluid in humans (18.2 liters). Doripenem penetrates well into the tissues of the uterus, prostate, gallbladder and urine, as well as the retroperitoneal fluid, reaching concentrations higher than MIC there.
The active substance is biotransformed into a microbiologically inactive metabolite mainly by dehydropeptidase-I.
In vitro, the metabolism of Doripenem was observed under the action of isoenzymes of the CYP450 system and other enzymes, both in the presence and absence of NADP.
Doripenem is excreted mainly by the kidneys in unchanged form. In healthy young adults, the final T 1/2 of Doripenem is about 1 hour, and the clearance from the plasma is approximately 15.9 l / h. The average renal clearance is 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 is subjected to both glomerular filtration and renal secretion. In healthy young adults, after a single dose of Doripenem in a dose of 500 mg, 71% of the dose was detected in the urine as unchanged dorypenem and 15% in the form of a metabolite with an open cycle, respectively. After administration of a healthy dose of a young age of one dose (500 mg) of radiolabeled Doripenem in feces, less than 1% of the total radioactivity was detected.
Pharmacokinetics in special clinical cases
After the administration of Doripenem 500 mg once to patients with impaired renal function, the AUC increases in comparison with AUC in healthy people with normal renal function (CC-80 ml / min):
Degree of kidney failure KK (ml / min) Increase AUC
light 51 - 79 in 1.6 times
average 31 - 50 in 2.8 times
heavy? 80 in 5.1 times
The dose of Doripenem should be reduced in patients with moderate and severe renal dysfunction.
At present, there is no data on the pharmacokinetics of doripenem in patients with impaired hepatic function. Doripenem is practically not metabolized in the liver, so it is assumed that liver disease does not affect its pharmacokinetics.
Compared with older adults, the elderly patients of Doripenem AUC were increased by 49%. These changes are mainly attributed to the age-related changes in QC. In elderly patients with a normal (for their age) renal function, a dose of Doripenem should not be decreased.
Women AUC Doripenem was 13% more than men. Men and women are recommended to administer the same dose of doripenem.
When using this drug among a variety of racial groups, there was no significant difference in the clearance of Doripenem, so adjust the dose is not recommended.
- nosocomial pneumonia, including pneumonia associated with ventilation;
- complicated intra-abdominal infections;
- Complicated urinary system infections, including complicated and uncomplicated pyelonephritis, incl. with concomitant bacteremia.
The drug is administered iv.
Recommended use and dose of doripenem for adults:
Dose Frequency of infusions Time of infusion (h) Duration of therapy **
Intrahospital (nosocomial) pneumonia, including those associated with mechanical ventilation
500 mg every 8 hours 1 or 4 * 7 to 14 days **
Complicated intra-abdominal infections
500 mg every 8 hours 1 5 - 14 days **
Complicated urinary tract infections, including pyelonephritis
500 mg every 8 h 1 10 days ** 1
* Infusions are recommended for treatment of patients with nosocomial pneumonia within 1 hour. If there is a risk of infection with less sensitive microorganisms, infusions are recommended within 4 hours.
** duration of therapy includes a possible transition to appropriate oral therapy after at least 3-day parenteral therapy that has caused clinical improvement (when switching to oral therapy, fluoroquinolones, broad-spectrum penicillins in combination with clavulanic acid, and antibiotics of any pharmacotherapeutic group).
1 in patients with concomitant bacteremia, the duration of therapy can be up to 14 days.
In patients with impaired renal function with CK> 50 ml / min, dose adjustment is not required. In patients with moderate renal dysfunction (KK from? 30 to? 50 ml / min), the drug is administered at a dose of 250 mg every 8 hours. In patients with severe renal dysfunction (CC> 10 to <30 ml / min), the drug is administered in a dose of 250 mg every 12 hours.
Doripenem is removed from the blood during hemodialysis; At present, there is insufficient information to formulate recommendations for patients on dialysis .
In elderly patients , whose kidney function corresponds to their age, dose adjustment is not required.
Patients with hepatic insufficiency do not need a dose adjustment.
Rules for the preparation and administration of a solution
To prepare a solution for infusions containing 500 mg of Doripenem, Doripenem powder is dissolved in 10 ml of sterile water d / or 0.9% sodium chloride solution (saline solution). Visually check the suspension for the presence in it of mechanical inclusions (this finished suspension is not used for direct administration). The finished suspension is injected with syringe and added to an infusion bag containing 100 ml of saline or 5% glucose solution, and gently mixed until completely dissolved.
To prepare a solution for infusions containing 250 mg of Doripenem, for patients with moderate or severe renal dysfunction , Doripenem powder is dissolved in 10 ml of sterile water d / and 0.9% sodium chloride solution (saline solution). Visually check the suspension for the presence in it of mechanical inclusions (this finished suspension is not used for direct administration). The finished suspension is added to the infusion bag with a syringe injection containing 100 ml of physiological saline or 5% glucose solution, and gently mixed until completely dissolved. Select 55 ml of the solution from the infusion set and discard (the remaining volume of the solution contains 250 mg of Doripenem).
Infusion solutions of the drug Doriprex В® vary from a clear and colorless to a 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 inspected prior to administration for the absence of mechanical inclusions and, when detected, is discarded.
The most common adverse effects were headache (10%), diarrhea (9%) and nausea (8%).
Determination of the frequency of undesirable effects: very often (? 1/10); often (? 1/100, <1/10); sometimes (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (? 1/100 000, <1/10 000).
From the side of the central nervous system : very often - a headache.
From the cardiovascular system: often - phlebitis.
On the part of the digestive system: often - nausea, diarrhea, increased activity of liver enzymes; sometimes - colitis caused by Clostridium difficile .
Dermatological reactions: often - itching, rash.
Allergic reactions: sometimes anaphylactic shock.
Other: often - candidiasis of the oral cavity, vaginal candidiasis.
During the period of post-production application
On the part of the hematopoiesis system : sometimes - neutropenia, thrombocytopenia.
Allergic reactions: very rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome.
It is impossible to establish the relative frequency of these reactions due to the fact that the doctors, when reporting these side effects, did not indicate the number of patients receiving Doripenem.
- age up to 18 years;
- hypersensitivity to the components of the drug;
- Hypersensitivity to other drugs group of carbapenems, as well as to beta-lactam antibiotics.
PREGNANCY AND LACTATION
Data on the use of Doripenem in a small number of pregnant women indicate that the drug does not adversely affect pregnancy, as well as the health of the fetus and newborn. Caution is needed when treating pregnant women with Doriprex В® .
If you need to use the drug Doriprex В® during lactation it is necessary to stop breastfeeding.
APPLICATION FOR CHILDREN
The drug is contraindicated for children under 18 years.
APPLICATION IN ELDERLY PATIENTS
In elderly patients , whose kidney function corresponds to their age, dose adjustment is not required.
Patients receiving beta-lactam antibiotics may experience severe, sometimes fatal, hypersensitivity reactions (anaphylactic reactions). Before starting treatment with Doripenem, the patient should be asked in detail about whether he had previously had hypersensitivity reactions to other carbapenems or to beta-lactam antibiotics. If a hypersensitivity reaction occurs on Doripenem, it should be immediately discontinued and treated accordingly. Serious hypersensitivity reactions (anaphylactic shock) require urgent therapy, including the introduction of GCS and pressor amines (adrenaline), as well as other measures including oxygen therapy, intravenous fluids, and, if necessary, the administration of antihistamines and the maintenance of airway patency .
Pseudomembranous colitis caused by Clostridium difficile can occur when treated with almost all antibacterial drugs and range from mild to life-threatening. That is why it is necessary to remember this complication if a patient receiving Doripenem has diarrhea.
Long-term use of Doripenem should be avoided to prevent excessive reproduction of microorganisms resistant to it.
Before using the drug it is recommended to carry out a bacteriological study. At the same time, it is necessary to select the appropriate samples for carrying out a bacteriological study in order to isolate the 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 the local sensitivity structure of microorganisms.
Impact on the ability to drive vehicles and manage mechanisms
Studies to evaluate the effect of Doripenem on these functions were not conducted. It is assumed that Doripenem, most likely, does not affect the ability to drive a car and work with mechanisms.
Cases of an overdose of Doripenem have not been described. In case of an overdose, stop the injection and perform symptomatic therapy until the complete excretion of Doripenem by the kidneys. At the same time, the patient's clinical condition should be monitored.
Doripenem is removed from the body by hemodialysis, but no case of hemodialysis has been described at the time of an overdose of Doripenem.
Probenezid competes with Doripenem for secretion of the renal tubules and reduces the renal clearance of Doripenem. Probenecid increases the AUC of Doripenem by 75% and T 1/2 from the plasma by 53%. Therefore, it is not recommended to simultaneously use probenecid and Doripex В® .
Doripenem does not inhibit the main isoenzymes of the cytochrome P450 system, and therefore most likely does not interact with drugs that are metabolized by this enzyme system. According to the results of in vitro studies, Doripenem does not have the ability to induce enzyme activity.
In healthy volunteers, Doripenem reduced the concentration of valproic acid in plasma to a subtherapeutic level (AUC decreased by 63%), which also agrees with the results obtained for other carbapenems. The pharmacokinetics of doripenem did not change at the same time. With the simultaneous use of doripenem and valproic acid or valproate, semiotria should monitor the concentration of the latter and consider the possibility of prescribing another treatment.
The drug can not be mixed with other drugs except sterile water d / and 0.9% sodium chloride for injection (normal saline) or 5% glucose solution.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in the original packaging of the reach of children, protected from light at a temperature of from 15 В° to 30 В° C. Shelf life - 2 years.
Conditions of storage of the finished solution : after adding the powder d doripenem sterile water and / or 0.9% sodium chloride for injection (normal saline) slurry can be stored in a vial for 1 h prior to dilution of the infusion solution.
Solvent Preservation stability of solution at 15-25 В° C Preservation solution stability at 2-8 В° C (in a refrigerator)
Saline 12 72 *
5% glucose solution ** 4 * 48
* After removal from the refrigerator infusion solution should be administered to the patient within the allowed storage time at room temperature. Thus the total storage time of the solution in the refrigerator, while warming the solution to room temperature, and the introduction of the solution to the patient must not exceed the total allowable time stored in the refrigerator.
** 5% glucose solution should not be used for infusions lasting more than 1 hour.