Zinforo, 600 mg 10 pcs

Pharmacotherapeutic group: Antibiotic, cephalosporin

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

After intravenous administration prodrug ceftaroline fosamil is rapidly converted to active ceftaroline.

The mechanism of action
Ceftarolin is an antibiotic of the class of cephalosporins with activity against Gram-positive and Gram-negative microorganisms. In in vitro studies bactericidal action of ceftarolin has been shown due to inhibition of bacterial cell wall biosynthesis due to binding to penicillin-binding proteins (PBP). Ceftaroline exhibits bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and against penicillin-insensitive Streptococcus pneumoniae (PNSP) due to its high affinity to altered PBP of these microorganisms.

The relationship between pharmacokinetics and pharmacodynamics
Antimicrobial activity of ceftaroline, as well as other beta-lactam antibiotics, correlates best with the time interval for which the drug concentration remains above the minimum suppressive concentration (%T > MPC) of the infecting microorganism.

The mechanism of resistance
Ceftarolin is not active against strains of Enterobacteriaceae producing extended spectrum beta-lactamases (ELBs) of the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B or class C metal-beta-lactamases (cephalosporinases AmpC). Resistance can also be associated with impaired bacterial cell wall permeability or active antibiotic excretion (efflux). A microorganism may have one or more resistance mechanisms.

Cross-resistance
Despite the possible development of cross-resistance, some strains resistant to other cephalosporins may be sensitive to ceftaroline.
Microorganisms with natural resistance: Chlamydophila spp. Legionella spp. Mycoplasma spp. Proteus spp. Pseudomonas aeruginosa

Interaction with other antimicrobial agents
. In vitro studies have shown no antagonism when ceftaroline is used in combination with other commonly prescribed antimicrobials (such as amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, tigecycline and vancomycin).

Sensitivity
In vitro antibiotic sensitivity varies by geographic region and over time, so local resistance information should be considered when choosing antibiotic therapy. If local resistance is such that the efficacy of the drug against certain infections becomes questionable, expert advice should be sought. Sensitivity to ceftarolin should be determined using standard methods.

The results should be interpreted according to local guidelines. Clinical efficacy against selected pathogens The pathogens (by indication) sensitive to ceftarolin in vitro for which ceftarolin has been shown to be effective in clinical trials are listed below.

Complicated skin and soft tissue infections

Gram-positive microorganisms
Staphylococcus aureus (including methicillin-resistant strains)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus) Streptococcus dysgalactiae

Gram-negative microorganisms
Escherichia coli
Klebsiella pneumoniae
Klebsiella oxytoca
Morganella morganii

Homeless pneumonia

Gram-positive microorganisms

br> Streptococcus pneumoniae (including cases with bacteremia) Staphylococcus aureus (methicillin-sensitive strains only)

Gram-negative microorganisms
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae

Efficacy against other significant pathogens The clinical efficacy of ceftarolin against the pathogens listed below has not been established, but in vitro studies suggest that they are sensitive to ceftarolin in the absence of acquired resistance mechanisms.

The Gram-positive anaerobes Peptostreptococcus spp.

Gram-negative anaerobes Fusobacterium spp.

Pharmacokinetics

The maximum concentration (Cmax) and area under the concentration-time curve (AUC) of ceftaroline increase almost in proportion to the dose with a single administration of the drug in the dose range from 50 to 1000 mg. No appreciable cephtarolin cumulation was observed after repeated intravenous administration of the drug at a dose of 600 mg for 60 minutes every 12 hours for 14 days in healthy volunteers with normal renal function.

Distribution
The degree of binding of ceftarolin to plasma proteins is low (about 20%); the drug does not penetrate into erythrocytes. The median equilibrium volume of distribution in healthy adult males after a single intravenous injection of 600 mg of isotope-labeled ceftaroline fosamil was 20.3 liters, almost the same as the extracellular fluid volume.

Metabolism
In plasma, the prodrug ceftaroline fosamil is rapidly converted to active ceftaroline under the action of phosphatases; prodrug concentrations are measurable in plasma, primarily during intravenous infusion. Hydrolysis of the beta-lactam ring of ceftaroline produces a microbiologically inactive metabolite, ceftaroline M-1. The average AUC ratio of ceftaroline M-1 to ceftaroline in plasma after a single intravenous injection of 600 mg of ceftaroline fosamil to healthy volunteers is approximately 20-30%. Metabolism of ceftaroline occurs without participation of cytochrome P450 system isoenzymes.

Excretion
Ceftaroline is excreted mainly by the kidneys. Renal clearance of ceftarolin is approximately equal or slightly lower than the glomerular filtration rate in the kidneys. In vitro transporter studies show that active secretion does not contribute to renal elimination of ceftaroline. The average half-life of ceftarolin in healthy adults is approximately 2.5 hours. After a single intravenous injection of 600 mg of isotope-labeled ceftaroline fosamyl in healthy adult men, approximately 88% radioactivity was detected in the urine and 6% in the feces.

Particular patient groups

Kidney failure
. After a single intravenous infusion of 600 mg ceftaroline fosamil for 60 minutes, the Cmax of ceftaroline in plasma was 28.4 ± 6.9 µg/mL, 28.2 ± 5.4 µg/mL and 30.8 ± 4.9 µg/mL in patients with normal renal function, mild renal impairment and moderate renal impairment, respectively. Cmax of ceftarolin was reached approximately 60 minutes after the start of infusion. The AUC of ceftaroline increased in proportion to the degree of renal failure and was 75.6 ± 9.7 µg×h/ml, 92.3 ± 25.3 µg×h/ml and 114.8 ± 14.1 µg×h/ml in patients with normal renal function, mild renal failure and moderate renal failure, respectively. Patients with moderate to severe renal failure, end-stage renal failure, including patients on hemodialysis, require dose adjustment (see section “Dosage and administration”).

Hepatic impairment
Studies of the pharmacokinetics of ceftarolin in patients with hepatic impairment have not been performed. Since ceftarolin does not undergo hepatic metabolism to a significant extent, hepatic insufficiency is not expected to significantly affect the systemic clearance of ceftarolin. Therefore, it is not recommended to adjust the dose of the drug in patients with hepatic impairment.

Elderly patients (≥65 years)
After a single intravenous injection of 600 mg of ceftaroline fosamil, the pharmacokinetic parameters of the drug were similar in healthy elderly (≥65 years) and healthy young patients (18-45 years). A slight increase in AUC0-∞ (by 33%) was observed in elderly volunteers, mainly due to age-related changes in renal function. There is no need to adjust the drug dose in elderly patients with creatinine clearance above 50 ml/min.

In children
The safety and efficacy of Zinfor® in children under 18 years of age has not been established.

Performance
Parameters of pharmacokinetics of ceftarolin were similar in men and women. There is no need to adjust the dose according to the gender of the patient.

Race
There were no significant differences in the pharmacokinetic parameters of ceftarolin in patients from different ethnic groups. There is no need to adjust the dose of the drug depending on the race of the patient.

Indications

Treatments for the following infections in adults:

complicated infections of the skin and soft tissues caused by sensitive strains of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxyloca and Morganella morganii;
community-acquired pneumonia caused by sensitive strains of the following gram-positive and gram-negative microorganisms: Streptococcus pneumoniae (including cases accompanied by bacteremia), Staphylococcus aureus (methicillin-sensitive strains only), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Klebsiella oxytoca and Escherichia coli.

Pharmacological effect

Pharmacotherapeutic group:
Antibiotic, cephalosporin

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

After intravenous administration, the prodrug ceftaroline fosamil is rapidly converted to the active ceftaroline.

Mechanism of action
Ceftaroline is an antibiotic of the cephalosporin class with activity against gram-positive and gram-negative microorganisms. In vitro studies have shown the bactericidal effect of ceftaroline due to inhibition of bacterial cell wall biosynthesis due to binding to penicillin-binding proteins (PBPs). Ceftaroline exhibits bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and against penicillin-insensitive Streptococcus pneumoniae (PNSP) due to its high affinity for the altered PBPs of these microorganisms.

Relationship between pharmacokinetics and pharmacodynamics
The antimicrobial activity of ceftaroline, as well as other beta-lactam antibiotics, is best correlated with the time interval during which the drug concentration remains above the minimum inhibitory concentration (MIC) of the infecting microorganism (%T > MIC).

Mechanism of resistance
Ceftaroline is not active against Enterobacteriaceae strains producing extended-spectrum beta-lactamases (ESBLs) of the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B or class C metallo-beta-lactamases (AmpC cephalosporinases). Resistance can also be associated with impaired permeability of the bacterial cell wall or with active elimination of the antibiotic (efflux). A microorganism may have one or more resistance mechanisms.

Cross resistance
Despite the possible development of cross-resistance, some strains resistant to other cephalosporins may be sensitive to ceftaroline.
Microorganisms with natural resistance: Chlamydophila spp. Legionella spp. Mycoplasma spp. Proteus spp. Pseudomonas aeruginosa

Interaction with other antimicrobial drugs
In vitro studies have not shown antagonism when ceftaroline was used in combination with other commonly prescribed antimicrobials (such as amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, tigecycline and vancomycin).

Sensitivity
Antibiotic susceptibility in vitro varies across geographic regions and over time, so local resistance information must be taken into account when choosing antibiotic therapy. If local resistance is such that the effectiveness of the drug against certain infections becomes questionable, expert advice should be sought. Sensitivity to ceftaroline should be determined using standard methods.

Interpretation of results should be carried out in accordance with local guidelines. Clinical efficacy against selected pathogenic microorganisms The following are pathogenic microorganisms (according to indications for use) sensitive to ceftaroline in vitro, against which ceftaroline has been shown to be effective in clinical studies.

Complicated skin and soft tissue infections

Gram-positive microorganisms
Staphylococcus aureus (including methicillin-resistant strains)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus) Streptococcus dysgalactiae

Gram-negative microorganisms
Escherichia coli
Klebsiella pneumoniae
Klebsiella oxytoca
Morganella morganii

Community-acquired pneumonia

Gram-positive microorganisms
Streptococcus pneumoniae (including cases accompanied by bacteremia) Staphylococcus aureus (methicillin-sensitive strains only)

Gram-negative microorganisms
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae

Efficacy against other important pathogens The clinical effectiveness of ceftaroline against the pathogens listed below has not been established, but in vitro studies suggest that they are susceptible to ceftaroline in the absence of acquired resistance mechanisms.

Gram-positive anaerobes Peptostreptococcus spp.

Gram-negative anaerobes Fusobacterium spp.

Pharmacokinetics

The maximum concentration (Cmax) and area under the concentration-time curve (AUC) of ceftaroline increase almost proportionally to the dose with a single dose of the drug over the dose range from 50 to 1000 mg. There was no significant accumulation of ceftaroline after repeated intravenous administration of the drug at a dose of 600 mg over 60 minutes every 12 hours for 14 days to healthy volunteers with normal renal function.

Distribution
The degree of binding of ceftaroline to plasma proteins is low (approximately 20%), the drug does not penetrate into red blood cells. The median volume of distribution at steady state in healthy adult men following a single intravenous dose of 600 mg isotope-labeled ceftaroline fosamil was 20.3 L, similar to the extracellular fluid volume.

Metabolism
In the blood plasma, under the influence of phosphatases, the prodrug ceftaroline fosamil is quickly converted into active ceftaroline; Prodrug concentrations are measurable in plasma, primarily during intravenous infusion. Hydrolysis of the beta-lactam ring of ceftaroline produces a microbiologically inactive metabolite, ceftaroline M-1. The ratio of mean AUC values ​​of ceftaroline M-1 to ceftaroline in plasma after a single intravenous administration of 600 mg ceftaroline fosamil to healthy volunteers is approximately 20-30%. The metabolism of ceftaroline occurs without the participation of isoenzymes of the cytochrome P450 system.

Excretion
Ceftaroline is excreted primarily by the kidneys. The renal clearance of ceftaroline is approximately equal to or slightly lower than the renal glomerular filtration rate. In vitro transporter studies indicate that active secretion does not contribute to the renal elimination of ceftaroline. The average elimination half-life of ceftaroline in healthy adults is approximately 2.5 hours. Following a single intravenous administration of 600 mg of ceftaroline-labeled fosamil to healthy adult men, approximately 88% of the radioactivity was detectable in urine and 6% in feces.

Special patient groups

Kidney failure
Following a single intravenous infusion of 600 mg ceftaroline fosamil over 60 minutes, the plasma Cmax of ceftaroline was 28.4 ± 6.9 mcg/mL, 28.2 ± 5.4 mcg/mL, and 30.8 ± 4.9 mcg/mL in patients with normal renal function, mild renal impairment, and moderate renal impairment, respectively. Cmax of ceftaroline was achieved approximately 60 minutes after the start of the infusion. The AUC of ceftaroline increased proportionally to the degree of renal impairment and was 75.6 ± 9.7 mcg x h/mL, 92.3 ± 25.3 mcg x h/mL, and 114.8 ± 14.1 mcg x h/mL in patients with normal renal function, mild renal impairment, and moderate renal impairment, respectively. Patients with moderate to severe renal failure, end-stage renal failure, including patients on hemodialysis, require dose adjustment (see section “Dosage and Administration”).

Liver failure
The pharmacokinetics of ceftaroline have not been studied in patients with hepatic impairment. Since ceftaroline does not undergo significant hepatic metabolism, hepatic impairment is not expected to significantly affect the systemic clearance of ceftaroline. Therefore, it is not recommended to adjust the dose of the drug in patients with liver failure.

Elderly patients (≥ 65 years)
Following a single intravenous dose of 600 mg ceftaroline fosamil, the pharmacokinetics of the drug were similar in healthy elderly subjects (≥ 65 years) and healthy young subjects (18-45 years). In elderly volunteers, a slight increase in AUC0-∞ (by 33%) was noted, which was mainly due to age-related changes in renal function. No dose adjustment is required in elderly patients with creatinine clearance above 50 ml/min.

Children
The safety and effectiveness of Zinforo® in children under 18 years of age have not been established.

Gender
The pharmacokinetic parameters of ceftaroline were similar in men and women. No dose adjustment is required depending on the gender of the patient.

Race
There were no significant differences in the pharmacokinetic parameters of ceftaroline in patients belonging to different ethnic groups. There is no need to adjust the dose of the drug depending on the race of the patient.

Special instructions

When using the drug, you must follow official recommendations for the proper use of antibacterial drugs.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious hypersensitivity reactions (sometimes fatal) may occur.

Patients with a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibiotics may also develop an allergic reaction to ceftaroline fosamil. Before starting therapy with Zinforo, the patient’s data should be carefully examined to identify hypersensitivity reactions to beta-lactam antibiotics. The drug is contraindicated in patients with a history of hypersensitivity to cephalosporins. The drug is also contraindicated in patients who have previously experienced severe immediate hypersensitivity reactions (eg, anaphylactic reaction) to any other antibacterial agent having a beta-lactam structure (eg, penicillins or carbapenems).

If a severe allergic reaction develops, it is necessary to stop administering the drug and take appropriate measures.

Diarrhea associated with Clostridium difficile

When using almost all antibacterial drugs, incl. Zinforo, the development of antibiotic-associated colitis and pseudomembranous colitis, which can vary in severity from mild to life-threatening forms, has been reported. The possibility of developing colitis should be taken into account if diarrhea occurs during the use of ceftaroline fosamil. In this case, it is necessary to stop therapy with Zinforo, carry out supportive measures and prescribe specific treatment for Clostridium difficile.

Patients with a history of seizures

As with the use of other cephalosporins, in toxicity studies of ceftaroline, the development of seizures was observed when taking the drug in doses exceeding Cmax by 7-25 times. Experience with the use of ceftaroline in patients with a history of seizures is limited, and therefore caution should be exercised when using Zinforo in this group of patients.

Kidney failure

Experience with ceftaroline in patients with severe renal failure and end-stage renal disease and in patients on hemodialysis is limited. Therefore, the use of Zinforo in this patient population is contraindicated.

Direct antiglobulin test (Coombs test)

A positive direct antiglobulin test (DAT) can be obtained during the use of cephalosporins. The rate of positive PAT in patients treated with ceftaroline fosamil was 10.7% in the pooled phase 3 studies. No patients with a positive PAT while receiving ceftaroline showed signs of hemolysis.

Insensitive microorganisms

When using ceftaroline fosamil, like other antibiotics, superinfection may develop.

Impact on the ability to drive vehicles and operate machinery

No studies have been conducted to study the effect of the drug Zinforo on the ability to drive vehicles and control other mechanisms. During therapy, dizziness may occur, so care should be taken when driving vehicles and when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. If dizziness occurs, you should refrain from performing these activities.

Active ingredient

Ceftaroline fosamil

Composition

Active ingredient:

ceftaroline fosamil acetate monohydrate 668.4 mg;

Excipients:

L-arginine – 395 mg

Pregnancy

There are no clinical data on the use of ceftaroline fosamil in pregnant women. Experimental studies in animals have not revealed any adverse effects of ceftaroline fosamil on fertility, pregnancy, childbirth or postpartum development.

Zinforo should not be used during pregnancy, unless the potential benefit to the mother outweighs the possible risk to the fetus.

There are no data on the penetration of ceftaroline into breast milk. However, due to the fact that many beta-lactam antibiotics are excreted in breast milk, if therapy with Zinforo is necessary, discontinuation of breastfeeding is recommended.

Contraindications

severe renal failure (creatinine clearance <30 ml/min) or end-stage renal failure; children under 18 years of age; hypersensitivity to any antibacterial agent having a beta-lactam structure (for example, cephalosporins, penicillins or carbapenems); hypersensitivity to ceftaroline fosamil or L-arginine.

The drug should be prescribed with caution to patients with a history of seizures.

Side Effects

Gastrointestinal tract: diarrhea, nausea, vomiting, abdominal pain, constipation.

Nervous system: headache, dizziness, convulsions.

Skin and subcutaneous tissues: rash, itching, urticaria.

Liver and biliary tract: increased transaminase activity, hepatitis.

Cardiovascular system: phlebitis, bradycardia, palpitations.

Metabolism and nutrition: hyperglycemia, hypokalemia, hyperkalemia.

General disorders and reactions at the injection site: fever, reactions at the infusion site (erythema, phlebitis, pain).

Blood and lymphatic system: anemia, thrombocytopenia, eosinophilia, neutropenia.

Immune system: hypersensitivity/anaphylaxis.

Infections and infestations: colitis caused by Clostridium difficile.

Kidneys and urinary tract: impaired renal function (increased blood creatinine concentration).

Interaction

Clinical studies examining drug interactions with ceftaroline have not been conducted.

In in vitro studies, ceftaroline did not inhibit the cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 and did not induce the isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. In this regard, the likelihood of interaction of ceftaroline with drugs that are metabolized by isoenzymes of the cytochrome P450 system is low. Ceftaroline is not metabolized by cytochrome P450 isoenzymes in vitro, therefore, the pharmacokinetic parameters of ceftaroline are unlikely to be affected when used together with inducers or inhibitors of cytochrome P450 isoenzymes.

In vitro, ceftaroline is not transported by the efflux transporters P-gp or BCRP. Ceftaroline does not inhibit P-gp and therefore interaction with substrates such as digoxin is not expected. Ceftaroline is a weak BCRP inhibitor, but this effect is not clinically significant.

In vitro studies showed that ceftaroline is not a substrate and did not inhibit organic cation transporters (OCT2) and anion transporters (OAT1, OAT3) in the kidneys; therefore, interactions with drugs that inhibit active renal secretion (eg, probenecid) or with drugs that are substrates of these transporters are unlikely.

Interaction with other antibacterial drugs

In vitro tests did not reveal antagonism when ceftaroline was coadministered with other commonly used antibacterial drugs (eg, amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, tigecycline, and vancomycin).

Overdose

Data on overdose are limited. The likelihood of overdose is higher in patients with impaired renal function. When using the drug in doses higher than recommended, the same adverse reactions were observed as when using the drug in recommended doses.

Treatment: symptomatic. Ceftaroline is partially eliminated by hemodialysis.

Storage conditions

Keep out of the reach of children.

Shelf life

2 years.

Manufacturer

ACS Dobfar S.p.A., Italy