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

Treatment in adults of the following infections:

Active ingredient

Composition

Active ingredient:

cephtaroline fosamyl acetate monohydrate668.4 mg;

Associates:

L-arginine – 395 mg

How to take, the dosage

Zinforo™ is administered intravenously as an infusion over 60 minutes.

The duration of therapy should be determined according to the type and severity of the infection and the patient’s response to therapy.

The following dosing regimen is recommended:

Interaction

There have been no clinical studies of drug interactions with ceftarolin.

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

In vitro ceftarolin is not tolerated by efflux transporters P-gp or BCRP. Ceftaroline does not inhibit P-gp; therefore, interactions with substrates such as digoxin are not expected. Ceftarolin is a weak BCRP inhibitor, but this effect is not clinically relevant.

In vitro studies have shown that ceftarolin is not a substrate, and has not inhibited organic cation transporters (OAT2) and anions (OAT1, OAT3) in the kidneys; therefore, interactions with drugs that inhibit active renal secretion (such as probenecid) or with drugs that are substrates of these transporters are unlikely.

Interaction with other antibacterial drugs

. In vitro tests have shown no antagonism when ceftarolin and other commonly used antibacterial drugs (e.g., amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, tigecycline and vancomycin) are used together.

Special Instructions

The official guidelines for the appropriate use of antibacterial drugs must be followed when using the drug.

Hypersensitivity reactions

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

Patients with a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibiotics may also develop an allergic reaction to ceftaroline fosamil. Before initiating therapy with Zinforo, patient data should be carefully reviewed for 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 had severe reactions of immediate hypersensitivity (e.g., anaphylactic reaction) to any other antibacterial agent having a beta-lactam structure (e.g., penicillins or carbapenems).

If a severe allergic reaction develops, the drug administration must be stopped and appropriate measures taken.

Diarrhea associated with Clostridium difficile

The development of antibiotic-associated colitis and pseudomembranous colitis, which may vary in severity from mild to life-threatening, has been reported with almost all antibacterial drugs, including Zinforo. It should be taken into account the possibility of colitis if diarrhea occurs during the use of ceftarolin fosamil. In this case, therapy with Zinforo should be discontinued, supportive measures should be taken and specific treatment for Clostridium difficile should be prescribed.

Patients with a history of seizure syndrome

As with other cephalosporins, seizure development has been observed in studies of ceftaroline toxicity when the drug is taken at doses 7-25 times greater than Cmax. The experience of using ceftarolin in patients with a history of seizure syndrome is limited; therefore, caution should be exercised when using Zinforo in this group of patients.

Renal failure

The experience of using ceftarolin in patients with severe and end-stage renal failure and in patients on hemodialysis is limited. Therefore, the use of Zinforo in this patient population is contraindicated.

The direct antiglobulin test (Coombs test)

A positive direct antiglobulin test (DAT) may be obtained with cephalosporins. The incidence of a positive PAT in patients treated with ceftaroline fosamil was 10.7% in pooled phase 3 studies. No patient with a positive PAT on ceftarolin showed evidence of hemolysis.

Intolerant microorganisms

Superinfection can occur when using ceftaroline fosamil, as with other antibiotics.

Impact on driving and operating machinery

There have been no studies of the effect of Zinforo on driving and operating other mechanisms. During the therapy dizziness may arise, therefore caution should be exercised while driving motor transport and engaging in other potentially dangerous activities, which require high concentration and quick psychomotor reactions. In case of dizziness one should refrain from performing the specified activities.

Contraindications

Side effects

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

Nervous system: headache, dizziness, seizures.

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 site of administration: fever, reactions at the site of infusion (erythema, phlebitis, pain).

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

Immune system: hypersensitivity/anaphylaxis.

Infections and invasions: colitis caused by Clostridium difficile.

Kidney and urinary tract: renal dysfunction (increased blood creatinine concentration).

Overdose

Treatment: symptomatic. Ceftarolin is partially excreted with hemodialysis.

Pregnancy use

The drug Zinforo should not be used in pregnancy unless the potential benefit to the mother outweighs the possible risk to the fetus.

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