Avceft (Powder) Instructions for Use

Marketing Authorization Holder

Jodas Expoim, LLC (Russia)

Manufactured By

Jodas Expoim, Pvt. Ltd. (India)

ATC Code

J01DD52 (Ceftazidime and beta-lactamase inhibitor)

Active Substances

Ceftazidime (Rec.INN registered by WHO)

Avibactam (Rec.INN registered by WHO)

Dosage Form

Avceft

Powder for solution for infusion 2000 mg+500 mg: vial 1, 10, 25, 48 or 100 pcs.

Dosage Form, Packaging, and Composition

Powder for concentrate for solution for infusion from white to yellow.

Excipients: sodium carbonate.

2500 mg – vials of colorless glass (1) – cardboard packs.
2500 mg – vials of colorless glass (10) – cardboard packs (for hospitals).
2500 mg – vials of colorless glass (25) – cardboard packs (for hospitals).
2500 mg – vials of colorless glass (48) – cardboard packs (for hospitals).
2500 mg – vials of colorless glass (100) – cardboard packs (for hospitals).

Clinical-Pharmacological Group

Combined antibacterial drug

Pharmacotherapeutic Group

Systemic antibacterial agents; other beta-lactam antibacterial agents; third-generation cephalosporins

Pharmacological Action

A combined drug, the active substances of which are Avibactam and Ceftazidime.

Mechanism of action

Avibactam is a non-beta-lactam beta-lactamase inhibitor. Avibactam forms a covalent bond with the enzyme, which is not subject to hydrolysis. It inhibits Ambler class A and C beta-lactamases and some class D beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), KPC and OXA-48 carbapenemases, as well as AmpC enzymes. Avibactam does not inhibit class B beta-lactamases (metallo-beta-lactamases) and is not able to inhibit many class D beta-lactamases. Avibactam does not have clinically significant antibacterial activity in vitro. Avibactam does not induce bla_AmpC transcription in Enterobacter cloacae, Citrobacter freundii or Pseudomonas aeruginosa in vitro at concentrations used for patient treatment.

Ceftazidime is a broad-spectrum antibiotic of the cephalosporin class, the activity of which against many significant gram-negative and gram-positive pathogenic bacteria has been demonstrated in vitro. Ceftazidime disrupts the synthesis of the bacterial cell wall peptidoglycan by interacting with penicillin-binding proteins (PBPs), leading to cell wall destruction and bacterial death.

Resistance

Mechanism of resistance. The drug is not active against bacteria producing metallo-beta-lactamases. Bacterial resistance mechanisms that could potentially affect the drug’s activity include mutant or acquired PBPs, reduced permeability of the outer membrane to avibactam or ceftazidime, active efflux of avibactam or ceftazidime, and beta-lactamases resistant to avibactam inhibition and capable of hydrolyzing Ceftazidime.

Cross-resistance. The absence of cross-resistance between the drug and fluoroquinolones or aminoglycosides has been demonstrated in vitro using clinically described isolates at the molecular level. Some isolates resistant to ceftazidime (or other cephalosporins) or carbapenems are susceptible to the Ceftazidime/Avibactam combination. Cross-resistance with antibacterial drugs from the beta-lactam group, including carbapenems, has been noted when the resistance mechanism is the production of metallo-beta-lactamases, such as VIM-2.

Interaction with other antibacterial drugs

In in vitro studies, when the drug was used concomitantly with metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin, and tigecycline, neither synergism nor antagonism was observed.

Susceptibility

The prevalence of acquired resistance of certain microorganism species may vary by region and over time. It is advisable to obtain local information on resistance, especially when treating severe infections. Susceptibility to the drug for specific clinical isolates should be determined using standard methods. Interpretation of microbiological study results should be performed in accordance with local guidelines.

Breakpoints for determining bacterial susceptibility

The minimum inhibitory concentration (MIC) breakpoints are presented in Table 1.

Table 1. MIC values for the Ceftazidime/Avibactam combination

Pharmacokinetic/pharmacodynamic relationship

The antibacterial activity of ceftazidime against certain microorganisms best correlated with the percentage of the dosing interval during which the free drug concentration was above the MIC of the Ceftazidime/Avibactam combination (%fT>MIC of the Ceftazidime/Avibactam combination). For avibactam, the pharmacokinetic/pharmacodynamic index is the percentage of the dosing interval during which the free drug concentration was above the threshold (%fT>Ct).

Clinical efficacy against specific pathogens

Clinical studies have demonstrated the efficacy of the drug against bacteria listed under each clinical indication that were susceptible to the Ceftazidime/Avibactam combination in vitro.

Complicated intra-abdominal infections

Gram-negative microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa.

Complicated urinary tract infections

Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa.

The clinical efficacy of the drug against the pathogens listed below, relevant for the approved indications for use, has not been established, but in vitro study results suggest that they are susceptible to the Ceftazidime/Avibactam combination in the absence of acquired resistance mechanisms.

Gram-negative microorganisms: Citrobacter koseri, Enterobacter aerogenes, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Serratia marcescens.

In vitro, the following microorganism species are resistant to the Ceftazidime/Avibactam combination

• Staphylococcus aureus (methicillin-susceptible and methicillin-resistant);
• Anaerobes (Enterococcus spp., Stenotrophomonas maltophilia, Acinetobacter spp.).

Pharmacokinetics

The degree of binding of ceftazidime and avibactam to plasma proteins is low, approximately 10% and 8%, respectively. In healthy adult volunteers after multiple administration of the drug at a dose of 2000 mg+500 mg as a 2-hour infusion every 8 hours, the V_d of ceftazidime and avibactam at steady state are comparable, approximately 22 L and 18 L, respectively. The pharmacokinetic parameters of ceftazidime and avibactam after single and multiple administration of the drug were similar to those determined after administration of ceftazidime or avibactam separately. Ceftazidime and Avibactam penetrate into the bronchial epithelial lining fluid at concentrations constituting 30% of plasma concentrations, with a similar concentration-time profile in the bronchial epithelial lining fluid and plasma.

Plasma exposures of ceftazidime and avibactam were comparable in patients with complicated intra-abdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia.

Ceftazidime poorly penetrates the intact blood-brain barrier, so ceftazidime concentrations in the cerebrospinal fluid in the absence of inflammation are low. However, when meningitis occurs, concentrations in the cerebrospinal fluid reach 4-20 mg/L or more. Clinical studies on the penetration of avibactam through the blood-brain barrier have not been conducted; however, in rabbits with meningitis, the exposures of ceftazidime and avibactam in the cerebrospinal fluid were 43% and 38% of the plasma AUC value, respectively. Ceftazidime concentrations exceeding the MIC for most common pathogens can be achieved in bone tissue, heart tissues, bile, sputum, synovial fluid, intraocular fluid, and pleural and peritoneal fluids. Ceftazidime crosses the placental barrier well and is excreted in breast milk. Avibactam penetrates into soft tissues in the area of skin infections, with tissue drug concentrations approximately equal to free drug concentrations in plasma.

Ceftazidime is not metabolized. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged Avibactam was the main drug component in human plasma and urine after administration of ¹⁴C avibactam.

The T_1/2 of ceftazidime and avibactam after IV administration is 2 hours. Ceftazidime is excreted by the kidneys unchanged via glomerular filtration; approximately 80-90% of the drug dose is excreted by the kidneys within 24 hours. Less than 1% of ceftazidime is excreted by the liver, and less than 0.25% of avibactam is excreted via the intestine. Avibactam is excreted by the kidneys unchanged, renal clearance is approximately 158 ml/min, indicating active secretion in the renal tubules, in addition to glomerular filtration; approximately 97% of the drug dose is excreted by the kidneys, 95% within 12 hours.

The pharmacokinetic parameters of ceftazidime and avibactam after single IV administration are approximately linear over the studied dose range (from 50 mg to 2000 mg). After multiple IV infusions of the drug at a dose of 2000 mg+500 mg every 8 hours for 11 days in healthy adult volunteers with normal renal function, no noticeable accumulation of ceftazidime and avibactam was observed.

Pharmacokinetics in special clinical cases

In patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease, including patients on hemodialysis, the elimination of ceftazidime and avibactam is reduced. In patients with CrCl ≤50 ml/min, the dose of ceftazidime and the dose of avibactam should be adjusted.

Mild to moderate hepatic impairment did not affect the pharmacokinetic parameters of ceftazidime in patients receiving it IV at a dose of 2 g every 8 hours for 5 days, provided that renal function was not impaired. Since Ceftazidime and Avibactam do not undergo significant metabolism in the liver, the systemic clearance of either active substance of the drug is not significantly impaired in hepatic impairment.

In elderly patients, a decrease in ceftazidime clearance was noted, mainly due to an age-related decrease in the renal clearance of ceftazidime. After IV bolus administration of ceftazidime at a dose of 2 g every 12 hours to patients aged ≥80 years, the mean T_1/2 ranged from 3.5 hours to 4 hours. After a single IV administration of 500 mg avibactam as a 30-minute infusion, the T_1/2 of avibactam in elderly patients increased, which could be associated with an age-related decrease in renal clearance.

The pharmacokinetic parameters of ceftazidime were similar in men and women. No adjustment of the ceftazidime dose and the avibactam dose is required based on gender.

Based on the results of population pharmacokinetic analysis, no adjustment of the ceftazidime-avibactam dose is required based on the race of patients.

Indications

Treatment of the following infections in adult patients: complicated intra-abdominal infections; complicated urinary tract infections, including pyelonephritis; hospital-acquired pneumonia, including ventilator-associated pneumonia; infections caused by aerobic gram-negative microorganisms in patients with limited choice of antibacterial therapy.

Official recommendations on the use of antibacterial drugs should be taken into account.

ICD codes

Dosage Regimen

The contents of one vial of the drug (2000 mg ceftazidime+500 mg avibactam) are administered IV as a 100 ml infusion at a constant rate over 120 minutes every 8 hours, if CrCl ≥51 ml/min.

The following duration of therapy is recommended

• Complicated intra-abdominal infections^1,2 – 5-14 days;
• Complicated urinary tract infections, including pyelonephritis² – 5-10 days³;
• Hospital-acquired pneumonia, including ventilator-associated pneumonia² – 7-14 days;
• Infections caused by aerobic gram-negative microorganisms in patients with limited choice of antibacterial therapy^1,2 – the duration of therapy depends on the severity of the infection, the pathogen, the clinical and bacteriological response to treatment⁴.

¹If the participation of anaerobic pathogens in the infectious process is confirmed or suspected, the drug should be used in combination with metronidazole.

²If the participation of gram-positive pathogens is confirmed or suspected, the drug should be used in combination with an antibacterial drug effective against these microorganisms.

³The indicated duration of therapy may include IV therapy with the drug followed by a switch to an appropriate antibacterial drug taken orally.

⁴Experience with the drug for more than 14 days is very limited.

Dose adjustment in elderly patients (≥65 years) is not required. The dose should be adjusted in case of renal impairment.

Patients with mild renal impairment (CrCl ≥51-<80 ml/min) do not require dose adjustment.

Table 2 provides recommendations for dose adjustment of the drug in patients with CrCl ≤50 ml/min.

Table 2. Recommended dosing regimen of the drug in patients with CrCl ≤50 ml/min

¹CrCl was calculated using the Cockcroft-Gault formula.

²Dosing recommendations are based on pharmacokinetic modeling.

³Ceftazidime and Avibactam are removed by hemodialysis. On hemodialysis days, the drug should be administered after the end of the session.

Insufficient data are available to provide specific recommendations for dose adjustment in patients receiving continuous venovenous hemofiltration and in patients receiving peritoneal dialysis.

Dose adjustment in patients with hepatic impairment is not required. Careful clinical monitoring is recommended to assess safety and efficacy.

The safety and efficacy of the drug in children and adolescents under 18 years of age have not been established.

Preparation of the solution for infusion

The powder for concentrate for solution for infusion should be dissolved with sterile water for injections. Standard aseptic techniques should be used during preparation and administration of the solution.

1. Through a syringe needle inserted into the vial stopper, inject 10 ml of sterile water for injections into the vial.

2. Then remove the needle and shake the vial until a clear solution is obtained. The resulting concentrate is a pale yellow solution, free of visible particles.

3. Then insert a syringe needle (to reduce internal pressure) into the vial stopper. Do not insert the pressure equalization needle until the powder is dissolved to preserve the sterility of the drug.

4. The resulting concentrate should be used immediately to prepare the solution for infusion. The concentration of ceftazidime and avibactam in the resulting concentrate is 167.3 mg/ml and 41.8 mg/ml, respectively. The resulting concentrate should be immediately transferred to an infusion bottle containing one of the compatible infusion fluids: 0.9% sodium chloride solution, 5% dextrose solution, 0.45% sodium chloride and 2.5% dextrose solution, Ringer’s lactate solution.

To obtain a ceftazidime-avibactam dose of 2000 mg+500 mg, the entire resulting concentrate (approximately 12 ml) is transferred to a bottle with compatible infusion fluid. To obtain a reduced ceftazidime-avibactam dose of 1000 mg+250 mg, 6 ml of concentrate should be transferred to the infusion bottle, and for a dose of 750 mg+187.5 mg – 4.5 ml of concentrate.

The solution for infusion can be prepared by adding the concentrate to a 100 ml bottle of infusion fluid, taking into account the characteristics and limitations of fluid administration in patients.

The time from the start of powder dissolution to the completion of the infusion solution preparation should not exceed 30 minutes.

Each vial is intended for single use only.

Unused drug or waste must be disposed of in accordance with local requirements.

Adverse Reactions

In six phase 2 and phase 3 clinical trials, the drug was administered to 1588 adult patients. The most frequent adverse reactions observed in ≥5% of patients receiving the drug were a positive direct Coombs test, nausea, and diarrhea. Nausea and diarrhea were usually mild or moderate in severity.

The following are adverse reactions observed during ceftazidime monotherapy and/or in phase 2 and phase 3 clinical trials of the drug, indicating system organ classes and frequency. The frequency of adverse reactions and/or potentially clinically significant laboratory abnormalities is presented using the following gradation: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), frequency not known (frequency cannot be estimated from the available data).

Infections and infestations common – candidiasis (including vulvovaginal candidiasis and oral candidiasis); uncommon – Clostridium difficile-associated colitis, pseudomembranous colitis.

Blood and lymphatic system disorders very common – positive direct Coombs test; common – eosinophilia, thrombocytosis; uncommon – neutropenia, leukopenia, thrombocytopenia, lymphocytosis; frequency not known – agranulocytosis, hemolytic anemia.

Immune system disorders frequency not known – anaphylactic reaction.

Nervous system disorders common – headache, dizziness; uncommon – paresthesia.

Gastrointestinal disorders common – diarrhea, abdominal pain, nausea, vomiting, increased ALT, increased AST, increased alkaline phosphatase, increased GGT, increased LDH; uncommon – taste perversion; frequency not known – jaundice.

Skin and subcutaneous tissue disorders common – maculopapular rash, urticaria; uncommon – pruritus; frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, drug rash with eosinophilia and systemic symptoms.

Renal and urinary disorders uncommon – increased blood creatinine, increased blood urea, acute renal failure; very rare – tubulointerstitial nephritis.

General disorders and administration site conditions common – infusion site thrombosis, infusion site phlebitis, pyrexia.

Contraindications

Children and adolescents under 18 years of age (efficacy and safety not established); hypersensitivity to avibactam, ceftazidime, or sodium carbonate (excipient included in the drug formulation); hypersensitivity to cephalosporins; severe immediate-type hypersensitivity reactions (e.g., anaphylactic reaction) to any other antibacterial agent with a beta-lactam structure (e.g., penicillins, monobactams, or carbapenems).

With caution non-severe hypersensitivity reactions to other drugs with a beta-lactam structure.

Use in Pregnancy and Lactation

Animal studies have not revealed any direct or indirect adverse effects of ceftazidime on pregnancy, embryofetal development, parturition, or postnatal development. Reproductive toxicity of avibactam was demonstrated in animal studies, but no teratogenic effects were identified.

Use of the drug during pregnancy is possible only if the potential benefit outweighs the possible risk.

Ceftazidime is excreted in breast milk in small amounts. It has not been established whether Avibactam is excreted in breast milk. A risk to the newborn/infant cannot be excluded. A decision should be made to discontinue breastfeeding or to discontinue/abstain from therapy with the drug, taking into account the potential benefit of therapy for the woman and the benefits of breastfeeding for the infant.

The effect of the drug on human fertility has not been studied. There are no data from studies on the effect of ceftazidime on animal fertility. In animal studies, Avibactam did not have adverse effects on fertility.

Use in Hepatic Impairment

Dosage adjustment in patients with impaired hepatic function is not required.

Use in Renal Impairment

In patients with CrCl ≤50 ml/min, the dose of the drug should be adjusted.

Pediatric Use

Use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Dosage adjustment in elderly patients (≥65 years) is not required.

Special Precautions

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious hypersensitivity reactions (sometimes fatal) may occur. If an allergic reaction occurs, administration of the medicinal product should be discontinued immediately and necessary medical measures should be initiated promptly.

Before initiating therapy with the drug, the patient’s history should be carefully reviewed for hypersensitivity reactions to ceftazidime, other cephalosporins, and other beta-lactam antibiotics. The drug is contraindicated in patients with a history of hypersensitivity to ceftazidime or cephalosporins. The drug is also contraindicated in patients who have previously had severe hypersensitivity reactions to any other antibacterial agent with a beta-lactam structure (e.g., penicillins, monobactams, or carbapenems).

Caution should be exercised when prescribing the drug to patients with non-severe hypersensitivity reactions to other drugs with a beta-lactam structure.

Limitations of clinical trial data

Hospital-acquired pneumonia, including ventilator-associated pneumonia. Use of the drug is based on experience with ceftazidime and on the results of analysis of the relationship between pharmacokinetic/pharmacodynamic parameters of ceftazidime-avibactam.

Patients with limited therapeutic options. The drug should be used for the treatment of patients with infections caused by gram-negative aerobic microorganisms and limited therapeutic options only after consultation with a physician experienced in the treatment of infectious diseases. Use of the drug for such infections is based on extrapolation of pharmacokinetic and pharmacodynamic data; clinical trials have not been conducted.

Clostridium difficile-associated diarrhea

Antibiotic-associated colitis and pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with the use of nearly all antibacterial agents, including ceftazidime-avibactam. Therefore, it is important to consider these diagnoses in patients who develop diarrhea during or after therapy with the drug. Therapy with the drug should be discontinued and specific treatment for Clostridium difficile infection should be considered. Medications that inhibit intestinal peristalsis are contraindicated.

Renal impairment

Avibactam and Ceftazidime are eliminated by the kidneys, so in patients with impaired renal function, the dose of the drug should be reduced according to the severity of the impairment. In patients with renal impairment, the efficacy and safety of therapy should be carefully monitored. Neurological disorders, including tremor, myoclonus, non-convulsive status epilepticus, convulsions, encephalopathy, and coma, have sometimes been observed in patients with renal impairment treated with ceftazidime at a dose not reduced according to the impaired renal function.

Spectrum of activity of the drug

Ceftazidime has little or no activity against most gram-positive microorganisms, as well as anaerobic microorganisms. Additional antibacterial agents should be used if the involvement of these microorganisms in the infectious process is confirmed or suspected.

The spectrum of inhibitory activity of avibactam includes many enzymes that can inactivate Ceftazidime, including Ambler class A and C β-lactamases. Avibactam does not inhibit class B β-lactamases (metallo-β-lactamases) and is not capable of inhibiting many class D β-lactamases.

Non-susceptible microorganisms

Prolonged use may lead to the overgrowth of non-susceptible microorganisms (e.g., enterococci, fungi), which may require discontinuation of treatment or appropriate therapy.

Effect on laboratory test results

Ceftazidime does not affect the results of enzymatic tests for detecting glucose in urine, but a slight effect (false-positive result) is observed when using Benedict’s reagent, Fehling’s reagent, or Clinitest tablets for urine glucose.

Ceftazidime does not affect the analysis of creatinine concentration using the alkaline picrate method.

Direct antiglobulin test (Coombs test) and potential risk of hemolytic anemia

A positive direct antiglobulin test (DAT) may occur during treatment with cephalosporins, which may interfere with blood cross-matching tests and/or lead to drug-induced immune hemolytic anemia. Although seroconversion in DAT results was frequently observed in clinical trials in patients receiving the drug, no signs of hemolysis were detected in these patients during treatment. However, the possibility of hemolytic anemia associated with therapy with the drug cannot be ruled out. In patients who develop anemia during or after therapy with the drug, hemolytic anemia should be considered.

Sodium-restricted diet

Each vial of the drug contains 6.44 mmol of sodium (approximately 148 mg). This should be taken into account when prescribing the drug to patients on a sodium-restricted diet.

Effect on ability to drive and use machines

No studies on the effects of the drug on the ability to drive and use machines have been performed, however, adverse reactions (e.g., dizziness) may affect the ability to drive and use machines.

Drug Interactions

Avibactam did not significantly inhibit cytochrome P450 isoenzymes. Avibactam and Ceftazidime at clinically relevant exposure ranges did not induce cytochrome P450 isoenzymes in vitro. Avibactam and Ceftazidime at clinically relevant exposure ranges do not inhibit major transporters in the kidneys and liver, so the likelihood of drug interactions via these mechanisms is considered low.

In vitro, Avibactam is a substrate of OAT1 and OAT3 transporters, which may contribute to its active uptake from the bloodstream and thus its excretion. Probenecid (a potent OAT inhibitor) inhibited this uptake by 56-70% in vitro, and therefore, when used concomitantly with avibactam, may affect the elimination of the latter. Clinical interaction studies of avibactam and probenecid have not been conducted, so it is not recommended to use Avibactam in combination with probenecid.

Clinical data confirm the absence of interaction between ceftazidime and avibactam, as well as between ceftazidime-avibactam and metronidazole.

Use of high doses of cephalosporins in combination with nephrotoxic drugs, such as aminoglycosides or potent diuretics (e.g., furosemide), may lead to impaired renal function.

Chloramphenicol is an antagonist of ceftazidime and other cephalosporins in vitro. The clinical significance of these data is unknown, but due to the possibility of antagonism in vivo, concomitant use of these drugs should be avoided.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.