Refex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REFEX (REFEX)

Composition:

Active substances: piperacillin, tazobactam;

1 vial of the drug (2 g/0.25 g) contains sodium piperacillin equivalent to piperacillin 2 g and sodium tazobactam equivalent to tazobactam 0.25 g; or 1 vial of the drug (4 g/0.5 g) contains sodium piperacillin equivalent to piperacillin 4 g and sodium tazobactam equivalent to tazobactam 0.5 g.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: white or almost white powder, possibly with lumps.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Piperacillin and beta-lactamase inhibitors.

ATC code J01CR05.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Piperacillin, a broad-spectrum semisynthetic penicillin, exerts bactericidal activity by inhibiting bacterial cell wall and septum synthesis.

Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases that commonly cause resistance to penicillins and cephalosporins, but it does not inhibit AmpC enzymes or metallo-beta-lactamases. Tazobactam extends the spectrum of piperacillin by covering most strains of microorganisms that produce beta-lactamases and are resistant to piperacillin alone.

Pharmacokinetic/pharmacodynamic relationship

The time during which the drug concentration in blood plasma exceeds its minimum inhibitory concentration (T > MIC) is considered the primary pharmacodynamic parameter determining the efficacy of piperacillin.

Mechanism of resistance

Two main mechanisms of bacterial resistance to piperacillin/tazobactam:

• Inactivation of piperacillin by beta-lactamases not inhibited by tazobactam: beta-lactamases of molecular classes B, C, and D. Additionally, tazobactam does not provide protection against extended-spectrum beta-lactamases (ESBLs) of molecular classes A and D.
• Alteration of penicillin-binding proteins (PBPs), leading to reduced affinity of piperacillin for its molecular target in bacteria.

Furthermore, changes in bacterial membrane permeability, as well as expression of efflux pumps capable of expelling multiple drugs, may cause or contribute to the development of bacterial resistance to piperacillin/tazobactam, particularly in Gram-negative bacteria.

Clinical breakpoints for susceptibility testing

Susceptibility

The prevalence of acquired resistance may vary geographically and over time for specific species, so local information on bacterial resistance is required, especially when treating severe infections. If necessary, when local resistance prevalence calls into question the appropriateness of using the medicinal product for certain infections, refer to official guidelines on the proper use of antibacterial agents.

Merino study (bloodstream infections caused by ESBL-producing organisms)

In a prospective, open-label, randomized, parallel-group, non-inferiority clinical trial, definitive therapy (i.e., based on in vitro susceptibility testing) with piperacillin/tazobactam compared to meropenem did not result in non-inferior 30-day mortality in adult patients with ceftriaxone-resistant bloodstream infections due to E. coli or K. pneumoniae.

Overall, 23 of 187 patients (12.3%) randomized to receive piperacillin/tazobactam died within 30 days compared to 7 of 191 patients (3.7%) randomized to receive meropenem (risk difference 8.6% [one-sided 97.5% CI −∞ to 14.5%]; P = 0.90 for non-inferiority). The difference did not meet the pre-specified non-inferiority margin of 5%.

Effects were consistent in the per-protocol population analysis: 18 of 170 patients (10.6%) achieved the primary outcome in the piperacillin/tazobactam group compared to 7 of 186 (3.8%) in the meropenem group (risk difference 6.8% [one-sided 97.5% CI −∞ to 12.8%]; P = 0.76 for non-inferiority).

Clinical and microbiological responses (secondary outcomes) on day 4 were observed in 121 of 177 patients (68.4%) in the piperacillin/tazobactam group compared to 138 of 185 (74.6%) randomized to meropenem (risk difference 6.2% [95% CI −15.5 to 3.1%]; P = 0.19). For secondary outcomes, two-sided statistical tests were used, with P < 0.05 considered statistically significant.

This study identified a mortality imbalance between the treatment groups. Deaths in the piperacillin/tazobactam group were considered to be related to underlying comorbidities rather than the concurrent infection.

Pharmacokinetics

Absorption

Peak concentrations of piperacillin and tazobactam after intravenous infusion at doses of 4 g/0.5 g over more than 30 minutes are 298 µg/mL and 34 µg/mL, respectively.

Distribution

Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. Binding to plasma proteins of piperacillin and tazobactam is independent of the presence of the other component of the drug. Protein binding of the tazobactam metabolite is negligible.

Piperacillin/tazobactam freely distributes into body tissues and fluids, including intestinal mucosa, gallbladder, lungs, bile, and bone. Tissue concentrations generally range from 50% to 100% of plasma concentrations. As with other penicillin-class agents, distribution of piperacillin and tazobactam into cerebrospinal fluid is low in the absence of meningeal inflammation.

Biotransformation

Piperacillin is metabolized to a desethyl metabolite, which exhibits minimal microbiological activity. Tazobactam is metabolized to a single, microbiologically inactive metabolite.

Elimination

Piperacillin and tazobactam are eliminated by the kidneys via glomerular filtration and tubular secretion.

Piperacillin is rapidly excreted unchanged, with 68% of the administered dose recovered in urine. Tazobactam and its metabolite are primarily eliminated by the kidneys, with 80% of the administered dose excreted unchanged and the remainder as a single metabolite. Piperacillin, tazobactam, and desethylpiperacillin are also secreted into bile.

After single or multiple doses of piperacillin/tazobactam administered to healthy volunteers, the plasma elimination half-life ranged from 0.7 to 1.2 hours. Dose and duration of infusion did not influence this parameter. The elimination half-life of both piperacillin and tazobactam increases with reduced renal clearance.

Administration of tazobactam did not significantly affect the pharmacokinetics of piperacillin. Piperacillin reduces the clearance of tazobactam.

Special patient populations

The elimination half-lives of piperacillin and tazobactam increase by approximately 25% and 18%, respectively, in patients with liver cirrhosis compared to healthy individuals.

The elimination half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. When creatinine clearance is below 20 mL/min, the half-life increases by 2-fold for piperacillin and 4-fold for tazobactam compared to patients with normal renal function.

Hemodialysis removes 30% to 50% of piperacillin/tazobactam, and an additional 5% of tazobactam is eliminated as metabolite. Peritoneal dialysis removes approximately 6% and 21% of the dose of piperacillin and tazobactam, respectively, including up to 18% of the tazobactam dose as metabolite.

Paediatric population

In pharmacokinetic studies in patients aged 9 months to 12 years, the approximate clearance was compared to that in adults. The mean value for this age group (standard deviation) was 5.64 (0.34) mL/min/kg. Approximate piperacillin clearance in patients aged 2 to 9 months was 80% of this value. The mean volume of distribution of piperacillin for this age group (standard deviation) was 0.243 (0.011) L/kg and was independent of age.

Elderly patients

The mean elimination half-life of piperacillin and tazobactam in elderly patients was 32% and 55% longer, respectively, compared to younger patients. This difference is likely attributable to age-related changes in creatinine clearance.

Race

No differences in the pharmacokinetics of piperacillin and tazobactam were observed between Asian (n = 9) and European (n = 9) healthy volunteers who received a single 4 g/0.5 g dose.

Clinical characteristics.

Indications.

Refex is indicated for the treatment of the following infections in adults and children aged 2 years and older:

Adults and children aged 12 years and older:

• severe pneumonia (including hospital-acquired and ventilator-associated pneumonia);
• complicated urinary tract infections (including pyelonephritis);
• complicated intra-abdominal infections;
• complicated skin and soft tissue infections (including infectious complications in diabetic foot syndrome).

Treatment of patients with bacteremia associated or concurrent with any of the above-mentioned infections.

Refex may be used for the treatment of fever in patients with neutropenia likely caused by bacterial infection.

Note: Treatment of bacteremia caused by extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae (resistant to ceftriaxone) in adult patients is not recommended (see section "Pharmacological properties").

Children aged 2 to 12 years:

• complicated intra-abdominal infections.

Refex may be used for the treatment of fever in children with neutropenia likely caused by bacterial infection.

It is recommended to follow official guidelines on the use of antibacterial agents.

Contraindications.

Hypersensitivity to the active substances, any penicillins, or any of the excipients of the medicinal product.

History of acute severe allergic reactions to any other beta-lactam agents (e.g., cephalosporins, monobactams, or carbapenems).

Interaction with other medicinal products and other forms of interaction.

Non-depolarizing muscle relaxants

Concomitant administration of piperacillin with vecuronium results in prolonged neuromuscular blockade. Due to a similar mechanism of action, neuromuscular blockade caused by any non-depolarizing muscle relaxant may be prolonged when piperacillin is administered.

Anticoagulants

When used concomitantly with heparin, oral anticoagulants, and other agents affecting the blood coagulation system, including platelet function, coagulation tests should be monitored regularly.

Methotrexate

Piperacillin may reduce methotrexate elimination. In patients receiving methotrexate, serum levels should be monitored to prevent toxic effects.

Probenecid

As with other penicillin group agents, concomitant administration of probenecid and piperacillin/tazobactam leads to prolonged elimination half-life and reduced renal clearance of both piperacillin and tazobactam. However, this does not affect the maximum plasma concentration of the active substances.

Aminoglycosides

Piperacillin alone or in combination with tazobactam does not significantly alter the pharmacokinetics of tobramycin in patients with normal renal function or mild to moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam, and metabolite M1 were also not significantly altered when tobramycin was administered.

In patients with severe renal impairment, inactivation of tobramycin and gentamicin by piperacillin has been observed.

Information on the concomitant use of piperacillin/tazobactam with aminoglycosides is provided in the sections "Incompatibilities" and "Dosage and administration".

Vancomycin

Studies have shown an increased incidence of acute kidney injury in patients receiving piperacillin/tazobactam and vancomycin concurrently, compared to vancomycin alone (see section "Special precautions for use"). In some of these studies, the interaction was reported to be vancomycin dose-dependent.

No pharmacokinetic interactions between piperacillin/tazobactam and vancomycin have been observed.

Effect on laboratory tests

As with other penicillin group agents, the use of Refex may result in false-positive urine glucose tests (when measured by non-enzymatic methods). Therefore, during Refex therapy, enzymatic methods are recommended for measuring urine glucose.

Some chemical methods for measuring urine protein may yield false-positive results. The use of the medicinal product does not affect protein determination in urine using test strips.

Direct Coombs test results may be positive.

False-positive results in the Platelia Aspergillus ELISA (enzyme-linked immunosorbent assay) by Bio-Rad Laboratories have been reported in patients treated with Refex. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses in the Platelia Aspergillus ELISA by Bio-Rad Laboratories have also been reported.

Positive results of the above-mentioned tests in patients receiving Refex must be confirmed by other diagnostic methods.

Special precautions for use.

When selecting this medicinal product for the treatment of a specific patient, consideration should be given to the appropriateness of using a broad-spectrum semisynthetic penicillin based on factors such as the severity of infection and the prevalence of resistance to other relevant antibacterial agents.

Prior to initiating therapy with Refex, a careful history regarding hypersensitivity reactions to penicillins, other beta-lactam agents (e.g., cephalosporins, monobactams, or carbapenems), and other allergens should be obtained. Serious and occasionally fatal hypersensitivity reactions (anaphylactic/anaphylactoid reactions, including shock) have been reported in patients receiving penicillin therapy, including piperacillin/tazobactam. These reactions are more likely to occur in individuals with a history of multiple allergen sensitivity. Serious hypersensitivity reactions require immediate discontinuation of the antibiotic and may require administration of epinephrine and other emergency measures.

Refex may cause severe skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (see section "Adverse reactions"). If skin rash develops in a patient, careful monitoring is required, and Refex should be discontinued if skin lesions progress.

Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in patients receiving piperacillin/tazobactam, more frequently after treatment lasting longer than 10 days. HLH is a life-threatening syndrome characterized by pathological immune system activation, with clinical signs and symptoms of excessive systemic inflammation (e.g., fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, high serum ferritin levels, cytopenia, and hemophagocytosis). Patients who develop early signs of pathological immune activation should be evaluated immediately. If HLH is diagnosed, piperacillin/tazobactam therapy should be discontinued.

Antibiotic-associated pseudomembranous colitis may present as severe, persistent diarrhea, which may be life-threatening. Symptoms of pseudomembranous colitis may occur during or after antibacterial therapy. In such cases, Refex should be discontinued.

Treatment with Refex may lead to the emergence of resistant microorganisms, potentially resulting in superinfections.

In some patients receiving beta-lactam antibiotics, symptoms of bleeding have been observed. These reactions were sometimes associated with coagulation disorders, including prolonged clotting time, platelet aggregation abnormalities, and prothrombin time, and occurred more frequently in patients with renal impairment. If bleeding symptoms occur, antibiotic administration should be stopped and appropriate treatment initiated.

Leukopenia and neutropenia may develop, especially during prolonged therapy; therefore, periodic monitoring of blood parameters is recommended.

As with other penicillin-class drugs, neurological complications such as seizures may occur following administration of high doses, particularly in patients with impaired renal function (see section "Adverse reactions").

Refex 2 g/0.25 g

The medicinal product contains 108 mg (4.7 mmol) of sodium per vial.

Refex 4 g/0.5 g

The medicinal product contains 216 mg (9.4 mmol) of sodium per vial.

This should be taken into account for patients on a controlled sodium diet.

Hypokalemia may develop in patients with low body potassium levels or those concurrently taking potassium-depleting agents; such patients should have their electrolyte balance monitored periodically.

Renal impairment

Due to potential nephrotoxicity (see section "Adverse reactions"), piperacillin/tazobactam should be used with caution in patients with impaired renal function and in hemodialysis patients. Intravenous doses and dosing intervals should be adjusted according to the degree of renal impairment (see section "Dosage and administration").

In a post hoc analysis using data from a large multicenter randomized controlled trial evaluating glomerular filtration rate (GFR) after administration of commonly used antibiotics in critically ill patients, piperacillin/tazobactam use was associated with a lower rate of reversible improvement in GFR compared to other antibiotics. This post hoc analysis indicated that piperacillin/tazobactam may delay recovery of renal function in such patients.

Concomitant use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of Refex in pregnant women are lacking or limited.

Animal studies have shown toxicity, but no evidence of teratogenicity was observed at maternally toxic doses.

Piperacillin and tazobactam cross the placenta. Piperacillin/tazobactam may be used during pregnancy only when clearly indicated and when the expected benefit outweighs the potential risk to the pregnant woman and the fetus.

Breastfeeding

Piperacillin passes into breast milk in negligible concentrations; tazobactam concentrations in breast milk have not been studied. Therefore, the medicinal product may be used during breastfeeding only when the expected benefit outweighs the potential risk to the mother and infant.

Fertility

Fertility studies in rats showed no effect on fertility or mating after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam.

Effect on ability to drive and use machines.

No studies on the effect on the ability to drive or operate machinery have been conducted.

Method of administration and dosage.

The dose and frequency of administration of Refex depend on the course and location of the infection, as well as the likely causative agents.

Adults and children aged 12 years and older

Infections

The usual dose is 4 g of piperacillin/0.5 g of tazobactam every 8 hours.

For nosocomial pneumonia and bacterial infections in patients with neutropenia, the recommended dose is 4 g of piperacillin/0.5 g of tazobactam every 6 hours. This regimen may also be used for the treatment of patients with other indicated infections, particularly in severe forms.

Table 1 shows the recommended dosing frequency for adult patients and children.

Table 1

Patients with renal impairment

The intravenous dose should be adjusted according to the degree of renal function impairment as follows (each patient should be closely monitored for signs of drug toxicity; the dose and frequency of administration should be adjusted accordingly).

Table 2

For patients undergoing hemodialysis, an additional dose of 2 g piperacillin/0.25 g tazobactam should be administered after each dialysis session, as hemodialysis removes 30–50% of piperacillin within 4 hours.

Patients with hepatic impairment

Dose adjustment is not required (see section "Pharmacological properties").

Elderly patients

Dose adjustment is not required for elderly patients with normal renal function or creatinine clearance above 40 mL/min.

Children aged 2 to 12 years

Infections

The following table provides the dosing frequency and recommended doses per kg body weight for children aged 2 to 12 years according to indications or clinical conditions.

Table 3

* Do not exceed the maximum dose of 4 g/0.5 g with an infusion duration of 30 minutes.

Patients with renal impairment

The intravenous dose should be adjusted according to the degree of renal function impairment as follows (patients should be carefully monitored for signs of drug toxicity; the dose and frequency of administration should be adjusted accordingly):

Table 4

For children undergoing hemodialysis, an additional dose of 40 mg piperacillin/5 mg tazobactam per kg should be administered after each dialysis session.

Children under 2 years of age

The safety and efficacy of Refex in children aged 0–2 years have not been established.

Duration of treatment

The usual duration of treatment for most indications is 5–14 days. However, the duration of treatment should depend on the severity of the infection, the causative pathogen, and the clinical and bacteriological response of the patient.

Method of administration

Refex 4 g/0.5 g should be administered by intravenous infusion over more than 30 minutes.

Instructions for solution preparation

Preparation of the solution for intravenous use must be performed under aseptic conditions. Before administration, the prepared solution should be visually inspected for the presence of particulate matter and discoloration. Only clear solutions free from particulate matter should be used.

Intravenous administration

The contents of the vial should be reconstituted with the solvent in the volume indicated in the table below. Shake the vial until the powder is completely dissolved. Reconstitution of the solution occurs within 5–10 minutes with continuous shaking.

Table 5

* Compatible reconstituting solvents:

• 0.9% (9 mg/mL) sodium chloride solution for injection;
• sterile water for injection(1);
• 5% glucose solution.

(1) The maximum recommended volume of sterile water for injection per single dose is 50 mL.

Reconstituted solutions should be withdrawn from the vial using a syringe. If reconstitution is performed according to the recommendations, withdrawal of the vial contents using a syringe will ensure availability of the declared amount of piperacillin/tazobactam.

Reconstituted solutions may be further diluted to the required volume (from 50 mL to 150 mL) using one of the following compatible diluents:

• 0.9% (9 mg/mL) sodium chloride solution for injection;
• 5% glucose solution;
• dextran 6% in 0.9% (9 mg/mL) sodium chloride;
• Ringer's lactate solution;
• Hartmann's solution;
• Ringer's acetate;
• Ringer's acetate/malate.

Concomitant administration with aminoglycosides

Due to in vitro inactivation of aminoglycosides by beta-lactam antibiotics, REFEX and aminoglycosides are recommended to be administered separately. If concomitant therapy with aminoglycosides is indicated, REFEX and aminoglycosides should be reconstituted, diluted, and administered separately.

A Y-type catheter must be used for administration. When administering concomitantly via a Y-type catheter, the following requirements must be observed.

Table 6

* Aminoglycoside dosage depends on body weight, the nature of the infection (serious or life-threatening), and renal function (creatinine clearance).

Compatibility of Refex with other aminoglycosides has not been established. Only the concentrations and diluents for amikacin and gentamicin combined with Refex doses listed in the table above have been confirmed compatible for co-administration via a Y-site catheter. Simultaneous co-administration via a Y-site catheter by any method other than that specified above may result in inactivation of the aminoglycoside by Refex.

See section "Incompatibilities" for details on incompatibilities.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

For single use only. Any unused solution must be discarded.

Children.

The medicinal product can be administered to children aged 2 years and older.

Overdose.

Symptoms

Cases of piperacillin/tazobactam overdose have been reported in the post-marketing period. Most of these cases, including nausea, vomiting, and diarrhea, occurred following administration of the usual recommended doses. Neuromuscular excitation or seizures may occur in patients who exceed the recommended intravenous doses (particularly in patients with renal impairment).

Treatment

In case of overdose, further administration of piperacillin/tazobactam should be discontinued. There is no known specific antidote.

Treatment is supportive and symptomatic, depending on the patient's condition.

Excess serum concentrations of piperacillin or tazobactam can be reduced by hemodialysis (see section "Special precautions for use").

Adverse reactions.

The most frequently reported adverse reaction was diarrhea (observed in 1 out of 10 patients).

Among the most serious adverse reactions are pseudomembranous colitis and toxic epidermal necrolysis, which have been observed in 1 to 10 patients per 10,000. The frequency of occurrence of pancytopenia, anaphylactic shock, and Stevens–Johnson syndrome cannot be estimated based on currently available data.

The table below lists adverse reactions classified by system organ classes using primarily preferred MedDRA terms.

Within each group, adverse effects are listed by frequency of occurrence in order of decreasing severity.

* Adverse reactions identified during the post-marketing period.

Description of selected adverse reactions

Piperacillin therapy has been associated with an increased incidence of fever and rash in patients with cystic fibrosis.

Effects of beta-lactam antibiotics

Beta-lactam antibiotics, including piperacillin/tazobactam, may lead to manifestations of encephalopathy and seizures (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.

The shelf life of freshly prepared solution is 24 hours when stored at a temperature not exceeding 25 °C and 48 hours when stored in a refrigerator (at a temperature of 2 to 8 °C).

Incompatibilities.

Rephex must not be mixed with other medicinal products in the same syringe or infusion bottle, except as specified in the section "Dosage and administration".

If Rephlex must be administered simultaneously with another antibiotic (e.g., aminoglycosides), the medicinal products should be administered separately. Mixing beta-lactam antibiotics with aminoglycosides in vitro may result in significant inactivation of the aminoglycoside.

Rephex must not be mixed with other substances in a syringe or infusion bottle, as compatibility has not been established.

Due to chemical instability, Rephlex must not be used in solutions containing sodium bicarbonate only.

Rephex must not be added to blood products or albumin hydrolysate.

Packaging.

Powder in vials. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Reig Jofre, S.A.

Manufacturer's address.

C/Jarama 111 Poligono Industrial, Toledo 45007, Spain.

Marketing Authorization Holder.

Yuria-Pharm LLC.

Address of Marketing Authorization Holder.

10 M. Amosova Street, Kyiv, 03680, Ukraine.