Perasin

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

Composition:

Active substances: piperacillin, tazobactam;

1 vial contains piperacillin (as piperacillin sodium) 2 g, tazobactam (as tazobactam sodium) 0.25 g (for dosage of 2.25 g), or

1 vial contains piperacillin (as piperacillin sodium) 4 g, tazobactam (as tazobactam sodium) 0.5 g (for dosage of 4.5 g).

Pharmaceutical form. Powder for solution for infusion.

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

Pharmacotherapeutic group. Combinations of penicillins, including beta-lactamase inhibitors. ATC code J01CR05.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Piperacillin is a semisynthetic broad-spectrum antibiotic of the penicillin class that inhibits bacterial activity by inhibiting the formation of the cell septum and synthesis of the bacterial cell wall.

Tazobactam is a beta-lactam structurally similar to penicillins and acts as an inhibitor of many beta-lactamases that typically cause resistance to penicillins and cephalosporins; however, it does not inhibit AmpC enzymes or metallo-beta-lactamases. Tazobactam extends the antibacterial spectrum of piperacillin to include many beta-lactamase-producing bacteria that are resistant to piperacillin alone.

Pharmacokinetic/pharmacodynamic relationship

The duration of time during which plasma concentration exceeds the minimum inhibitory concentration (% T> MIC) is considered the primary factor determining the pharmacodynamic efficacy of piperacillin.

Mechanisms of resistance

There are two main mechanisms of resistance to the medicinal product Perasin:

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

Furthermore, changes in bacterial membrane permeability, as well as expression of multidrug efflux pumps, may contribute to bacterial resistance to Perasin, particularly in Gram-negative bacteria.

Clinical breakpoints

EUCAST (European Committee on Antimicrobial Susceptibility Testing) has established clinical breakpoints for piperacillin/tazobactam (2009-12-02, v1). For antimicrobial susceptibility testing, a tazobactam concentration of 4 mg/L is used.

Pathogenic microorganism	Strain-related threshold values, strain-dependent (S ≤/R >)
Enterobacteriaceae	8/16
Pseudomonas	16/16
Gram-negative and gram-positive anaerobes	8/16
Non-strain-dependent threshold values	4/16

Susceptibility of streptococci is presumed based on susceptibility to penicillin.

Susceptability of staphylococci is presumed based on susceptibility to oxacillin.

Susceptibility

The prevalence of acquired resistance in selected strains may vary depending on geographical location and time for individual species; therefore, local resistance data are desirable, especially when treating severe infections. If necessary, when local resistance prevalence calls into question the appropriateness of using the medicinal product for treating at least some types of infections, expert advice should be sought.

Groups of strains depending on susceptibility to piperacillin/tazobactam

Primarily susceptible strains

Aerobic gram-positive microorganisms Enterococcus faecalis Listeria monocytogenes Staphylococcus aureus, methicillin-susceptible£ Staphylococcus species, Coagulase negative, methicillin-susceptible Streptococcus pyogenes Streptococci (group B)

Aerobic gram-negative microorganisms Citrobacter koseri Haemophilus influenzae Moraxella catarrhalis Proteus mirabilis

Anaerobic gram-positive microorganisms Clostridium species Eubacterium species Peptostreptococcus species

Anaerobic gram-negative microorganisms group Bacteroides fragilis Fusobacterium species Porphyromonas species Prevotella species

Strains for which acquired resistance may be a problem

Aerobic gram-positive microorganisms Enterococcus faecium $, + Streptococcus pneumoniae group Streptococcus viridans

Aerobic gram-negative microorganisms Acinetobacter baumannii $ Burkholderia cepacia Citrobacter freundii Enterobacter species Escherichia coli Klebsiella pneumoniae Morganella morganii Proteus vulgaris Providencia spp. Pseudomonas aeruginosa Serratia species

Microorganisms with inherent resistance

Aerobic gram-positive microorganisms Corynebacterium jeikeium Aerobic gram-negative microorganisms Legionella species Stenotrophomonas maltophilia +, $

Other microorganisms Chlamydophila pneumoniae Mycoplasma pneumoniae

$ Strains with moderate inherent susceptibility. + Strains exhibiting a high level of resistance (over 50%). £ All methicillin-resistant staphylococci are resistant to piperacillin/tazobactam.

Pharmacokinetics.

Absorption

Maximum concentrations of piperacillin and tazobactam after intravenous administration (over more than 30 minutes) at a dose of 4.5 g are 298 mcg/mL and 34 mcg/mL, respectively.

Distribution

Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. Protein binding of piperacillin and tazobactam is independent of the presence of other compounds. Protein binding of tazobactam metabolites is negligible.

Piperacillin and tazobactam freely distribute into body tissues and fluids, including interstitial fluid, gallbladder, lungs, bile, and bones. Tissue concentrations generally range from 50% to 100% of plasma concentrations. As with other penicillin-class drugs, distribution into cerebrospinal fluid is low unless patients have inflamed meninges.

Metabolism

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; 68% of the administered dose is excreted 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 in healthy volunteers, the plasma elimination half-life ranged from 0.7 to 1.2 hours. Dose and duration of infusion did not affect this parameter. The elimination half-life of both piperacillin and tazobactam increases with decreased renal clearance. Administration of tazobactam does not significantly affect the pharmacokinetics of piperacillin. Piperacillin reduces the clearance of tazobactam.

Special patient populations

The elimination half-life of piperacillin and tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy volunteers.

The elimination half-life of piperacillin and tazobactam increases with decreased 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 approximately 18% of the tazobactam dose as metabolite.

Pediatric population

In pharmacokinetic studies in this age group, clearance estimates in patients aged 9 months to 12 years were compared with those in adults. The mean value for the 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 the 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 longer by 32% and 55%, respectively, compared to younger patients. This difference is likely due to age-related changes in creatinine clearance.

Race

No difference in the pharmacokinetics of piperacillin and tazobactam was observed between Asian (n = 9) and Caucasian (n = 9) healthy volunteers who received a single 4.5 g dose.

Clinical characteristics.

Indications.

Perasin medicinal product 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 associated with diabetic foot syndrome).

Treatment of patients with bacteremia that occurs in conjunction with or may be related to any of the above-mentioned infections.

Perasin medicinal product may be used for the treatment of patients with neutropenia and fever likely caused by bacterial infection.

Use for bacteremia caused by E. coli and K. pneumoniae (resistant to ceftriaxone) producing extended-spectrum beta-lactamases is not recommended in adult patients (see section "Pharmacological properties").

Children aged 2 to 12 years:

• complicated intra-abdominal infections.

Perasin medicinal product may be used for the treatment of pediatric patients with neutropenia and fever likely caused by bacterial infection.

Official guidelines for the use of antibacterial agents should be followed.

Contraindications.

Hypersensitivity to the active substance, antibacterial agents of the penicillin group, or to any excipient of the medicinal product.

History of severe immediate allergic reactions to 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.

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

Methotrexate. Piperacillin may reduce methotrexate excretion. Serum levels of methotrexate should be monitored in patients receiving methotrexate.

Probenecid. As with other penicillin group agents, concomitant administration of probenecid and Perasin results in prolonged elimination half-life and reduced renal clearance of both piperacillin and tazobactam. However, this does not affect the maximum plasma concentration of either agent.

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.

Inactivation of tobramycin and gentamicin by piperacillin has been observed in patients with severe renal insufficiency.

For information on co-administration of piperacillin/tazobactam with aminoglycosides, see sections "Dosage and administration" and "Incompatibilities".

Vancomycin. Studies have shown an increased incidence of acute kidney injury in patients receiving piperacillin/tazobactam and vancomycin concomitantly compared to vancomycin alone. Some of these studies indicate that the interaction is dose-dependent with respect to vancomycin.

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

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

Some chemical methods for measuring urinary protein may yield false-positive results. No interference is expected with protein measurement using test strips.

The direct Coombs test may be positive.

Cross-reactivity with polysaccharides and polyfuranoses not components of the Aspergillus cell wall has been reported when using the Bio-Rad Laboratories Platelia Aspergillus EIA test system.

Positive results of the above-mentioned tests in patients receiving Perasin should 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 the infection and the prevalence of resistance to other appropriate antibacterial agents.

Before initiating therapy with Perasin, the patient should be carefully evaluated for previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g., cephalosporins, monobactams, or carbapenems), and other allergens. Serious, and sometimes fatal, hypersensitivity reactions (anaphylactic/anaphylactoid, including shock) have been reported in patients receiving penicillin therapy, including the medicinal product containing piperacillin/tazobactam. These reactions are more likely to occur in individuals with a history of multiple allergen sensitivities. Serious hypersensitivity reactions require immediate discontinuation of the antibiotic and may necessitate administration of epinephrine and other emergency measures.

The medicinal product Perasin may cause serious skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If skin rash develops, patients should be closely monitored, and if the rash progresses, the drug should be discontinued.

In cases of severe persistent diarrhea, pseudomembranous colitis, a life-threatening condition caused by antibiotics, should be considered. Symptoms may appear during or after antibacterial therapy. In such cases, the drug should be discontinued immediately.

Use of Perasin may lead to emergence of resistant organisms, which in turn may cause superinfection.

In some patients receiving beta-lactam antibiotics, bleeding symptoms have been observed. These reactions were sometimes associated with coagulation abnormalities: prolonged clotting time, platelet aggregation, and prothrombin time. Such abnormalities were most frequently observed in patients with renal impairment. If bleeding occurs, antibiotic administration should be discontinued and appropriate treatment initiated.

Since leukopenia and neutropenia may develop during prolonged therapy, periodic monitoring of blood parameters is recommended.

As with other penicillin-class drugs, exceeding recommended doses (especially in patients with impaired renal function) may result in neurological complications such as neuromuscular excitability or seizures.

This medicinal product contains sodium; therefore, this should be taken into account in patients on a low-sodium diet.

Hypokalemia may develop in patients with low potassium levels or in those taking potassium-lowering medications. Electrolyte balance should be monitored periodically in such patients.

Renal impairment

Due to potential nephrotoxicity, piperacillin/tazobactam should be used with caution in patients with renal impairment or those undergoing hemodialysis. Intravenous doses and dosing intervals should be adjusted according to the degree of renal function impairment.

In a secondary analysis of 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 was associated with a lower rate of reversible GFR decline compared to other antibiotics. However, this secondary analysis indicated that piperacillin/tazobactam was linked to delayed renal recovery in these patients.

Concomitant use of piperacillin/tazobactam and vancomycin may increase the risk of acute kidney injury.

Hemophagocytic lymphohistiocytosis (HLH)

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

Pregnancy and breastfeeding.

Pregnancy. There are no or limited data on the use of Perasin in pregnant women. Animal studies have shown fetal toxicity, but teratogenicity was not observed at doses toxic to the maternal organism. Piperacillin and tazobactam cross the placenta. Perasin may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding. Piperacillin passes into breast milk in small amounts. Tazobactam concentrations in breast milk have not been studied. Treatment with this medicinal product during breastfeeding should only be considered if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility. Studies in rats showed that intraperitoneal administration of tazobactam or the combination of piperacillin/tazobactam had no effect on reproductive function or fertility.

Ability to influence the reaction rate when driving or operating machinery.

The effect of the drug on the ability to drive vehicles or operate machinery has not been established.

Method of Administration and Dosage

Dosage

The dose and frequency of administration of the medicinal product Perasin depend on the severity and location of the infection, as well as the likely causative pathogens.

Adults and children aged 12 years and older

Infections

The usual dose of Perasin (4 g piperacillin/0.5 g tazobactam) is 4.5 g every 8 hours.

In neutropenia and severe pneumonia, the recommended dose of the drug (4 g piperacillin/0.5 g tazobactam) is 4.5 g every 6 hours.

This dosing regimen may also be used for the treatment of patients with particularly severe forms of other identified infections.

The table below provides the recommended frequency of administration for adult patients and children aged 12 years and older, specifying the indications or conditions:

Dosing frequency	Indications for use of Piperacillin 4.5 g
Every 6 hours	Severe pneumonia
	Neutropenia in adults likely associated with bacterial infection
Every 8 hours	Complicated urinary tract infections (including pyelonephritis)
	Complicated intra-abdominal infections
	Skin and soft tissue infections (including infectious complications in diabetic foot syndrome)

Patients with renal impairment

The intravenous dose should be adjusted according to the degree of renal function impairment as indicated below (each patient must be monitored for signs of active substance toxicity; the dose and dosing interval should be appropriately adjusted):

Creatinine clearance (mL/min)	Recommended dose of piperacillin/tazobactam
> 40	No dose adjustment required
20-40	Maximum recommended dose: 4 g/0.5 g every 8 hours
< 20	Maximum recommended dose: 4 g/0.5 g every 12 hours

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

Patients with hepatic impairment

Dose adjustment is not required.

Geriatric patients

For elderly patients with normal renal function or creatinine clearance greater than 40 mL/min, dose adjustment is not required.

Children aged 2 to 12 years

Infections

The table below provides the recommended dosage and frequency according to body weight for children aged 2 to 12 years, with indications or conditions specified:

Dose according to body weight and frequency of administration	Indications or conditions
80 mg piperacillin/10 mg tazobactam per 1 kg body weight/every 6 hours	Neutropenia in children with fever likely due to bacterial infection*
100 mg piperacillin/12.5 mg tazobactam per 1 kg body weight/every 8 hours	Complicated intra-abdominal infections*

* Do not exceed the maximum dose of 4.5 g administered within 30 minutes.

Patients with renal impairment

The intravenous dose must be adjusted according to the degree of renal function impairment as indicated below (each patient should be monitored for signs of drug toxicity; the dose and dosing interval should be appropriately adjusted):

Creatinine clearance (mL/min)	Recommended dose of piperacillin/tazobactam
> 50	No dose adjustment required
≤ 50	70 mg piperacillin/8.75 mg tazobactam per kg body weight every 8 hours

For children undergoing hemodialysis, an additional dose of 40 mg piperacillin/5 mg tazobactam per kg body weight is required after each dialysis session.

Children under 2 years of age

The efficacy and safety of the medicinal product Perasin for treatment of children under 2 years of age have not been established.

Data from controlled clinical studies are lacking.

Treatment duration

The usual treatment duration for most indications is 5–14 days. However, the treatment duration should be determined based on the patient's condition, severity of infection, and results of clinical and bacteriological examinations.

Method of administration

The medicinal product Perasin is administered as an intravenous infusion (over more than 30 minutes).

Instructions for preparation of solution for 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. With continuous shaking, reconstitution of the solution takes 5–10 minutes.

Contents of the vial	Volume of solvent* to be added to the vial	Volume displacement	Final concentration per 1 ml
Piperacillin/tazobactam 2 g/0.25 g	10 ml	1.6 ml	Piperacillin: 172.4 mg/ml. Tazobactam: 21.5 mg/ml.
Piperacillin/tazobactam 4 g/0.5 g	20 ml	3 ml	Piperacillin: 173.9 mg/ml. Tazobactam: 21.7 mg/ml.

* Reconstituting solvents:

• Sterile water for injection¹.
• 0.9% sodium chloride solution for injection.
• 5% aqueous glucose solution.

¹ The maximum recommended volume of sterile water for injection per 50 ml dose is 50 ml.

Reconstituted solutions must 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) with one of the following compatible diluents:

• 0.9% sodium chloride solution for injection;
• 5% glucose solution;
• 6% dextran in 0.9% sodium chloride solution.

Unused medicinal product or waste should be disposed of in accordance with applicable regulations.

The medicinal product Perasin is intended for single use only. Any unused solution must not be reused.

Children.

The drug may be administered to children aged 2 years and older.

Overdose.

Symptoms. Cases of overdose have been reported. Most of these cases, including nausea, vomiting, and diarrhea, occurred following administration of usual recommended doses. Neuromuscular excitability or seizures may occur in patients who exceed the recommended intravenous doses (especially in patients with renal impairment).

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.

Adverse Reactions

The most commonly reported adverse reaction of the medicinal product was diarrhea (observed in 1 out of 10 patients). Among the most serious adverse reactions were pseudomembranous colitis and toxic epidermal necrolysis, which occurred in 1 to 10 out of 10,000 patients.

The frequency of occurrence of pancytopenia, anaphylactic shock, and Stevens-Johnson syndrome cannot be estimated based on the available data.

The table below lists adverse reactions classified by system organ classes using preferred terms of MedDRA. The data on adverse reactions are presented below according to their frequency of occurrence, listed in order of decreasing severity.

Adverse reactions are listed by frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); and frequency not known (cannot be estimated from the available data).

System Organ Classes	Adverse Reactions
Infections and infestations
Common	Candidiasis superinfection*
Uncommon	Pseudomembranous colitis
Blood and lymphatic system disorders
Common	Thrombocytopenia, anemia*
Uncommon	Leukopenia
Rare	Agranulocytosis
Frequency unknown	Pancytopenia*, neutropenia, hemolytic anemia*, thrombocytosis*, eosinophilia*
Immune system disorders
Frequency unknown	Anaphylactoid shock*, anaphylactic shock*, anaphylactoid reactions*, anaphylactic reactions*, hypersensitivity reactions*.
Metabolism and nutrition disorders
Uncommon	Hypokalemia
Psychiatric disorders
Common		Insomnia
Frequency unknown		Delirium*
Nervous system disorders
Common	Headache
Uncommon	Seizures*
Cardiac disorders
Uncommon	Arterial hypotension, phlebitis, thrombophlebitis, hot flush
Respiratory, thoracic and mediastinal disorders
Rare	Nosebleed
Frequency unknown	Eosinophilic pneumonia
Gastrointestinal disorders
Very common	Diarrhea
Common	Abdominal pain, vomiting, constipation, nausea, dyspepsia
Rare	Stomatitis
Hepatobiliary disorders
Frequency unknown	Hepatitis*, jaundice
Skin and subcutaneous tissue disorders
Common	Rash, pruritus
Uncommon	Multiform erythema*, urticaria, maculopapular rash*
Rare	Toxic epidermal necrolysis*
Frequency unknown	Stevens-Johnson syndrome*, exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms*, acute generalized exanthematous pustulosis*, bullous dermatitis, purpura
Musculoskeletal and connective tissue and bone disorders
Uncommon	Arthralgia, myalgia
Renal and urinary disorders
Frequency unknown	Renal failure, tubulointerstitial nephritis*
General disorders and administration site conditions
Common	Feeling hot, injection site reactions
Uncommon	Chills
Investigations
Common	Elevated aminotransferase, aspartate aminotransferase levels, decreased total blood protein and albumin levels, positive direct Coombs test, elevated creatinine, alkaline phosphatase, blood urea nitrogen levels, prolonged activated partial thromboplastin time
Uncommon	Decreased blood glucose levels, elevated blood bilirubin levels, prolonged prothrombin time
Frequency unknown	Increased bleeding time, elevated blood gamma-glutamyl transferase levels

* Adverse reactions identified during the post-marketing period.

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

Effects of beta-lactam antibiotics

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Reconstituted solutions (prepared under aseptic conditions) remain stable for up to 24 hours at a temperature not exceeding 25 °C, and up to 48 hours when stored refrigerated (2–8 °C).

Keep out of reach and sight of children.

Incompatibility

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

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

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

Perasin should be administered through a separate infusion line, apart from any other medicinal products, unless compatibility has been demonstrated.

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

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

Packaging

Vial; 1 or 10 vials per cardboard box.

Prescription status

Prescription only.

Manufacturer

ANTIBIOTICE SA

ANTIBIOTICE SA

Manufacturer's address and location of its operations

1 Valea Lupului Street, Iasi 707410, Romania

1, Valea Lupului Street, 707410, Iasi, Romania