Penibaktam (Powder) Instructions for Use

Marketing Authorization Holder

Kraspharma, PJSC (Russia)

ATC Code

J01CR05 (Piperacillin and beta-lactamase inhibitor)

Active Substances

Piperacillin (Rec.INN registered by WHO)

Tazobactam (Rec.INN registered by WHO)

Dosage Forms

	Penibaktam	Powder for solution for infusion 2 g+0.25 g: vial 1, 10 or 50 pcs.
		Powder for solution for infusion 4 g+0.5 g: vial 1, 10 or 50 pcs.

Dosage Form, Packaging, and Composition

Powder for solution for infusion white or white with a yellowish tint.

2.25 g – vials (1) – cardboard packs.
2.25 g – vials (10) – cardboard boxes.
2.25 g – vials (50) – cardboard boxes (for hospitals).
2.25 g – vials (1) (with solvent 10 ml – 1 pc.) – cardboard packs.
2.25 g – vials (1) (with solvent 5 ml – 2 pcs.) – cardboard packs.

Powder for solution for infusion white or white with a yellowish tint.

4.5 g – vials (1) – cardboard packs.
4.5 g – vials (10) – cardboard boxes.
4.5 g – vials (50) – cardboard boxes (for hospitals).
4.5 g – vials (1) (with solvent 10 ml – 2 pcs.) – cardboard packs.

Clinical-Pharmacological Group

Broad-spectrum penicillin antibiotic with a beta-lactamase inhibitor

Pharmacotherapeutic Group

Systemic antibacterial agents; beta-lactam antibacterial agents, penicillins; combinations of penicillins, including combinations with beta-lactamase inhibitors

Pharmacological Action

Combined medicinal product.

Piperacillin is a bactericidal semi-synthetic broad-spectrum antibiotic that suppresses the synthesis of the microbial cell wall.

Tazobactam is an inhibitor of beta-lactamases (including plasmid and chromosomal), which are most often the cause of resistance to penicillins and cephalosporins (including third-generation cephalosporins). The presence of tazobactam significantly expands the spectrum of action of piperacillin.

Most strains of microorganisms resistant to piperacillin and producing beta-lactamases are susceptible.

Active against gram-negative aerobic bacteria: Escherichia coli, Salmonella spp., Shigella spp., Citrobacter spp. (including Citrobacter freundii, Citrobacter diversus), Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae), Morganella morganii, Moraxella spp. (including Moraxella catarrhalis), Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Pseudomonas aeruginosa (only piperacillin-susceptible strains) and other Pseudomonas spp. (including Burkholderia cepacia, Pseudomonas fluorescens), Neisseria spp. (including Neisseria meningitidis, Neisseria gonorrhoeae), Haemophilus spp. (including Haemophilus influenzae, Haemophilus parainfluenzae), Serratia spp. (including Serratia marcescens, Serratia liquefaciens), Pasteurella multocida, Yersinia spp., Campylobacter spp., Gardnerella vaginalis, Enterobacter spp. (including Enterobacter cloacae, Enterobacter aerogenes), Providencia spp, Stenotrophomonas maltophilia, Acinetobacter spp. (producing and non-producing chromosomal beta-lactamase); gram-negative anaerobic bacteria: Bacteroides spp. (Bacteroides fragilis, Bacteroides disiens, Bacteroides capillosus, Bacteroides melaninogenicus, Bacteroides oralis, Bacteroides distasonis, Bacteroides uniformis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides bivius, bacteroides asaccharolyticus), Fusobacterium nucleatum; gram-positive aerobic bacteria: Streptococcus spp. (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus bovis), Streptococcus group viridans (C and G), Enterococcus spp. (Enterococcus faecalis, Enterococcus faecium), Staphylococcus spp. (methicillin-susceptible Staphylococcus aureus strains, Staphylococcus epidermidis, Staphylococcus saprophyticus), Listeria monocytogenes, Nocardia spp.; gram-positive anaerobic bacteria: Clostridium spp. (including Clostridium perfringens, Clostridium difficile), Peptostreptococcus spp., Eubacterium spp.; Veillonella spp., Actinomyces spp.

Pharmacokinetics

C_max of piperacillin after IV infusion of 2.25 or 4.5 g over 30 min is reached immediately after its completion and is 134 and 298 mcg/ml, respectively; corresponding mean plasma concentrations are 15, 24 and 34 mcg/ml (piperacillin plasma concentrations after its administration in combination with tazobactam are similar to those after administration of equivalent doses of piperacillin monodrug). Mean C_max values of tazobactam in plasma are 15 and 34 mcg/ml, respectively.

Binding to plasma proteins of piperacillin and tazobactam is about 30% (tazobactam metabolite practically does not bind to proteins). Piperacillin and Tazobactam penetrate well into tissues and body fluids, including the intestinal mucosa, gallbladder, lungs, bile, bone tissue and tissues of the female reproductive system (uterus, ovaries and fallopian tubes). Mean tissue concentrations range from 50 to 100% of those in plasma. It practically does not penetrate the intact blood-brain barrier.

Excreted in breast milk.

Piperacillin is metabolized to a weakly active desethyl metabolite, Tazobactam to an inactive metabolite.

Excreted by the kidneys via glomerular filtration and tubular secretion: Piperacillin – 68% unchanged, Tazobactam – 80% unchanged and a small amount as a metabolite. Piperacillin, Tazobactam and desethylpiperacillin are also excreted in bile.

Tazobactam does not cause significant changes in the pharmacodynamics of piperacillin. Piperacillin appears to reduce the elimination rate of tazobactam.

T_1/2 of piperacillin and tazobactam are 0.7-1.2 h.

Indications

Bacterial infections caused by susceptible microflora in adults and children over 12 years of age: lower respiratory tract infections (pneumonia, lung abscess, pleural empyema); abdominal infections (peritonitis, pelvioperitonitis, cholangitis, gallbladder empyema, appendicitis (including complicated by abscess or perforation)). urinary tract infections, including complicated ones (pyelonephritis, cystitis, prostatitis, epididymitis, gonorrhea, endometritis, vulvovaginitis, postpartum endometritis and adnexitis); bone and joint infections, including osteomyelitis; skin and soft tissue infections (phlegmon, furunculosis, abscess, pyoderma, lymphadenitis, lymphangitis, infected trophic ulcers, infected wounds and burns); intra-abdominal infections (including in children over 2 years of age); bacterial infection in patients with neutropenia (including in children under 12 years of age); sepsis; meningitis; prevention of postoperative infection.

ICD codes

Dosage Regimen

Administer by intravenous infusion over 30 minutes.

For adults and children over 12 years, the usual dosage is 4.5 g every 8 hours for 7 to 10 days; adjust duration based on infection severity and clinical response.

For nosocomial pneumonia and other serious infections, use a dosage of 4.5 g every 6 hours.

For complicated intra-abdominal infections, administer 3.375 g every 6 hours with metronidazole.

In patients with renal impairment, adjust the dosing interval based on creatinine clearance (CrCl).

For CrCl 20-40 mL/min, administer 2.25 g every 6 hours.

For CrCl below 20 mL/min, administer 2.25 g every 8 hours.

For patients on hemodialysis, administer a 2.25 g loading dose followed by 2.25 g after each dialysis session; administer the dose following hemodialysis.

Reconstitute the 2.25 g vial with 10 mL of a compatible diluent; the 4.5 g vial requires 20 mL.

Use Sterile Water for Injection, 0.9% Sodium Chloride, or Dextrose 5% for reconstitution; shake well until dissolved.

Further dilute the reconstituted solution in a compatible IV bag containing 50 mL to 150 mL of the same diluent.

Do not mix with other drugs in the same IV solution; administer aminoglycosides separately.

Inspect the solution visually for particulate matter and discoloration before administration; discard if present.

Use the reconstituted solution immediately; stability times vary depending on the diluent and storage temperature.

Adverse Reactions

Allergic reactions urticaria, skin itching, rash, bullous dermatitis, multiforme erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic/anaphylactoid reactions (including anaphylactic shock).

From the digestive system diarrhea, nausea, vomiting, constipation, dyspepsia, jaundice, stomatitis, abdominal pain, pseudomembranous colitis, hepatitis.

From the hematopoietic organs leukopenia, neutropenia, thrombocytopenia, anemia, bleeding (including purpura, nosebleeds, increased time, bleeding), hemolytic anemia, agranulocytosis, false-positive direct Coombs test, pancytopenia, increased partial thromboplastin time, increased prothrombin time, thrombocytosis.

From the urinary system interstitial nephritis, renal failure.

From the nervous system headache, insomnia, convulsions.

From the cardiovascular system decreased blood pressure, facial flushing.

Laboratory parameters hypoalbuminemia, hypoglycemia, hypoproteinemia, hypokalemia, eosinophilia, increased activity of “hepatic” transaminases (ALT, AST), hyperbilirubinemia, increased activity of alkaline phosphatase, GGT, increased concentration of creatinine and urea in blood serum.

Local reactions phlebitis, thrombophlebitis, hyperemia and induration at the injection site.

Other fungal superinfections, fever, arthralgia.

Contraindications

Hypersensitivity (including to penicillins, cephalosporins, other beta-lactam antibiotic inhibitors); children’s age (under 2 years).

With caution

Severe bleeding (including history), cystic fibrosis (increased risk of hyperthermia and skin rash), pseudomembranous colitis, children over 2 years of age, chronic renal failure (creatinine clearance less than 20 ml/min), patients on hemodialysis, with concomitant use of high doses of anticoagulants, with hypokalemia, pregnancy, lactation period.

Use in Pregnancy and Lactation

With caution use during pregnancy and during lactation (breastfeeding).

Use in Renal Impairment

With caution chronic renal failure. In chronic renal failure, the daily doses of piperacillin/tazobactam are adjusted depending on creatinine clearance.

Pediatric Use

Contraindication children under 2 years of age.

With caution: children over 2 years of age.

Special Precautions

During treatment, especially long-term, leukopenia and neutropenia may develop, so peripheral blood counts should be periodically monitored.

In some cases (most often in patients with renal failure), increased bleeding and concomitant changes in laboratory parameters of the blood coagulation system (blood clotting time, platelet aggregation and prothrombin time) may occur. If bleeding occurs, administration of the drug should be discontinued and appropriate therapy prescribed.

Antibiotic-induced pseudomembranous colitis may present with severe, persistent diarrhea that is life-threatening. Pseudomembranous colitis can develop both during antibacterial therapy and after its completion. In such cases, administration of the drug should be stopped immediately and appropriate therapy prescribed (e.g., metronidazole, vancomycin orally). Drugs that inhibit intestinal peristalsis are contraindicated.

It is necessary to consider the possibility of the appearance of resistant microorganisms that can cause superinfection, especially during a long course of treatment. This drug contains 2.79 mEq (64 mg) of sodium per gram of piperacillin, which may lead to an overall increase in sodium intake. In patients with hypokalemia or taking drugs that promote potassium excretion, hypokalemia may develop during treatment (serum electrolyte levels should be checked regularly).

In patients with chronic renal failure on hemodialysis, the dose of the drug and the frequency of administration must be adjusted depending on creatinine clearance.

During use, a false-positive urine glucose test result is possible when using the method based on the reduction of copper ions. Therefore, it is recommended to perform a test based on the enzymatic oxidation of glucose (glucose oxidase method).

Effect on ability to drive vehicles and mechanisms

Given the possibility of developing side effects from the nervous system during treatment with the drug, caution should be exercised when working with machinery and driving vehicles.

Drug Interactions

Concomitant use of the drug with probenecid increases T_1/2 and reduces the renal clearance of both piperacillin and tazobactam, however C_max in plasma of both drugs remain unchanged.

Concomitant use of the drug and vecuronium bromide may lead to a prolonged neuromuscular blockade caused by the latter (a similar effect may be observed with the combination of piperacillin and other non-depolarizing muscle relaxants).

When used concomitantly with high doses of heparin, indirect anticoagulants or other drugs affecting the blood coagulation system, including platelet function, it is necessary to monitor the state of the blood coagulation system more frequently.

Piperacillin may delay the excretion of methotrexate (to avoid a toxic effect, it is necessary to monitor the serum concentration of methotrexate).

Pharmaceutical Compatibility with Other Medicines

Do not mix in the same syringe or infusion set with other medicines, including aminoglycosides. When used concomitantly with other antibiotics, the drugs should be administered separately; it is most preferable to separate the administration of piperacillin+Tazobactam and aminoglycosides in time.

It should not be used concomitantly with solutions containing sodium bicarbonate or added to blood products or albumin hydrolysates.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.