Santaz (Powder) Instructions for Use

Marketing Authorization Holder

S.P. Incomed, LLC (Russia)

Manufactured By

Interpharma, LLC (Russia)

ATC Code

J01CR05 (Piperacillin and beta-lactamase inhibitor)

Active Substances

Piperacillin (Rec.INN registered by WHO)

Tazobactam (Rec.INN registered by WHO)

Dosage Form

Santaz

Powder for solution for intravenous administration 4 g+0.5 g: vial 1 pc.

Dosage Form, Packaging, and Composition

Powder for solution for intravenous administration white or almost white, hygroscopic.

Colorless glass vials with a capacity of 30 ml (1) – 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

Piperacillin is a semi-synthetic broad-spectrum bactericidal antibiotic active against many gram-positive and gram-negative aerobic and anaerobic bacteria. Piperacillin inhibits the synthesis of the microorganism’s cell wall membrane.

Tazobactam, a sulfone derivative of triazolylmethylpenicillanic acid, is a potent inhibitor of many beta-lactamases (including plasmid and chromosomal beta-lactamases) that often cause resistance to penicillins and cephalosporins, including third-generation cephalosporins. The presence of tazobactam in the combination drug enhances the antimicrobial activity and broadens the spectrum of action of piperacillin by including bacteria that produce beta-lactamases, which are usually resistant to piperacillin and other beta-lactam antibiotics.

The drug is active against

Gram-negative bacteria: beta-lactamase-producing and non-producing strains of Escherichia coli, Citrobacter spp. (including Citrobacter freundii, Citrobacter diversus), Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae), Enterobacter spp. (including Enterobacter cloaca, Enterobacter aerogenes), Proteus vulgaris, Proteus mirabilis, Providencia rettgerri, Providencia stuartii, Plesiomonas shigelloides, Morganella morganii, Serratia spp. (including Serratia marcescens, Serratia liquefaciens), Salmonella spp., Shigella spp., Pseudomonas aeruginosa and other Pseudomonas spp. (including Pseudomonas cepacia, Pseudomonas fluorescens), Xanthomonas maltophilia, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella spp. (including Branhamella catarrhalis), Acinetobacter spp., Haemophilus influenzae, Haemophilus parainfluenza, Pasteurella multocida, Yersinia spp., Campylobacter spp., Gardnerella vaginalis.

Gram-positive bacteria: beta-lactamase-producing and non-producing strains of Streptococcus spp. (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus bovis, Streptococcus agalactiae, Streptococcus spp. of the viridans group subgroups C and G), Enterococcus spp. (Enterococcus faecalis, Enterococcus faecium), Staphylococcus aureus (methicillin-susceptible), Staphylococcus saprophyticus, Staphylococcus epidermidis (coagulase-negative), Listeria monocytogenes, Nocardia spp.

Anaerobic bacteria: beta-lactamase-producing and non-producing strains of Bacteroides spp. (Bacteroides bivius, Bacteroides disiens, Bacteroides capillosus, Bacteroides melaninogenicus, Bacteroides oralis), Bacteroides fragilis subgroup (Bacteroides fragilis, Bacteroides vulgatus, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron), Bacteroides uniformis, Bacteroides asaccharolyticus), Peptostreptococcus spp., Fusobacterium spp., Eubacterium spp., Clostridium spp. (including Clostridium difficile, Clostridium perfringens), Veillonella spp. and Actinomyces spp.

Pharmacokinetics

C_max of piperacillin and tazobactam in plasma is reached immediately after the completion of intravenous administration.

When increasing the dose of the Piperacillin 2 g/Tazobactam 250 mg combination to 4 g/500 mg, respectively, a disproportionate increase (approximately 28%) in the concentration of piperacillin and tazobactam is observed.

The plasma protein binding for both piperacillin and tazobactam is approximately 30%, with the presence of tazobactam not affecting this parameter for piperacillin, and the presence of piperacillin not affecting it for tazobactam.

Piperacillin and Tazobactam are widely distributed in body tissues and fluids, including the intestinal mucosa, gallbladder, lungs, bile, female genital organs (uterus, ovaries, and fallopian tubes), and bones. Average tissue concentrations range from 50 to 100% of plasma concentrations.

Piperacillin is metabolized to a minimally active desethyl metabolite; Tazobactam is metabolized to an inactive metabolite. Piperacillin and Tazobactam are excreted by the kidneys via glomerular filtration and tubular secretion. Piperacillin is rapidly excreted unchanged, with 68% of the administered dose found in the urine. Tazobactam and its metabolite are rapidly excreted via renal excretion, with 80% of the administered dose found unchanged, and the remaining amount as a metabolite. Piperacillin, Tazobactam, and desethylpiperacillin are also excreted in bile and eliminated via the intestines.

T_1/2 of piperacillin and tazobactam from plasma is approximately 0.7-1.2 h. With a decrease in creatinine clearance, the T_1/2 of piperacillin and tazobactam is prolonged.

Renal impairment

As creatinine clearance (CrCl) decreases, the T_1/2 of piperacillin and tazobactam increases. When CrCl is less than 20 ml/min, the T_1/2 of piperacillin and tazobactam increases by 2 and 4 times, respectively, compared to patients with normal renal function.

During hemodialysis, 30 to 50% of piperacillin and 5% of the tazobactam dose as a metabolite are removed. During peritoneal dialysis, approximately 6% and 21% of piperacillin and tazobactam are removed, respectively, with 18% of tazobactam removed as its metabolite.

Hepatic impairment

Although in patients with impaired liver function the T_1/2 of piperacillin and tazobactam increases, dose adjustment is not required.

Indications

Infectious and inflammatory diseases caused by microorganisms susceptible to piperacillin.

Adults and children over 12 years

• Lower respiratory tract infections;
• Urinary tract infections (complicated and uncomplicated);
• Intra-abdominal infections;
• Skin and soft tissue infections;
• Septicemia;
• Gynecological infections (including endometritis and adnexitis in the postpartum period);
• Bacterial infections in patients with neutropenia (in combination with aminoglycosides);
• Bone and joint infections;
• Mixed infections (caused by gram-positive/gram-negative aerobic and anaerobic microorganisms).

Children aged 2 to 12 years

• Intra-abdominal infections;
• Infections in the setting of neutropenia (in combination with aminoglycosides).

ICD codes

Dosage Regimen

IV slowly by bolus injection over at least 3-5 min or by infusion over 20-30 min.

The drug doses and duration of treatment are determined by the severity of the infectious process and the dynamics of clinical and bacteriological parameters.

Adults and children over 12 years with normal renal function

The recommended dose of the drug, administered every 8 hours, is 4.5 g (4 g piperacillin/0.5 g tazobactam).

The total daily dose depends on the severity and location of the infection and can range from 2.25 g (2 g piperacillin/0.25 g tazobactam) to 4.5 g (4 g piperacillin/0.5 g tazobactam) of the drug administered every 6 or 8 hours.

Children aged 2 to 12 years

For neutropenia

In sick children with normal renal function and body weight less than 50 kg with fever occurring in the setting of neutropenia, the dose of the drug is 90 mg (80 mg piperacillin/10 mg tazobactam) per kilogram of body weight, administered every 6 hours in combination with an appropriate dose of an aminoglycoside.

In children with body weight greater than 50 kg, the dose corresponds to the adult dose and is administered in combination with aminoglycosides.

For intra-abdominal infection In children with body weight up to 40 kg and normal renal function, the recommended dose is 112.5 mg/kg of the drug (100 mg piperacillin/12.5 mg tazobactam) every 8 hours.

Children with body weight greater than 40 kg and normal renal function are prescribed the same dose as adults, i.e., 4.5 g of the drug (4 g piperacillin/0.5 g tazobactam) every 8 hours.

Treatment should be carried out for at least 5 days and no more than 14 days, considering that the drug administration is continued for at least another 48 hours after the disappearance of clinical signs of infection.

Renal impairment

For patients with chronic renal failure or patients on hemodialysis, the dose and frequency of administration should be adjusted according to the degree of renal impairment.

Recommended drug doses for adults and children (body weight >50 kg) with renal failure

For patients on hemodialysis, the maximum daily dose is 8 g/1 g piperacillin/tazobactam. Furthermore, since 30-50% of piperacillin is removed during a 4-hour hemodialysis session, one additional dose of 2 g/0.25 g piperacillin/tazobactam should be administered after each dialysis session.

Children 2-12 years with renal failure

The pharmacokinetics of piperacillin+[Tazobactam] in children with renal failure have not been studied. There are no data on doses for the combination of renal failure and neutropenia. For children 2-12 years with renal failure, it is recommended to adjust the dose as follows:

Recommended drug doses for children (body weight <50 kg) with renal failure

This dose change is only a guide. Each patient should be monitored for timely detection of signs of overdose. The drug dose and the interval between administrations should be adjusted accordingly.

No dose adjustment is required for impaired liver function.

In elderly patients, dose adjustment is necessary only in the presence of impaired renal function.

Method of solution preparation

The drug is dissolved in one of the solvents listed below according to the indicated volumes. The vial is rotated in a circular motion until the contents are completely dissolved (with constant rotation usually for 5-10 minutes). The finished solution is a colorless or light yellow liquid.

Solvents compatible with the drug: 0.9% sodium chloride solution; sterile water for injection; 5% dextrose solution.

Then, the prepared solution can be diluted to the volume required for IV administration (for example, from 50 ml to 150 ml) with one of the compatible solvents listed below: 0.9% sodium chloride solution; sterile water for injection (maximum recommended volume – 50 ml); 5% dextrose solution.

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 bleeding time), 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, seizures.

From the cardiovascular system decreased BP, flushing.

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

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

Other fungal superinfections, fever, arthralgia.

Contraindications

• Hypersensitivity to piperacillin, tazobactam, beta-lactam antibiotics (including penicillins, cephalosporins), to beta-lactamase inhibitors.
• Children under 2 years of age.

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 (CrCl less than 20 ml/min), patients on hemodialysis, with concomitant use of high doses of anticoagulants, with hypokalemia.

Use in Pregnancy and Lactation

There is insufficient data on the use of the Piperacillin+[Tazobactam] combination in pregnant women. Piperacillin and Tazobactam cross the placental barrier. The drug can be prescribed to pregnant women only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Piperacillin is secreted in breast milk in low concentrations; the excretion of tazobactam into milk has not been studied. If it is necessary to use the drug during lactation, breastfeeding should be discontinued during treatment.

Use in Renal Impairment

Use with caution: chronic renal failure (creatinine clearance less than 20 ml/min), patients on hemodialysis.

Pediatric Use

Contraindicated in children under 2 years of age.

Use with caution: children over 2 years of age, chronic renal failure (creatinine clearance less than 20 ml/min), patients on hemodialysis.

Special Precautions

Before starting treatment, the patient should be interviewed in detail to identify possible hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Severe allergic reactions are more likely to develop in patients with hypersensitivity to multiple allergens. Such reactions require discontinuation of the drug administration and the administration of epinephrine and other emergency measures.

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

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

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) are likely. If bleeding occurs, the drug administration should be discontinued and appropriate therapy prescribed.

The possibility of the emergence of resistant microorganisms that can cause superinfection, especially during a long course of treatment, should be considered. This preparation contains 2.79 mEq (64 mg) of sodium per gram of piperacillin, which may lead to a general increase in sodium intake. In patients with hypokalemia or those taking drugs that promote potassium excretion, hypokalemia may develop during treatment (serum electrolyte levels should be checked regularly).

There is no experience of use in children under 2 years of age.

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

During the use of the drug, a false-positive result of the urine glucose test 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 a car or operate machinery

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.

Overdose

Symptoms: nausea, vomiting, diarrhea, increased neuromuscular excitability, and convulsions.

Treatment: symptomatic treatment is prescribed depending on the clinical manifestations. Hemodialysis may be prescribed to reduce high serum concentrations of piperacillin or tazobactam.

Drug Interactions

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

Simultaneous use of the drug and vecuronium bromide may lead to a prolonged neuromuscular blockade caused by the latter (a similar effect may be observed when piperacillin is combined with 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, the state of the blood coagulation system should be monitored more frequently.

Piperacillin may delay the excretion of methotrexate (to avoid a toxic effect, the serum concentration of methotrexate should be monitored).

No pharmacokinetic interaction with vancomycin was identified.

Piperacillin, including when used in combination with tazobactam, did not have a significant effect on the pharmacokinetics of tobramycin. The pharmacokinetics of piperacillin, tazobactam, and metabolites also did not change significantly with simultaneous use with tobramycin.

Pharmaceutical compatibility with other drugs

The drug should not be mixed in the same syringe or dropper with other drugs, 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.

The drug should not be used together with solutions containing sodium bicarbonate or added to blood products or albumin hydrolysates.

Storage Conditions

Store the drug out of the reach of children, in a dry place, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

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.