PIPRATAZ 250mg/2gr 

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Piperacillin/Tazobactam 

Vial 250mg/2gr

Piprataz® (Piperacillin and Tazobactam)

Description
Piprataz® is an injectable antibacterial combination product consisting of the semisynthetic antibiotic Piperacillin sodium and the beta - lactamase inhibitor Tazobactam sodium for intravenous injection.

Clinical pharmacology
Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a (beta)-lactamase inhibitor of the Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated (beta)-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

Antibacterial activity
Aerobic and facultative Gram-positive microorganisms:
Staphylococcus aureus (excluding methicillin and oxacillin-resistant isolates)
Aerobic and facultative Gram-negative microorganisms:
Acinetobacter baumanii ,Escherichia coli ,Haemophilus influenzae (excluding (beta)-lactamase negative, ampicillin-resistant isolates) ,Klebsiella pneumoniae ,Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible)
Gram-negative anaerobes:
Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus)
The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam. However, the safety and effectiveness of piperacillin/tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
Aerobic and facultative Gram-positive microorganisms:
Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only) ,Staphylococcus epidermidis (excluding methicillin and oxacillin resistant isolates) ,Streptococcus agalactiae † ,Streptococcus pneumoniae †  (penicillin-susceptible isolates only) ,Streptococcus pyogenes † ,Viridans group streptococci †
Aerobic and facultative Gram-negative microorganisms:
Citrobacter koseri,Moraxella catarrhalis ,Morganella morganii ,Neisseria gonorrhoeae ,Proteus mirabilis ,Proteus vulgaris ,Serratia marcescens ,Providencia stuartii ,Providencia rettgeri ,Salmonella enterica
Gram-positive anaerobes:
Clostridium perfringens
Gram-negative anaerobes:
Bacteroides distasonis
Prevotella melaninogenica
Aerobic Gram-Positive Microorganisms:
Enterococcus faecalis, Streptococcus pneumonia, Listeria monocytogenes,

Pharmacokinetics
Oral absorption                                         -----
Presystemic metabolism                      ----
Plasma half – life range                        0.7-1.2 h                                                         
                                             Volume of distribution             0.23 L.kg-1
                                             Plasma protein binding                 30%

Indication
1-    Appendicitis (complicated by rupture or abscess) and peritonitis
2-    Uncomplicated and complicated skin and skin structure infections
3-    Postpartum endometritis or pelvic inflammatory disease
4-    Community-acquired pneumonia(moderate severity only)
5-    Nosocomial pneumonia(moderate to severe)

Contraindication
Piprataz® is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors.

Precaution
•    Care is necessary if very high doses of Piprataz® are given, especially if renal function is poor, because of the risk of neuromuscular excitability or convulsions.
•    Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.
•    Piprataz® therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
•    Renal, hepatic, and haematological status should be monitored during prolonged and high-dose therapy
•    Prescribing Piprataz® in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.
•    In patients with creatinine clearance •    Piprataz® should not be used for the treatment of complicated urinary tract infections because of in adequate efficacy at the usual dose (3.375 grams every six hours)

Pregnancy
Pregnancy Category B
Adequate and well-controlled studies in humans have not been done; this drug should be used during pregnancy only if clearly needed.

Breast feeding
Piprataz® is excreted in low concentrations in human milk. Caution should be exercised when Piprataz® is administered to a nursing woman 

Dosage
Piprataz® should be administered by intravenous infusion over 30 minutes.
Usual adult and adolescent dose
•    Antibacterial-
Nosocomial pneumonia: Intravenous infusion, 3.375 grams every four hours in addition to therapy with an aminoglycoside for seven to fourteen days.
Other infections: Intravenous infusion, 3.375 grams o 4.5 grams every six to eight hours for seven to ten days.
Usual pediatric dose
•    Antibacterial-
Infants and children up to 12 years of age: dosage has not been established.
Children 12 years of age and older: see usual adult and adolescent dose

Preparation for IV injection
Piprataz®2.25 g, 3.375 g, and 4.5 g should be reconstituted with 10 ml, 15 ml, and 20 ml, of Sodium Chloride 0.9% for Injection, Sterile Water for Injection, Dextrose 5% respectively. Swirl until dissolved.
Compatible Reconstitution Diluents:
Preparation for IV infusion:
Reconstituted Piprataz® solution should be further diluted (recommended volume per dose of 50 ml to 150 ml) in a compatible intravenous diluents solution (Sodium Chloride 0.9 % for Injection, Sterile Water for Injection and Dextrose 5%).

Warning
•    Before initiating therapy with Piprataz®, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, Piprataz® should be discontinued and appropriate therapy instituted.
Interaction
•     Concurrent use of Piprataz® with tobramycin decreased the urinary recovery of tobramycin by 38%; concurrent administration of tobrmycin concentration by 11%
•    Concurrent use Vecuronium or Nondepolarizing muscle relaxants with Piprataz® may prolong neuromuscular blockade
•    Probenecid may result in increased and prolonged blood levels of Piprataz®.
•    Piprataz® may decrease the efficacy of oral contraceptives
•    The mixing of Piprataz® with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside
•    Concurrent use of Piprataz® and Heparin may increase risk of bleeding, because of addictive effect.
•    Co-administration of Methotrexate and Piprataz® may result in increased and prolonged blood levels of Methotrexate.

Incompatibilities
Extemporaneous admixtures of beta-lactam antibacterials and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites at least 1 hour apart. Do not mix them in the same intravenous bag, bottle, or tubing

 Laboratory value alteration

•    The administration of Piprataz® concentrations may result in false-positive reactions when testing for the presence of glucose in urine using clinitest®, benedict's solution or fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as clinistix®) be used.
•    Cross- reactions with non-Aspegillus polysaccharides and polyfuranoses with the Bio-Rad laboratories Platelia Aspergillus EIA test have been reported.
•    Blood urea nitrogen (BUN) and creatinine serum increased concentrations have been associated with Piprataz®.

Adverse reactions
The events with the highest incidence :
Diarrhea, headache, constipation , nausea , insomnia, rash , including maculopapular, bullous, urticarial, and eczematoid, vomiting , dyspepsia , pruritus , stool changes , fever , agitation, pain, moniliasis, hypertension , dizziness , abdominal pain , chest pain, edema , anxiety , rhinitis , and dyspnea .

Adverse systemic clinical events reported in 1.0% or less of the patients:
•    Body as a whole --rigors, back pain, malaise
•    Cardiovascular --tachycardia, including supraventricular and ventricular; bradycardia; arrhythmia, including atrial fibrillation, ventricular fibrillation, cardiac arrest, cardiac failure, circulatory failure, myocardial infarction
•    Central nervous system --tremor, convulsions, vertigo
•    Gastrointestinal --melena, flatulence, hemorrhage, gastritis, hiccough, ulcerative stomatitis
•    Pseudomembranous colitis was reported in one patient during the clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment.
•    Hearing and Vestibular System --tinnitus
•    Hypersensitivity --anaphylaxis
•    Metabolic and Nutritional --symptomatic hypoglycemia, thirst
•    Musculoskeletal --myalgia, arthralgia
•    Platelets, Bleeding, Clotting --mesenteric embolism, purpura, epistaxis, pulmonary embolism
•    Psychiatric --confusion, hallucination, depression
•    Reproductive, Female --leukorrhea, vaginitis
•    Respiratory --pharyngitis, pulmonary edema, bronchospasm, coughing
•    Skin and Appendages --genital pruritus, diaphoresis
•    Special senses --taste perversion
•    Urinary --retention, dysuria, oliguria, hematuria, incontinence
•    Vision --photophobia
•    Vascular (extracardiac) --flushing

Overdose
Symptoms: There have been postmarketing reports of overdose with Piperacillin/Tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Treatment: should be supportive and symptomatic according the patient's clinical presentation. Excessive serum concentrations of either Piperacillin or Tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of Piperacillin/Tazobactam, the percentage of the Piperacillin and Tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively
Storage and stability condition
•    Store below 25oC.
•     Protect from light and moisture.
•    Vials should not be frozen after reconstitution
•    Discard reconstituted vial after 1 hours if stored at room temperature, or after 7 days if stored at refrigerated temperature( 2ºC  to 8 ºC )
•   
Packaging
•    Each Piprataz® 2.25 g vial provides piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 250 mg of tazobactam.
•    Each Piprataz® 3.375 g vial provides piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 375 mg of tazobactam.
•    Each Piprataz® 4.5 g vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 500 mg of tazobactam

 Boxes of 1 vial.