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TAZOCIN® Wyeth-Ayerst Piperacillin Sodium--Tazobactam Sodium Antibiotic--b-lactamase Inhibitor
 
Action and Clinical

Tazocin is an injectable antibacterial combination consisting of the semisynthetic antibiotic piperacillin sodium and the b-lactamase inhibitor tazobactam sodium for i.v. administration.

Piperacillin exerts bactericidal activity by inhibiting septum formation and cell wall synthesis. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam is a b-lactamase inhibitor. Tazobactam, in combination with piperacillin enhances and extends the antibiotic spectrum of piperacillin to include b-lactamase producing bacteria normally resistant to piperacillin.

Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite which lacks pharmacological and antibacterial activities. Both tazobactam and piperacillin are eliminated by the kidney via glomerular filtration and tubular secretion. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the dose as unchanged drug and the remainder as the single metabolite. Piperacillin is excreted rapidly as unchanged drug, with 68% of the dose in the urine. Piperacillin from Tazocin is excreted in the bile to a small extent (<1%) and no tazobactam or desethyl metabolite is excreted in the bile.

Tazobactam and piperacillin are widely distributed into tissues and body fluids including, but not limited to, intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary and fallopian tube) interstitial fluid and bile. Mean tissue concentrations were generally 50 to 100% of those in plasma. Distribution of tazobactam and piperacillin into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.

In subjects with renal impairment, the half-lives of tazobactam and piperacillin, after single doses, increase with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is 4-fold for tazobactam and 2-fold for piperacillin compared to subjects with normal renal function. Dosage adjustments for Tazocin are recommended when creatinine clearance is below 40 mL/min in patients receiving the recommended daily dose of Tazocin (see Dosage).

Hemodialysis removes 30 to 40% of a Tazocin dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 21% and 6% of the tazobactam and piperacillin doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis see Dosage.

Tazobactam and piperacillin half-lives increase by approximately 18 to 25% in patients with hepatic cirrhosis compared to healthy subjects. However, dosage adjustment of Tazocin due to hepatic cirrhosis is not necessary.

Indications And Clinical Uses :

For the treatment of patients with systemic and/or local bacterial infections, caused by piperacillin resistant, piperacillin/tazobactam susceptible, b-lactamase producing strains of the designated microorganisms in the specified conditions listed below.

Intra-Abdominal Infections: Appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin resistant, b-lactamase producing strains of E. coli or members of the B. fragilis group.

Skin and Skin Structure Infections: Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscess, acute ischemic/diabetic foot infections caused by piperacillin resistant b-lactamase producing strains of S. aureus (not methicillin-resistant strains).

Gynecological Infections: Postpartum endometritis or pelvic inflammatory disease caused by piperacillin resistant, b-lactamase producing strains of E. coli.

Community-Acquired Lower Respiratory Tract Infections: Community-acquired pneumonia (moderate severity only) caused by piperacillin resistant, b-lactamase producing strains of H. influenzae.

While Tazocin is indicated only for the conditions listed above, infections caused by piperacillin susceptible organisms are also amenable to Tazocin treatment due to its piperacillin content. The tazobactam component of this combination product does not decrease the activity of the piperacillin component against piperacillin susceptible organisms. Therefore, the treatment of polymicrobial infections caused by piperacillin susceptible organisms and b-lactamase producing organisms susceptible to Tazocin should not require the addition of another antibiotic.

Tazocin may be useful as presumptive therapy in the indicated conditions prior to identification of causative organisms because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic organisms. Appropriate cultures should usually be performed before initiating antimicrobial treatment in order to isolate and identify the organisms causing infection and to determine their susceptibility to Tazocin. Antimicrobial therapy should be adjusted, if appropriate, once results of culture(s) and antimicrobial susceptibility testing are known.

Contra-Indications:

Patients with a history of allergic reactions to any of the penicillins and/or cephalosporins or b-lactamase inhibitors.WarningWarnings:

Warnings in Clinical States:

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in individuals receiving therapy with penicillins. These reactions are more apt to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with cephalosporins. Before initiating therapy with Tazocin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. If an allergic reaction occurs during therapy with Tazocin, the antibiotic should be discontinued and appropriate therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with epinephrine, oxygen and i.v. steroids and airway management, including intubation, should also be administered as indicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including piperacillin/tazobactam and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. difficile is one primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an oral antibacterial drug effective against C. difficile colitis.

Precautions:

General: Bleeding manifestations or significant leukopenia following prolonged administration have occurred in some patients receiving b-lactam antibiotics, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.

The possibility of the emergence of resistant organisms that might cause superinfections should be kept in mind. If this occurs, appropriate measures should be taken.

As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given i.v. (particularly in the presence of renal failure).

Tazocin is a monosodium salt of piperacillin and a monosodium salt of tazobactam containing a total of 2.35 mmol (54 mg) of Na

As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Because of chemical instability, Tazocin should not be used for i.v. administration with solutions containing only sodium bicarbonate (see Dosage, Incompatibility).

Tazocin should not be added to blood products.

Children: Safety and efficacy in children below the age of 12 have not been established.

Pregnancy and Teratology: Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility due to piperacillin/tazobactam administered up to a dose which is similar to the maximum recommended human daily dose based on body-surface area (mg/m

Piperacillin: Reproduction and teratology studies have been performed in mice and rats and have revealed no evidence of impaired fertility or harm to the fetus due to piperacillin administered up to a dose which is half (mice) or similar (rats) to the human dose based on body-surface area (mg/m

Tazobactam: Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility due to tazobactam administered up to a dose 3 times the human dose based on body-surface area (mg/m

There are however, no adequate and well-controlled studies with the piperacillin/tazobactam combination or with piperacillin or tazobactam alone in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation: Caution should be exercised when Tazocin is administered to nursing mothers. Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in milk have not been studied.

Geriatrics: Patients over 65 years of age are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal insufficiency (see Dosage).

Drug Interactions :

Aminoglycosides: The mixing of Tazocin with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.

When Tazocin is co-administered with tobramycin, the area under the curve, renal clearance, and urinary recovery of tobramycin were decreased by 11%, 32% and 38%, respectively. The alterations in the pharmacokinetics of tobramycin when administered in combination with piperacillin/tazobactam may be due to in vivo and in vitro inactivation of tobramycin in the presence of piperacillin/tazobactam. The inactivation of aminoglycosides in the presence of penicillin class drugs has been recognized. It has been postulated that penicillin-aminoglycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity. In patients with severe renal dysfunction (i.e., chronic hemodialysis patients), the pharmacokinetics of tobramycin are significantly altered when tobramycin is administered in combination with piperacillin. The alteration of tobramycin pharmacokinetics and the potential toxicity of the penicillin-aminoglycoside complexes in patients with mild to moderate renal dysfunction who are administered an aminoglycoside in combination with piperacillin/tazobactam is unknown.

Probenecid: Concomitant administration of Tazocin and probenecid results in prolonged half-life of piperacillin (21%) and tazobactam (71%).

Vancomycin: No pharmacokinetic interactions are found between Tazocin and vancomycin.

Heparin: Coagulation parameters should be tested more frequently and monitored regularly, during simultaneous administration of high doses of heparin, oral anticoagulants and other drugs that may affect the blood coagulation system and/or the thrombocyte function.

Vecuronium: Piperacillin used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Tazocin could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing muscle relaxants could be prolonged in the presence of piperacillin (see prescribing information for vecuronium bromide).

Lactated Ringers solution is not compatible with Tazocin (see Table III).

Where Tazocin is administered concurrently with another antibiotic the drugs should not be mixed in the same solution but must be administered separately.

Drug/Laboratory Test Interactions : As with other penicillins, the administration of Tazocin may result in a false-positive reaction for glucose in the urine using a copper-reduction method (Clinitest). It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Diastix or Tes-Tape) be used.

Adverse Reactions:

:During the clinical investigations, 2 621 patients worldwide were treated with Tazocin in phase 3 trials. In the key North America clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, Tazocin was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%).

Adverse local reactions that were reported, irrespective of relationship to therapy with Tazocin, were phlebitis (1.3%), injection site reaction (0.5%), pain (0.2%), inflammation (0.2%), thrombophlebitis (0.2%) and edema (0.1%).

Adverse Clinical Events: Based on patients from the North American trials (n=1 063), the events with the highest incidence in patients, irrespective of relationship to Tazocin therapy, were diarrhea (11.3%); headache (7.7%); constipation (7.7%); nausea (6.9%); insomnia (6.6%); rash (4.2%), including maculopapular, bullous, urticarial, and eczematoid; vomiting (3.3%); dyspepsia (3.3%); pruritus (3.1%); stool changes (2.4%); fever (2.4%); agitation (2.1%); pain (1.7%); moniliasis (1.6%); hypertension (1.6%); dizziness (1.4%); abdominal pain (1.3%); chest pain (1.3%); edema (1.2%); anxiety (1.2%); rhinitis (1.2%); and dyspnea (1.1%).

Additional adverse systemic clinical events reported in 1% or less of the patients are listed below within each body system: Autonomic Nervous System: hypotension, ileus, syncope.

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.

CNS: tremor, convulsions, vertigo.

Gastrointestinal: melena, flatulence, hemorrhage, gastritis, hiccough, ulcerative stomatitis.

Pseudomembranous colitis was reported in 1 patient during the clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see Warnings).

Hearing: tinnitus.

Hypersensitivity: anaphylaxis. Incidence of rash and fever is higher in patients with cystic fibrosis.

Metabolic and Nutritional: symptomatic hypoglycemia, thirst.

Musculoskeletal: myalgia, arthralgia.

Platelet, Bleeding, Clotting: mesenteric embolism, purpura, epistaxis, pulmonary embolism (see Precautions, General).

Psychiatric: confusion, hallucination, depression.

Reproduction, 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.

Adverse Laboratory Events: Changes in laboratory parameters, without regard to drug relationship, include: Hematologic: decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. The leukopenia/neutropenia associated with Tazocin administration appears to be reversible and most frequently associated with prolonged administration, i.e.,³ 21 days of therapy. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills).

Coagulation: positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time.

Hepatic: transient elevations of AST, ALT, alkaline phosphatase, bilirubin.

Renal: increases in serum creatinine, blood urea nitrogen.

Urinalysis: proteinuria, hematuria, pyuria.

Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium and calcium), hyperglycemia, decreases in total protein or albumin. In individuals with liver disease or those receiving cytotoxic therapy or diuretics, Tazocin has been reported rarely to produce a decrease in serum potassium levels at high doses of piperacillin.

The following adverse reactions have also been reported for Pipracil: Skin and Appendages: erythema multiforme and Stevens-Johnson syndrome, rarely reported.

Gastrointestinal: cholestatic hepatitis.

Renal: rarely, interstitial nephritis.

Skeletal: prolonged muscle relaxation (see Precautions, Drug Interactions).

Symptoms And Treatment Of Overdose :

OverdoseInformation on overdosage of Tazocin in humans in not available.:

Excessive serum levels of either tazobactam or piperacillin may be reduced by hemodialysis, although no specific antidote is known. As with other penicillins, neuromuscular excitability or convulsions have occurred following large i.v. doses, primarily in patients with impaired renal function.

In the case of motor excitability or convulsions, general supportive measures, including administration of anticonvulsive agents (e.g., diazepam or barbiturates) may be considered.

Dosage And Administration:

The usual total daily dose for adults is 12 g/1.5 g, given as 3 g/0.375 g every 6 hours.

Clinical trial data in the treatment of intra-abdominal infections support the efficacy of 4 g/0.5 g given every 8 hours.

Renal Insufficiency: In patients with renal insufficiency, the i.v. dose should be adjusted to the degree of actual renal function impairment. The suggested daily doses are shown in Table I.

Table I--Tazocin

Dosage Recommendations

Creatinine Clearance (mL/min) Recommended Dosage Regimen

>40 12 g/1.5 g/day in divided doses of 3 g/0.375 g q6h

20-40 8 g/1 g/day in divided doses of 2 g/0.25 g q6h

<20 6 g/0.75 g/day in divided doses of 2 g/0.25 g q8h

For patients on hemodialysis, the maximum dose is 2 g/0.25 g piperacillin/tazobactam given every 8 hours. In addition, because hemodialysis removes 30 to 40% of Tazocin dose in 4 hours, one additional dose of 0.75 g piperacillin/tazobactam should be administered following each dialysis period. For patients with renal failure, measurement of serum levels of Tazocin will provide additional guidance for adjusting dosage.

Duration of Therapy: The usual duration of treatment is from 7 to 10 days. The duration should be guided by the severity of the infection and the patient's clinical and bacteriological progress.

Administration: Tazocin should be administered by i.v. infusion over 30 minutes (see ).

Reconstituted Solutions: Reconstitute Tazocin with at least 5 mL of a suitable diluent per g of piperacillin from the list of diluents provided below. Shake well until dissolved. It should be further diluted to the desired final volume with an acceptable diluent (see Tables II and III).

Table II--Tazocin

Reconstitution

Vial Size (piperacillin/ tazobactam) Volume of Diluent to be Added to Vial Approximate Available Volume Nominal Concentration per mL

2.25 g (2 g/0.25 g) 10 mL 11.60 mL 0.194 g/mL (0.172 g/mL/0.022 g/mL)

3.375 g (3 g/0.375 g) 15 mL 17.36 mL 0.194 g/mL (0.172 g/mL/0.022 g/mL)

4.5 g (4 g/0.5 g) 20 mL 23.15 mL 0.194 g/mL (0.172 g/mL/0.022 g/mL)

Table III--Tazocin

Reconstitute Tazocin per gram of piperacillin with 5 mL of a Compatible Reconstitution Diluent (listed below) Further dilute the reconstituted Tazocin with 50 mL to 150 mL of a Compatible I.V. Diluent Solution (listed below)

0.9% Sodium Chloride for Injection Sterile Water for Injection Dextrose 5% Bacteriostatic Saline/Parabens Bacteriostatic Water/Parabens Bacteriostatic Saline/Benzyl Alcohol Bacteriostatic Water/Benzyl Alcohol 0.9% Sodium Chloride for Injection Sterile Water for Injection* Dextran 6% in Saline Dextrose 5%

*Maximum recommended volume per dose of Sterile Water for Injection is 50 mL.

Lactated Ringers solution is not compatible with Tazocin.

Intermittent I.V. Infusion: Reconstitute as previously described, with 5 mL of an acceptable diluent per 1 g of piperacillin and then further dilute in the desired volume (at least 50 mL). This diluted solution must be used immediately. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.

When concomitant therapy with aminoglycosides is indicated, Tazocin and the aminoglycoside should be reconstituted and administered separately, due to the in vitro inactivation of the aminoglycoside (see Precautions, Drug Interactions).

Stability of Tazocin following Reconstitution: Tazocin is stable in glass and plastic containers (plastic syringes, i.v. bags and tubing) when reconstituted with acceptable diluents.

Stability studies have demonstrated chemical stability [potency, pH of reconstituted solution, and clarity of solution] for up to 12 hours at room temperature and up to 48 hours at refrigerated temperatures in glass vials. Discard unused portions after storage for 12 hours at room temperature or 48 hours when refrigerated.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Incompatibilities: Not to be added to blood products.

Because of chemical instability, Tazocin should not be used for i.v. administration with solutions containing sodium bicarbonate alone. It may be used with i.v. admixtures containing other ingredients as well as sodium bicarbonate for up to 24 hours at room temperature and 48 hours refrigerated.

Solutions containing Tazocin and protein hydrolysates or amino acids should be used within 12 hours if stored at room temperature and 24 hours if refrigerated.

Availability And Storage:

Vials: 2.25 g: Each vial contains: piperacillin sodium equivalent to piperacillin 2 g and tazobactam sodium equivalent to tazobactam 0.25 g. Sodium: 4.69 mmol (108 mg). Vials of 2.25 g, boxes of 10.

3.375 g: Each vial contains: piperacillin sodium equivalent to piperacillin 3 g and tazobactam sodium equivalent to tazobactam 0.375 g. Sodium: 7.03 mmol (162 mg). Vials of 3.375 g, boxes of 10.

4.5 g: Each vial contains: piperacillin sodium equivalent to piperacillin 4 g and tazobactam sodium equivalent to tazobactam 0.5 g. Sodium: 9.37 mmol (216 mg). Vials of 4.5 g, boxes of 10.

Store at controlled room temperature 15 to 30°C.

Sensitivity Discs: Tazocin 110 µg sensitivity discs (piperacillin 100 µg + tazobactam 10 µg) are available and must be refrigerated upon receipt.