Timentin (Ticarcillin Disodium)

TIMENTIN®

SmithKline Beecham

Ticarcillin Disodium-Potassium Clavulanate

Antibiotic-b-Lactamase Inhibitor

Action and Clinical

Ticarcillin exerts a bactericidal action against sensitive organisms during the stage of active multiplication through the inhibition of the biosynthesis of bacterial cell wall mucopeptides. Clavulanic acid inhibits specific b-lactamases of some microorganisms and allows ticarcillin to inhibit ticarcillin resistant organisms which produce clavulanic acid sensitive b-lactamases.IndicationsIndications:

Indications And Clinical Uses:

For the treatment of the following infections when caused by Timentin-susceptible strains of the designated bacteria: Bacterial septicemia when caused by b-lactamase (excluding Type I) producing strains of E. coli, S. aureus, and Klebsiella species.

Lower respiratory infections when caused by b-lactamase (excluding Type I) producing strains of S. aureus, H. influenzae and Klebsiella species.

Bone infections when caused by b-lactamase producing strains of S. aureus.

Skin structure infections when caused by b-lactamase (excluding Type I) producing strains of S. aureus, E. coli and Klebsiella species.

Urinary tract infections when caused by b-lactamase (excluding Type I) producing strains of E. coli and Klebsiella species.

Gynecologic infections when caused by b-lactamase (excluding Type I) producing strains of Bacteroides species, E. coli, S. aureus, S. epidermidis and Klebsiella species.

Intra-abdominal infections including peritonitis and intra-abdominal abscess, when caused by b-lactamase (excluding Type 1) producing strains of E. coli, K. pneumoniae, B. fragilis, and P. aeruginosa. The efficacy and safety of Timentin for the treatment of intra-abdominal infections in infants and children under the age of 12 have not been established.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibilities to Timentin. Therapy may, however, be initiated before results of such tests are known when there is reason to believe the infection may involve any of the b-lactamase (excluding Type I) producing organisms listed above. Modification of the treatment may be required once these results become available or if there is no clinical response.

The treatment of mixed infections caused by ticarcillin susceptible organisms and b-lactamase (excluding Type 1) producing organisms susceptible to Timentin should not require the addition of another antibiotic due to the ticarcillin content of Timentin.

Prophylaxis: The administration of Timentin perioperatively (preoperatively, intraoperatively and postoperatively) may reduce the incidence of certain infections in patients undergoing elective surgical procedures (i.e. colorectal surgery and abdominal hysterectomy) that may be classified as contaminated or potentially contaminated.

In patients undergoing cesarean section, who are considered to be at increased risk of infection, intraoperative (after clamping the umbilical cord) and postoperative use of Timentin may reduce the incidence of surgery related postoperative infections.

The data from all the surgical prophylaxis trials were combined to obtain a sufficient number of patients to suggest that Timentin may be of value in reducing infection following colorectal surgery, abdominal hysterectomy or high risk cesarean section.

If signs of postsurgical infection should appear, specimens for culture should be obtained for identification of the causative organism(s) so that appropriate therapy may be instituted.

Contra-Indications:

Patients with a history of hypersensitivity to the penicillin, clavam, or cephalosporin, group of b-lactams.

Warnings in Clinical States:

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

Patients with renal impairment or underlying hemostatic problems should be observed for bleeding manifestations. Such patients should be dosed strictly according to recommendations (see Dosage). If bleeding occurs the administration of Timentin should be discontinued and appropriate therapy instituted.

Patients receiving Timentin may develop hemorrhagic manifestations associated with coagulation abnormalities, such as changes in bleeding time and platelet function, particularly if co-administered with drugs such as ASA or anticoagulants. If these occur, the administration of Timentin should be discontinued and appropriate therapy instituted. On withdrawal of the drug, the bleeding time and coagulation abnormalities should revert to normal after approximately 7 days. Other causes of abnormal bleeding should also be considered.

Precautions:

The total daily dosage should be reduced when Timentin is administered to patients with transient or persistent reduction of urinary output due to renal insufficiency (see Dosage) because high and prolonged serum antibiotic concentrations can occur from usual doses.

Periodic assessment of organ system functions, including renal, hepatic and hematopoietic function should be made during prolonged therapy with Timentin.

The passage of any penicillin from blood into brain is facilitated by inflamed meninges and during cardiopulmonary bypass. In the presence of these conditions and particularly when accompanied by renal failure, sufficiently high serum ticarcillin concentration can be attained to produce CNS adverse effects: these include myoclonia, convulsive seizures and depressed consciousness.

Timentin has been reported to cause hypokalemia; therefore, the possibility of this occurring should be kept in mind particularly when treating patients with fluid and electrolyte imbalance. Periodic monitoring of serum potassium is advisable and, when necessary, corrective therapy implemented.

The theoretical sodium content is 4.83 mEq (111 mg)/g of Timentin. Therefore, electrolyte levels and cardiac status should be monitored carefully during treatment, particularly in patients with hypertension or congestive heart failure.

The possibility of overgrowth by non-susceptible organisms and species originally sensitive to Timentin should be kept in mind, particularly during prolonged treatment. If superinfection occurs during therapy, appropriate measures should be taken.

Children: The safety and efficacy for the treatment of infections in infants from birth to 1 month of age have not been established.

Pregnancy: Safety in the treatment of infections during human pregnancy is unknown. Timentin should only be used during pregnancy if the anticipated benefit to the mother justifies the potential risk to the fetus.

Lactation: Penicillins have been shown to be excreted in human breast milk. It is not known whether clavulanic acid is excreted in breast milk. Nursing should be avoided during treatment with Timentin.

Drug/Laboratory Test Interactions : Timentin should not be mixed with an aminoglycoside in the same container. Penicillins can cause substantial inactivation of aminoglycosides.

Probenecid interferes with the renal tubular secretion of ticarcillin, thereby increasing serum concentrations and prolonging serum half-life of the antibiotic. However, probenecid has no effect on the renal clearance or serum concentrations of clavulanic acid.

High urine concentrations of ticarcillin (>1 500 mg/L 2 hours after an i.v. injection of 3.1 g Timentin) may produce false positive protein reactions (pseudoproteinuria) with the following methods: sulfosalicylic acid and boiling test, acetic acid test, biuret reaction, and nitric acid test. The bromphenol blue (Multi-stix) reagent strip test has been reported to be reliable.

The presence of clavulanic acid in Timentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Adverse Reactions:

The following adverse reactions may occur during therapy: Hypersensitivity: skin rash, pruritus, urticaria, arthralgia, myalgia, drug fever, chills, chest discomfort, bronchospasm, wheezing, and anaphylactic reactions.

CNS: headache, giddiness, neuromuscular hyperirritability or convulsive seizures.

Gastrointestinal: disturbances of taste and smell, stomatitis, flatulence, nausea, vomiting and diarrhea, epigastric pain.

Hemic and Lymphatic: thrombocytopenia, leukopenia, neutropenia, eosinophilia and reduction of hemoglobin or hematocrit. Prolongation of prothrombin time and bleeding time.

Abnormalities of Hepatic and Renal Function Tests: elevation of serum aspartate aminotransferase AST, serum alanine aminotransferase ALT, serum alkaline phosphatase, serum LDH, serum bilirubin. Elevation of serum creatinine and/or BUN, hypernatremia. Reduction in serum potassium and uric acid.

Local: pain, burning, erythema, swelling and induration at the injection site and phlebitis and thrombophlebitis with i.v. administration.

Other: Increased muscle weakness in patients with myasthenia gravis has been reported.

Symptoms And Treatment Of Overdose:

OverdoseTimentin overdosage has the potential to cause neuromuscular hyperirritability or convulsive seizures. Ticarcillin may be removed from circulation by hemodialysis. The molecular weight, degree of protein binding and pharmacokinetic profile of clavulanic acid together with information from a single patient with renal insufficiency all suggest that this compound may also be removed by hemodialysis.

Dosage And Administration:

Timentin should be administered only by i.v. infusion over 30 minutes.

Adults: Dosage for any individual patient must take into consideration the site and severity of infection, the susceptibility of the organisms causing infection, and the status of the patient’s host defense mechanisms.

The recommended dosage for adults (60 kg or greater) is 3.1 g every 4 to 6 hours.

For patients weighing less than 60 kg, the recommended dosage is 200 to 300 mg/kg/day, based on ticarcillin content, given in divided doses every 4 to 6 hours.

The duration of therapy depends upon the severity of infection. Generally, Timentin should be continued for at least 2 days after signs and symptoms of infection have disappeared. The usual duration is 10 to 14 days; however, in difficult and complicated infections, more prolonged therapy may be required. In certain infections, involving abscess formation, appropriate surgical drainage should be performed in conjunction with antimicrobial therapy.

Adults with Impaired Renal Function: The serum half-life of Timentin in patients with renal insufficiency is prolonged, consequently, the dosage regimen must be adjusted. Clinical efficacy data are insufficient at present to establish an appropriate dosage regimen for Timentin in patients with renal dysfunction. However, on the basis of theoretical pharmacokinetic considerations (namely absence of any change in the pharmacokinetics of ticarcillin due to clavulanic acid and the apparent greater tissue clearance of clavulanic acid as compared to ticarcillin) it is suggested that for infections complicated by renal dysfunction, the dosage regimen as used currently for ticarcillin alone may generally be adopted (see below).

Prophylaxis: For surgical prophylaxis, administration should not exceed the recommended dosage regimen, since the continued administration of any antibiotic increases the risk of adverse reactions while, in the majority of surgical procedures, does not reduce the incidence of subsequent infection.

A 3 dosage regimen is recommended as follows: Patients undergoing cesarean section: Administer the first dose of 3.1 g Timentin as soon as the umbilical cord is clamped. The second and third dosage of 3.1 g should be administered at 4 hour intervals after the initial dose for a total of 3 doses.

Patients undergoing Abdominal Hysterectomy or Colorectal Surgery: Administer the first dose of 3.1 g Timentin one-half to 1 hour prior to the initial incision. The second and third dosage of 3.1 g should be administered at 4 hour intervals after the initial dose for a total of 3 doses.

Infants and Children (Under 40 kg, 1 month to 12 years of age): Clinical and pharmacokinetic data are limited in these age groups. These daily dosages should not exceed the adult dose.

Administration: Timentin must not be administered by bolus i.v. injection or by i.m. injection. The dissolved drug should be further diluted to the desired volume using a suitable solution listed below. The further diluted i.v. solution of Timentin should be administered over a period of 30 minutes by direct infusion or through a Y-type i.v. infusion set which may already be in place. If this method or the piggyback method of administration is used, it is advisable to discontinue temporarily the administration of any other solutions during the infusion of Timentin.

Timentin should not be physically mixed or administered at the same site with any other antimicrobial agent such as an aminoglycoside.

Reconstitution: For I.V. Infusion: 3.1 g: Reconstitute each vial with 13 mL Sterile Water for Injection USP; when dissolved, the concentration of ticarcillin will be approximately 200 mg/mL with a corresponding concentration of 6.7 mg/mL for clavulanic acid (stock solution). Conversely, each 5 mL of the 3.1 g dose reconstituted with approximately 13 mL of diluent will contain approximately 1 g of ticarcillin and 33 mg of clavulanic acid.

31 g: Reconstitute each vial with 76 mL Sterile Water for Injection USP; when dissolved, concentration of ticarcillin will be approximately 300 mg/mL with a corresponding concentration of 10 mg/mL for clavulanic acid (stock solution). Conversely, each 5.0 mL of the 31 g dose reconstituted with approximately 76 mL of diluent will contain approximately 1.5 g of ticarcillin and 50 mg of clavulanic acid.

Solutions of I.V. Infusion: Sodium Chloride Injection USP, Dextrose Injection 5% USP, sterile water for injection USP and Lactated Ringer’s solution USP.

Note: When Timentin is given in combination with another antimicrobial such as an aminoglycoside, each drug should be given separately in accordance with the recommended dosage and routes of administration for each drug.

After reconstitution and prior to administration, Timentin, as with other parenteral drugs, should be inspected visually for particulate matter and discoloration.

Stability of Solutions: Timentin stock solution at 200 mg/mL or 300 mg/mL (ticarcillin) is stable for up to 6 hours at room temperature (21 to 24°C) or up to 72 hours under refrigeration (4°C).

Availability And Storage:

Supplied 3.1 g: Each vial contains: sterile ticarcillin disodium equivalent to ticarcillin 3 g and sterile potassium clavulanate equivalent to clavulanic acid 0.1 g.

31 g: Each vial contains: sterile ticarcillin disodium equivalent to ticarcillin 30 g and sterile potassium clavulanate equivalent to clavulanic acid 1 g.

Store at or below 24°C.

TIMENTIN® SmithKline Beecham Ticarcillin Disodium-Potassium Clavulanate Antibiotic-b-Lactamase Inhibitor

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