A Le Xian

A Le Xian is indicated in the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

Septicemia (including bacteremia) caused by β-lactamase–producing strains of Klebsiella spp.*, E. coli*, S. aureus*, or P. aeruginosa* (or other Pseudomonas species*)

Lower Respiratory Infections caused by β-lactamase–producing strains of S. aureus, H. influenzae*, or Klebsiella spp.*

Bone and Joint Infections caused by β-lactamase–producing strains of S. aureus

Skin and Skin Structure Infections caused by β-lactamase–producing strains of S. aureus, Klebsiella spp.*, or E. coli*

Urinary Tract Infections (complicated and uncomplicated) caused by β-lactamase– producing strains of E. coli, Klebsiella spp., P. aeruginosa* (or other Pseudomonas spp.*), Citrobacter spp.*, Enterobacter cloacae*, S. marcescens*, or S. aureus*

Gynecologic Infections endometritis caused by β-lactamase–producing strains of P. melaninogenicus*, Enterobacter spp. (including E. cloacae*), E. coli, K. pneumoniae*, S. aureus, or S. epidermidis

Intra-abdominal Infections peritonitis caused by β-lactamase–producing strains of E. coli, K. pneumoniae, or B. fragilis* group

*Efficacy for this organism in this organ system was studied in fewer than 10 infections.

NOTE: For information on use in pediatric patients ( ≥ 3 months of age) see PRECAUTIONS - Pediatric Use and Clinical Studies sections. There are insufficient data to support the use of A Le Xian in pediatric patients under 3 months of age or for the treatment of septicemia and/or infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b.

While A Le Xian is indicated only for the conditions listed above, infections caused by ticarcillin-susceptible organisms are also amenable to treatment with A Le Xian due to its ticarcillin content. Therefore, mixed infections caused by ticarcillin-susceptible organisms and β-lactamase–producing organisms susceptible to ticarcillin/clavulanic acid should not require the addition of another antibiotic.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ticarcillin/clavulanic acid. Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative bacteria, A Le Xian is particularly useful for the treatment of mixed infections and for presumptive therapy prior to the identification of the causative organisms. A Le Xian has been shown to be effective as single drug therapy in the treatment of some serious infections where normally combination antibiotic therapy might be employed. Therapy with A Le Xian may be initiated before results of such tests are known when there is reason to believe the infection may involve any of the β-lactamase–producing organisms listed above.

Based on the in vitro synergism between ticarcillin/clavulanic acid and aminoglycosides against certain strains of P. aeruginosa, combined therapy has been successful, especially in patients with impaired host defenses. Both drugs should be used in full therapeutic doses.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of A Le Xian and other antibacterial drugs, A Le Xian should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

A Le Xian should be administered by intravenous infusion (30 min.).

Adults: The usual recommended dosage for systemic and urinary tract infections for average (60 kg) adults is 3.1 grams of A Le Xian (3.1-gram vial containing 3 grams ticarcillin and 100 mg clavulanic acid) given every 4 to 6 hours. For gynecologic infections, A Le Xian should be administered as follows: Moderate infections, 200 mg/kg/day in divided doses every 6 hours, and for severe infections, 300 mg/kg/day in divided doses every 4 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.

Pediatric Patients ( ≥ 3 months): For patients < 60 kg: In patients < 60 kg, A Le Xian is dosed at 50 mg/kg/dose based on the ticarcillin component. A Le Xian should be administered as follows: Mild to moderate infections, 200 mg/kg/day in divided doses every 6 hours; for severe infections, 300 mg/kg/day in divided doses every 4 hours.

For patients ≥ 60 kg: For mild to moderate infections, 3.1 grams of A Le Xian (3 grams of ticarcillin and 100 mg of clavulanic acid) administered every 6 hours; for severe infections, 3.1 grams every 4 hours. Renal Impairment: For infections complicated by renal insufficiency†, an initial loading dose of 3.1 grams should be followed by doses based on creatinine clearance and type of dialysis as indicated below:

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 duration of therapy depends upon the severity of infection. Generally, A Le Xian should be continued for at least 2 days after the 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.

Frequent bacteriologic and clinical appraisals are necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed. Persistent infections may require treatment for several weeks, and doses smaller than those indicated above should not be used.

In certain infections, involving abscess formation, appropriate surgical drainage should be performed in conjunction with antimicrobial therapy.

Intravenous Administration
Directions For Use
3.1-Gram Vials

The 3.1-gram vial should be reconstituted by adding approximately 13 mL of Sterile Water for Injection, USP, or Sodium Chloride Injection, USP, and shaking well. When dissolved, the concentration of ticarcillin will be approximately 200 mg/mL with a corresponding concentration of 6.7 mg/mL for clavulanic acid. Conversely, each 5.0 mL of the 3.1-gram dose reconstituted with approximately 13 mL of diluent will contain approximately 1 gram of ticarcillin and 33 mg of clavulanic acid.

Intravenous Infusion: The dissolved drug should be further diluted to desired volume using the recommended solution listed in the COMPATIBILITY AND STABILITY Section (STABILITY PERIOD) to a concentration between 10 mg/mL to 100 mg/mL. The solution of reconstituted drug may then be administered over a period of 30 minutes by direct infusion or through a Y-type intravenous infusion set. If this method of administration is used, it is advisable to discontinue temporarily the administration of any other solutions during the infusion of A Le Xian.

Stability: For I.V. solutions, see STABILITY PERIOD below.

When A Le Xian 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, A Le Xian, as with other parenteral drugs, should be inspected visually for particulate matter. If this condition is evident, the solution should be discarded.

The color of reconstituted solutions of A Le Xian normally ranges from light to dark yellow, depending on concentration, duration, and temperature of storage while maintaining label claim characteristics.

Compatibility And Stability
3.1-Gram Vials
(Dilutions Derived From A Stock Solution Of 200 Mg/Ml)

The concentrated stock solution at 200 mg/mL is stable for up to 6 hours at room temperature 21° to 24°C (70° to 75°F) or up to 72 hours under refrigeration 4°C (40°F).

If the concentrated stock solution (200 mg/mL) is held for up to 6 hours at room temperature 21° to 24°C (70° to 75°F) or up to 72 hours under refrigeration 4°C (40°F) and further diluted to a concentration between 10 mg/mL and 100 mg/mL with any of the diluents listed below, then the following stability periods apply.

Stability Period (3.1-gram Vials)

If the concentrated stock solution (200 mg/mL) is stored for up to 6 hours at room temperature and then further diluted to a concentration between 10 mg/mL and 100 mg/mL, solutions of Sodium Chloride Injection, USP, and Lactated Ringer's Injection, USP, may be stored frozen –18°C (0°F) for up to 30 days. Solutions prepared with Dextrose Injection 5%, USP, may be stored frozen –18°C (0°F) for up to 7 days. All thawed solutions should be used within 8 hours or discarded. Once thawed, solutions should not be refrozen.

NOTE: A Le Xian is incompatible with Sodium Bicarbonate.

Unused solutions must be discarded after the time periods listed above.

A Le Xian is contraindicated in patients with a history of hypersensitivity reactions to any of the penicillins.

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY 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 PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH A Le Xian, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, A Le Xian SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE PROVIDED AS INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including A Le Xian, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against

C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

When very high doses of A Le Xian are administered, especially in the presence of impaired renal function, patients may experience convulsions. (See ADVERSE REACTIONS and OVERDOSAGE.)

PRECAUTIONS

General

While A Le Xian possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.

Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions have 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 impairment. If bleeding manifestations appear, treatment with A Le Xian should be discontinued and appropriate therapy instituted.

A Le Xian has only rarely been reported to cause hypokalemia; however, the possibility of this occurring should be kept in mind particularly when treating patients with fluid and electrolyte imbalance. Periodic monitoring of serum potassium may be advisable in patients receiving prolonged therapy.

The theoretical sodium content is 4.51 mEq (103.6 mg) per gram of A Le Xian. This should be considered when treating patients requiring restricted salt intake.

As with any penicillin, an allergic reaction, including anaphylaxis, may occur during administration of A Le Xian, particularly in a hypersensitive individual.

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind, particularly during prolonged treatment. If superinfections occur, appropriate measures should be taken.

Prescribing A Le Xian 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 the development of drug-resistant bacteria.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, results from assays for gene mutation in vitro using bacteria (Ames tests) and yeast, and for chromosomal effects in vitro in human lymphocytes, and in vivo in mouse bone marrow (micronucleus test) indicate that A Le Xian is without any mutagenic potential.

Pregnancy (Category B)

Reproduction studies have been performed in rats given doses up to 1,050 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to A Le Xian. There are, however, no adequate and well-controlled studies 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.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when A Le Xian is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of A Le Xian have been established in the age group of 3 months to 16 years. Use of A Le Xian in these age groups is supported by evidence from adequate and well-controlled studies of A Le Xian in adults with additional efficacy, safety, and pharmacokinetic data from both comparative and non-comparative studies in pediatric patients. There are insufficient data to support the use of A Le Xian in pediatric patients under 3 months of age or for the treatment of septicemia and/or infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b.

In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, or in patients who require prophylaxis against central nervous system infection, an alternate agent with demonstrated clinical efficacy in this setting should be used.

Geriatric Use

An analysis of clinical studies of A Le Xian was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 1,078 subjects treated with at least one dose of A Le Xian, 67.5% were < 65 years old, and 32.5% were ≥ 65 years old. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).

A Le Xian contains 103.6 mg (4.51 mEq) of sodium per gram of A Le Xian. At the usual recommended doses, patients would receive between 1,285 and 1,927 mg/day (56 and 84 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.

As with other penicillins, the following adverse reactions may occur:

Hypersensitivity Reactions

Skin rash, pruritus, urticaria, arthralgia, myalgia, drug fever, chills, chest discomfort, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylactic reactions.

Central Nervous System

Headache, giddiness, neuromuscular hyperirritability, or convulsive seizures.

Gastrointestinal Disturbances

Disturbances of taste and smell, stomatitis, flatulence, nausea, vomiting and diarrhea, epigastric pain, and pseudomembranous colitis have been reported. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.)

Hemic and Lymphatic Systems

Thrombocytopenia, leukopenia, neutropenia, eosinophilia, reduction of hemoglobin or hematocrit, and prolongation of prothrombin time and bleeding time.

Abnormalities of Hepatic Function Tests

Elevation of serum aspartate aminotransferase (SGOT), serum alanine aminotransferase (SGPT), serum alkaline phosphatase, serum LDH, serum bilirubin. There have been reports of transient hepatitis and cholestatic jaundice—as with some other penicillins and some cephalosporins.

Renal and Urinary Effects

Hemorrhagic cystitis, elevation of serum creatinine and/or BUN, hypernatremia, reduction in serum potassium, and uric acid.

Local Reactions

Pain, burning, swelling, and induration at the injection site and thrombophlebitis with intravenous administration.

Available safety data for pediatric patients treated with A Le Xian demonstrate a similar adverse event profile to that observed in adult patients.

Drug Abuse And Dependence

Neither abuse of nor dependence on A Le Xian has been reported.

As with other penicillins, neurotoxic reactions may arise when very high doses of A Le Xian are administered, especially in patients with impaired renal function. (See WARNINGS and ADVERSE REACTIONS - Central Nervous System.)

In case of overdosage, discontinue A Le Xian, treat symptomatically, and institute supportive measures as required. 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.