Xilbac

Xilbac is indicated for the treatment of infections due to susceptible strains of the designated microorganisms in the conditions listed below.

Skin and Skin Structure Infections caused by beta-lactamase producing strains of Staphylococcus aureus, Escherichia coli,² Klebsiella spp.² (including K. pneumoniae²), Proteus mirabilis,² Bacteroides fragilis,² Enterobacter spp.², and Acinetobacter calcoaceticus.²

NOTE: For information on use in pediatric patients see PRECAUTIONS – Pediatric Use and Clinical Studies.

Intra-Abdominal Infections caused by beta-lactamase producing strains of Escherichia coli, Klebsiella spp. (including K. pneumoniae²), Bacteroides spp. (including B. fragilis), and Enterobacter spp.²

Gynecological Infections caused by beta-lactamase producing strains of Escherichia coli,² and Bacteroides² spp. (including B. fragilis²).

While Xilbac is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with Xilbac due to its ampicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and beta-lactamase producing organisms susceptible to Xilbac should not require the addition of another antibacterial.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify the organisms causing infection and to determine their susceptibility to Xilbac.

Therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies when there is reason to believe the infection may involve any of the beta-lactamase producing organisms listed above in the indicated organ systems. Once the results are known, therapy should be adjusted if appropriate.

To reduce the development of drug-resistant bacteria and maintain effectiveness of Xilbac and other antibacterial drugs, Xilbac should be used only to treat 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.

²Efficacy for this organism in this organ system was studied in fewer than 10 infections.

Xilbac may be administered by either the IV or the IM routes.

For IV administration, the dose can be given by slow intravenous injection over at least 10–15 minutes or can also be delivered in greater dilutions with 50–100 mL of a compatible diluent as an intravenous infusion over 15–30 minutes.

Xilbac may be administered by deep intramuscular injection. (see Directions For Use-Preparation For Intramuscular Injection).

The recommended adult dosage of Xilbac is 1.5 g (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) to 3 g (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) every six hours. This 1.5 to 3 g range represents the total of ampicillin content plus the sulbactam content of Xilbac, and corresponds to a range of 1 g ampicillin/0.5 g sulbactam to 2 g ampicillin/1 g sulbactam. The total dose of sulbactam should not exceed 4 grams per day.

Pediatric Patients 1 Year Of Age Or Older

The recommended daily dose of Xilbac in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided doses every 6 hours. This 300 mg/kg/day dosage represents the total ampicillin content plus the sulbactam content of Xilbac, and corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day. The safety and efficacy of Xilbac administered via intramuscular injection in pediatric patients have not been established. Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations, and the total dose of sulbactam should not exceed 4 grams per day. The course of intravenous therapy should not routinely exceed 14 days. In clinical trials, most children received a course of oral antimicrobials following initial treatment with intravenous Xilbac. (see Clinical Studies).

Impaired Renal Function

In patients with impairment of renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of Xilbac in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations:

TABLE 5 Xilbac Dosage Guide for Patients with Renal Impairment

When only serum creatinine is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

Compatibility, Reconstitution And Stability

Xilbac sterile powder is to be stored at or below 30°C (86°F) prior to reconstitution.

When concomitant therapy with aminoglycosides is indicated, Xilbac and aminoglycosides should be reconstituted and administered separately, due to the in vitro inactivation of aminoglycosides by any of the aminopenicillins.

Directions For Use

General Dissolution Procedures

Xilbac sterile powder for intravenous and intramuscular use may be reconstituted with any of the compatible diluents described in this insert. Solutions should be allowed to stand after dissolution to allow any foaming to dissipate in order to permit visual inspection for complete solubilization.

Preparation For Intravenous Use

1.5 g and 3.0 g Bottles

Xilbac sterile powder in piggyback units may be reconstituted directly to the desired concentrations using any of the following parenteral diluents. Reconstitution of Xilbac, at the specified concentrations, with these diluents provide stable solutions for the time periods indicated in the following table: (After the indicated time periods, any unused portions of solutions should be discarded).

TABLE 6

If piggyback bottles are unavailable, standard vials of Xilbac sterile powdeUr smea Py ebrei oudssed. Initially, the vials may be reconstituted with Sterile Water for Injection to yield solutions containing 375 mg Xilbac per mL (250 mg ampicillin/125 mg sulbactam per mL). An appropriate volume should then be immediately diluted with a suitable parenteral diluent to yield solutions containing 3 to 45 mg Xilbac per mL (2 to 30 mg ampicillin/1 to 15 mg sulbactam/per mL).

1.5 g ADD-Vantage^® Vials

Xilbac in the ADD-Vantage^® system is intended as a single dose for intravenous administration after dilution with the ADD-Vantage^® Flexible Diluent Container containing 50 mL, 100 mL or 250 mL of 0.9% Sodium Chloride Injection, USP.

3 g ADD-Vantage^® Vials

Xilbac in the ADD-Vantage^® system is intended as a single dose for intravenous administration after dilution with the ADD-Vantage^® Flexible Diluent Container containing 100 mL or 250 mL of 0.9% Sodium Chloride Injection, USP.

Xilbac in the ADD-Vantage^® system is to be reconstituted with 0.9% Sodium Chloride Injection, USP only. See INSTRUCTIONS FOR USE OF THE ADD-Vantage^® VIAL section. Reconstitution of Xilbac, at the specified concentration, with 0.9% Sodium Chloride Injection, USP provides stable solutions for the time period indicated below:

TABLE 7

In 0.9% Sodium Chloride Injection, USP

The final diluted solution of Xilbac should be completely administered within 8 hours in order to assure proper potency.

Preparation For Intramuscular Injection

1.5 g and 3.0 g Standard Vials

Vials for intramuscular use may be reconstituted with Sterile Water for Injection USP, 0.5% Lidocaine Hydrochloride Injection USP or 2% Lidocaine Hydrochloride Injection USP. Consult the following table for recommended volumes to be added to obtain solutions containing 375 mg Xilbac per mL (250 mg ampicillin/125 mg sulbactam per mL). Note: Use only freshly prepared solutions and administer within one hour after preparation.

TABLE 8

The use of Xilbac is contraindicated in individuals with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to ampicillin, sulbactam or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

Xilbac is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Xilbac.

WARNINGS

Hypersensitivity

Serious and occasionally fatal hypersensitivity (anaphylactic) 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 hypersensitivity reactions 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 therapy with a penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction occurs, Xilbac should be discontinued and the appropriate therapy instituted.

Hepatotoxicity

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of Xilbac. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

Severe Cutaneous Adverse Reactions

Severe skin reactions, such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), dermatitis exfoliative, erythema multiforme, and acute generalized exanthematous pustulosis (AGEP) have been reported in patients on ampicillin/sulbactam therapy. If a severe skin reaction occurs, ampicillin/sulbactam should be discontinued and appropriate therapy should be initiated (see CONTRAINDICATIONS and ADVERSE REACTIONS).

Clostridium Difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Xilbac, 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General

A high percentage of patients with mononucleosis who receive ampicillin develop a skin rash. Thus, ampicillin class antibacterial should not be administered to patients with mononucleosis. In patients treated with Xilbac the possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted.

Prescribing Xilbac in the absence of 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 drugresistant bacteria.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential.

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Xilbac. 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. (see PRECAUTIONS-Drug/Laboratory Test Interactions).

Labor And Delivery

Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of Xilbac in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

Nursing Mothers

Low concentrations of ampicillin and sulbactam are excreted in the milk; therefore, caution should be exercised when Xilbac is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Xilbac have been established for pediatric patients one year of age and older for skin and skin structure infections as approved in adults. Use of Xilbac in pediatric patients is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetic studies, a controlled clinical trial conducted in pediatric patients and post-marketing adverse events surveillance. (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and Clinical Studies).

The safety and effectiveness of Xilbac have not been established for pediatric patients for intra-abdominal infections.

Adult Patients

Xilbac is generally well tolerated. The following adverse reactions have been reported in clinical trials.

Local Adverse Reactions

Pain at IM injection site – 16%

Pain at IV injection site – 3%

Thrombophlebitis – 3%

Phlebitis – 1.2%

Systemic Adverse Reactions

The most frequently reported adverse reactions were diarrhea in 3% of the patients and rash in less than 2% of the patients.

Additional systemic reactions reported in less than 1% of the patients were: itching, nausea, vomiting, candidiasis, fatigue, malaise, headache, chest pain, flatulence, abdominal distension, glossitis, urine retention, dysuria, edema, facial swelling, erythema, chills, tightness in throat, substernal pain, epistaxis and mucosal bleeding.

Pediatric Patients

Available safety data for pediatric patients treated with Xilbac demonstrate a similar adverse events profile to those observed in adult patients. Additionally, atypical lymphocytosis has been observed in one pediatric patient receiving Xilbac.

Adverse Laboratory Changes

Adverse laboratory changes without regard to drug relationship that were reported during clinical trials were:

Hepatic: Increased AST (SGOT), ALT (SGPT), alkaline phosphatase, and LDH.

Hematologic: Decreased hemoglobin, hematocrit, RBC, WBC, neutrophils, lymphocytes, platelets and increased lymphocytes, monocytes, basophils, eosinophils, and platelets.

Blood Chemistry: Decreased serum albumin and total proteins.

Renal: Increased BUN and creatinine.

Urinalysis: Presence of RBC's and hyaline casts in urine.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of Xilbac or other products containing ampicillin. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency, or potential causal connection to Xilbac.

Blood And Lymphatic System Disorders

Hemolytic anemia, thrombocytopenic purpura, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Some individuals have developed positive direct Coombs Tests during treatment with Xilbac, as with other beta-lactam antibacterials.

Gastrointestinal Disorders

Cholestatic hepatitis, cholestasis, hyperbilirubinemia, jaundice, abnormal hepatic function, gastritis, stomatitis, black "hairy" tongue and Clostridium difficile associated diarrhea (see CONTRAINDICATIONS and WARNINGS).

General Disorders And Administration Site Conditions

Injection site reaction

Immune System Disorders

Serious and fatal hypersensitivity (anaphylactic) reactions (See WARNINGS).

Nervous System Disorders

Convulsion

Renal And Urinary Disorders

Tubulointerstitial nephritis

Skin And Subcutaneous Tissue Disorders

Toxic epidermal necrolysis, Stevens-Johnson syndrome, and acute generalized exanthematous pustulosis (AGEP), urticaria, erythema multiforme, and exfoliative dermatitis (see CONTRAINDICATIONS and WARNINGS).

Neurological adverse reactions, including convulsions, may occur with the attainment of high CSF levels of beta-lactams. Ampicillin may be removed from circulation by hemodialysis. The molecular weight, degree of protein binding and pharmacokinetics profile of sulbactam suggest that this compound may also be removed by hemodialysis.