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Composition: Each Fortibiotic 1500 mg vial contains : Ampicillin sodium 1064 mg ampicillin 1000 mg Sulbactam sodium 544 mg 500 mg sulbactam

Indications And Usage: INDICATIONS AND USAGE Fortibiotic 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 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 Bacteroides spp.2 (including B. fragilis2) . While Fortibiotic is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with Fortibiotic due to its ampicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and beta-lactamase producing organisms susceptible to Fortibiotic should not require the addition of another antibiotic. Fortibiotic IM/IV may also be administered peri-operatively to reduces the incidence of post-operative wound infections in patients undergoing abdominal or pelvic surgery, in which peritoneal contamination may be present . In termination of pregnancy or cesarean section, 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 Fortibiotic . 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 Fortibiotic and other antibacterial drugs, Fortibiotic 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. 2 Efficacy for this organism in this organ system was studied in fewer than 10 infections.

Contraindications: The use of Fortibiotic is contraindicated in individuals with a history of hypersensitivity reactions to any of the penicillins.

Adverse Reactions: Adult Patients Fortibiotic is generally well tolerated. The following adverse reactions have been reported. Local Adverse Reactions Pain at IM injection site – 16% Pain at IV injection site – 3% Thrombophlebitis – 3% 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 Fortibiotic demonstrate a similar adverse events profile to those observed in adult patients. Additionally, atypical lymphocytosis has been observed in one pediatric patient receiving Fortibiotic 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. The following adverse reactions have been reported with ampicillin-class antibiotics and can also occur with Fortibiotic . Gastrointestinal Gastritis, stomatitis, black "hairy" tongue and enterocolitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. Hypersensitivity Reactions Urticaria, erythema multiform, and an occasional case of exfoliative dermatitis have been reported. These reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with a penicillin. Hematologic In addition to the adverse laboratory changes listed above for Fortibiotic , agranulocytosis has been reported during therapy with penicillins. All of 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 Fortibiotic , as with other beta-lactam antibiotics. OVERDOSAGE 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.

Dosage & Administration: Fortibiotic may be administered by either the IV or the IM routes (following dilution). However, the intent of the pharmacy bulk package is for preparation of solutions for IV infusion only. 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. Fortibiotic may be administered by deep intramuscular injection. The recommended adult dosage of Fortibiotic 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 Fortibiotic , 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 Fortibiotic 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 Fortibiotic , and corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day. The safety and efficacy of Fortibiotic 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 Fortibiotic . 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 Fortibiotic in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations: Fortibiotic Dosage Guide for Patients with Renal Impairment    Creatinine Clearance (mL/min/1.73m2)Ampicillin/Sulbactam Half-Life (Hours)Recommended Fortibiotic Dosage≥3011.5–3.0 g q 6h-q 8h15–2951.5–3.0 g q 12h5–1491.5–3.0 g q 24hWhen 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.      Males        weight (kg) × (140 – age)                          72 × serum creatinine      Females     0.85 × above value COMPATIBILITY, RECONSTITUTION AND STABILITY When concomitant therapy with aminoglycosides is indicated, Fortibiotic 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 Fortibiotic sterile powder for intravenous and intramuscular use may be reconstituted with any of the compatible diluents described in this insert.DiluentMaximum Concentration (mg/mL) Fortibiotic (Ampicillin/Sulbactam)Use Periods ( in Hours )Sterile Water for Injection45 (30/15)8 hrs at 21C˚45 (30/15)48 hrs at 4C˚30 (20/10)72 hrs at 4C˚0.9% Sodium Chloride Injection, (USP)45 (30/15)8 hrs at 21C˚45 (30/15)48 hrs at 4C˚30 (20/10)72 hrs at 4C˚5% Dextrose Injection30 (20/10)2 hrs at 21C˚30 (20/10)4 hrs at 4C˚3 (2/1)2 hrs at 21C˚Lactated Ringer’s Injection45 (30/15)8 hrs at 21C˚45 (30/15)24 hrs at 4C˚M/6 Sodium Lactate Injection45 (30/15)8 hrs at 21C˚45 (30/15)12 hrs at 4C˚5% Dextrose in 0.45% Saline 3(2/1)4 hrs at 21C˚15 (10/5)4 hrs at 4C˚10% Invert Sugar 3(2/1)4 hrs at 21C˚30 (20/10)3 hrs at 4C˚

Drug Interactions: Drug Interactions Probenecid decreases the renal tubular secretion of ampicillin and sulbactam. Concurrent use of probenecid with Fortibiotic may result in increased and prolonged blood levels of ampicillin and sulbactam. The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving bothdrugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with Fortibiotic and allopurinol administered concurrently. Fortibiotic and aminoglycosides should not be reconstituted together due to the in vitro inactivation of aminoglycosides by the ampicillin component of Fortibiotic .

Clinical Pharmacology In Adults: General Immediately after completion of a 15-minute intravenous infusion of Fortibiotic , peak serum concentrations of ampicillin and sulbactam are attained. Ampicillin serum levels are similar to those produced by the administration of equivalent amounts of ampicillin alone. Peak ampicillin serum levels ranging from 109 to 150 mcg/mL are attained after administration of 2000 mg of ampicillin plus 1000 mg sulbactam and 40 to 71 mcg/mL after administration of 1000 mg ampicillin plus 500 mg sulbactam. The corresponding mean peak serum levels for sulbactam range from 48 to 88 mcg/mL and 21 to 40 mcg/mL, respectively. After an intramuscular injection of 1000 mg ampicillin plus 500 mg sulbactam, peak ampicillin serum levels ranging from 8 to 37 mcg/mL and peak sulbactam serum levels ranging from 6 to 24 mcg/mL are attained. The mean serum half-life of both drugs is approximately 1 hour in healthy volunteers. Approximately 75 to 85% of both ampicillin and sulbactam are excreted unchanged in the urine during the first 8 hours after administration of Fortibiotic to individuals with normal renal function. Somewhat higher and more prolonged serum levels of ampicillin and sulbactam can be achieved with the concurrent administration of probenecid. In patients with impaired 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 Fortibiotic in such patients should be administered less frequently in accordance with the usual practice for ampicillin. Ampicillin has been found to be approximately 28% reversibly bound to human serum protein and sulbactam approximately 38% reversibly bound. The following average levels of ampicillin and sulbactam were measured in the tissues and fluids listed:TABLE 1. Concentration of Fortibiotic in Various Body Tissues and Fluids  Fluid or TissueDose (grams) Ampicillin/SulbactamConcentration (mcg/mL or mcg/g) Ampicillin/SulbactamBlister Fluid (Cantharides)0.5/0.5 IV8/20Tissue Fluid1/0.5 IV8/4Intestinal Mucosa0.5/0.5 IV11/18Appendix2/1 IV3/40Penetration of both ampicillin and sulbactam into cerebrospinal fluid in the presence of inflamed meninges has been demonstrated after IV administration of Fortibiotic . The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving Fortibiotic are similar to those observed in adults. Immediately after a 15-minute infusion of 50 to 75 mg Fortibiotic /kg body weight, peak serum and plasma concentrations of 82 to 446 mcg ampicillin/mL and 44 to 203 mcg sulbactam/mL were obtained. Mean half-life values were approximately 1 hour. MICROBIOLOGY Ampicillin is similar to benzyl penicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of cell wall mucopeptide biosynthesis. Ampicillin has a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria. (Ampicillin is, however, degraded by beta-lactamases and therefore the spectrum of activity does not normally include organisms which produce these enzymes). A wide range of beta-lactamases found in microorganisms resistant to penicillins and cephalosporins have been shown in biochemical studies with cell free bacterial systems to be irreversibly inhibited by sulbactam. Although sulbactam alone possesses little useful antibacterial activity except against the Neisseriaceae, whole organism studies have shown that sulbactam rest