AMPICILLIN SODIUM AND SULBACTAM SODIUM

Ampicillin and Sulbactam for Injection, USP is a sterile antibacterial fixed-combination drug product consisting of the semisynthetic antibacterial ampicillin sodium and the beta-lactamase inhibitor sulbactam sodium for intravenous administration. Ampicillin sodium is derived from the penicillin nucleus, 6-aminopenicillanic acid. Chemically, it is monosodium (2S, 5R,6R)-6-[(R)-2-amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0] heptane-2-carboxylate and has a molecular weight of 371.39. Its chemical formula is C 16 H 18 N 3 NaO 4 S. The structural formula is: Sulbactam sodium is a derivative of the basic penicillin nucleus. Chemically, sulbactam sodium is sodium penicillinate sulfone; sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate 4,4-dioxide. Its chemical formula is C 8 H 10 NNaO 5 S with a molecular weight of 255.22. The structural formula is: Ampicillin and sulbactam for injection, USP is available as a white to off-white dry powder for reconstitution. Ampicillin and sulbactam for injection, USP dry powder is freely soluble in aqueous diluents to yield pale yellow to yellow solutions. The pH of the solutions is between 8.0 and 10.0. Dilute solutions (up to 30 mg ampicillin and 15 mg sulbactam per mL) are essentially colorless to pale yellow. The pH of dilute solutions remains the same. Ampicillin and Sulbactam for Injection, USP pharmacy bulk package is a bottle containing a sterile preparation of ampicillin sodium and sulbactam sodium for parenteral use that contains many single doses. The Pharmacy Bulk Package is for use in a pharmacy admixture setting; it provides many single doses of Ampicillin and Sulbactam for Injection for addition to suitable parenteral fluids in the preparation of admixtures for intravenous infusion. (See DIRECTIONS FOR USE – Directions for Proper Use of Pharmacy Bulk Package section.) Each 15 g bottle contains ampicillin 10 g and sulbactam 5 g (equivalent to 10.627 g ampicillin sodium and 5.470 g sulbactam sodium). ampicillin structure sulbactam structure

Ampicillin and Sulbactam for Injection, USP, 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 , * Klebsiella spp. * (including K. pneumoniae * ), Proteus mirabilis, * Bacteroides fragilis , * Enterobacter spp ., * and Acinetobacter calcoaceticus . * NOTE: For information on use in pediatric patients see PRECAUTIONS–Pediatric Use and CLINICAL STUDIES sections. Intra-Abdominal Infections caused by beta-lactamase producing strains of Escherichia coli, Klebsiella spp. (including K. pneumoniae*), Bacteroides spp. (including B. fragilis), and Enterobacter spp.* Gynecological Infections caused by beta-lactamase producing strains of Escherichia coli ,* and Bacteroides spp. * (including B. fragilis *). *Efficacy for this organism in this organ system was studied in fewer than 10 infections. While Ampicillin and Sulbactam for Injection is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with Ampicillin and Sulbactam for Injection due to its ampicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and beta-lactamase producing organisms susceptible to Ampicillin and Sulbactam for Injection 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 Ampicillin and Sulbactam for Injection. 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 Ampicillin and Sulbactam for Injection and other antibacterial drugs, Ampicillin and Sulbactam for Injection 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.

The pharmacy bulk package is for preparation of solutions for IV infusion only. Ampicillin and Sulbactam for Injection should be administered diluted with 50 mL to 100 mL of a compatible diluent as an intravenous infusion over 1530 minutes. The recommended adult dosage of Ampicillin and Sulbactam for Injection is 1.5 g (ampicillin 1 g and sulbactam 0.5 g) to 3 g (ampicillin 2 g and sulbactam 1 g) every six hours. This 1.5 to 3 g range represents the total of ampicillin content plus the sulbactam content of Ampicillin and Sulbactam for Injection and corresponds to a range of 1 g ampicillin and 0.5 g sulbactam to 2 g ampicillin and 1 g sulbactam. The total dose of sulbactam should not exceed 4 g per day. Pediatric Patients 1 Year of Age or Older: The recommended daily dose of Ampicillin and Sulbactam for Injection 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 Ampicillin and Sulbactam for Injection, and corresponds to 200 mg ampicillin and 100 mg sulbactam per kg per day. The safety and efficacy of Ampicillin and Sulbactam for Injection 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 g per day. The course of intravenous therapy should not routinely exceed 14 days. In clinical trials, most most pediatric patients received a course of oral antimicrobials following initial treatment with intravenous Ampicillin and Sulbactam for Injection (see CLINICAL STUDIES section). 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 Ampicillin and Sulbactam for Injection in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations: TABLE 3 Ampicillin and Sulbactam for Injection, USP Dosage Guide for Patients with Renal Impairment Creatinine Clearance (mL/min/1.73m 2 ) Ampicillin/Sulbactam Half-Life (Hours) Recommended Ampicillin and Sulbactam for Injection, USP Dosage 30 1 1.5 g to 3 g every 6 to 8 hours 15 - 29 5 1.5 g to 3 g every 12 hours 5 - 14 9 1.5 g to 3 g every 24 hours 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. Males weight (kg) × (140 - age) 72 × serum creatinine Females 0.85 × above value COMPATIBILITY, RECONSTITUTION AND STABILITY When concomitant therapy with aminoglycosides is indicated, Ampicillin and Sulbactam for Injection and aminoglycosides should be reconstituted and administered separately, due to the in vitro inactivation of aminoglycosides by any of the aminopenicillins. Intravenous Administration Directions for Proper Use of Pharmacy Bulk Package General Dissolution Procedures: Ampicillin and Sulbactam for Injection sterile powder for intravenous 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. Reconstituted Bulk Solution Should Not be Used For Direct Infusion Prior to intravenous administration, Ampicillin and Sulbactam for Injection must be reconstituted and further diluted before use. a) Reconstitute the 15 g vial with either 92 mL Sterile Water for Injection or 0.9% Sodium Chloride Injection, added in two separate aliquots in a suitable work area, such as a laminar flow hood. Add 50 mL of solution, shake to dissolve. Then add an additional 42 mL and shake. The solution should be allowed to stand after dissolution to allow any foaming to dissipate in order to permit visual inspection for complete solubilization. The resultant solution will have a total concentration of approximately 150 mg/mL (ampicillin concentration of 100 mg/mL and sulbactam concentration of 50 mg/mL). The resultant volume is approximately 100 mL. The closure may be penetrated only one time after reconstitution, if needed, using a suitable sterile transfer device or dispensing set that allows for measured dispensing of the contents. After reconstitution, use within two hours if stored at room temperature, or within four hours if stored under refrigeration. b) Dilute in a suitable parental diluent (see Table 4) to yield solutions containing a total concentration between 3 mg/mL and 45 mg/mL (ampicillin concentration of 2 mg/mL to 30 mg/mL and sulbactam concentration of 1 mg/mL to 15 mg/mL) are recommended for intravenous use. Storage of Diluted Ampicillin and Sulbactam for Injection Solutions If the reconstituted bulk solution is stored for less than one hour at room temperature 20°C (68°F) prior to further dilution, the use periods indicated in Table 4 apply for the diluted solutions. If the bulk solution is stored for one to two hours at room temperature 20°C (68°F) and then diluted with Sterile Water for Injection or 0.9% Sodium Chloride Injection to the following concentrations, the use periods indicated in Table 5 apply. Any unused portions of solution that remain after the indicated time periods should be discarded. Table 4 Diluent Maximum Concentration (mg/mL) Ampicillin and Sulbactam for Injection (Ampicillin/Sulbactam) Use Periods Sterile Water for Injection 45 (30/15) 8 hours at 21°C 45 (30/15) 48 hours at 4°C 30 (20/10) 72 hours at 4°C 0.9% Sodium Chloride Injection 45 (30/15) 8 hours at 21°C 45 (30/15) 48 hours at 4°C 30 (20/10) 72 hours at 4°C 5% Dextrose Injection 30 (20/10) 2 hours at 21°C 30 (20/10) 4 hours at 4°C 3 (2/1) 2 hours at 21°C Lactated Ringers Injection 45 (30/15) 8 hourss at 21°C 45 (30/15) 24 hours at 4°C M/6 Sodium Lactate Injection 45 (30/15) 8 hours at 21°C 45 (30/15) 12 hours at 4°C 5% Dextrose in 0.45% Saline 3 (2/1) 4 hours at 21°C 15 (10/5) 4 hours at 4°C 10% Invert Sugar 3 (2/1) 4 hours at 21°C 30 (20/10) 3 hours at 4°C Table 5 IV Solution Maximum Concentration (mg/mL) Ampicillin and Sulbactam for Injection (Ampicillin/Sulbactam) Use Periods Sterile Water for Injection, USP 45 (30/15) 4 hours at 21°C 45 (30/15) 24 hours at 4°C 0.9% Sodium Chloride Injection, USP 45 (30/15) 4 hours at 21°C 45 (30/15) 24 hourss at 4°C Animal Pharmacology: While reversible glycogenosis was observed in laboratory animals, this phenomenon was dose- and time-dependent and is not expected to develop at the therapeutic doses and corresponding plasma levels attained during the relatively short periods of combined ampicillin/sulbactam therapy in man.

The use of Ampicillin and Sulbactam for injection 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). Ampicillin and Sulbactam for injection is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Ampicillin and Sulbactam for injection.

Adult Patients: Ampicillin and Sulbactam for Injection 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 Ampicillin and Sulbactam for Injection demonstrate a similar adverse events profile to those observed in adult patients. Additionally, atypical lymphocytosis has been observed in one pediatric patient receiving Ampicillin and Sulbactam for Injection. 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 post-marketing use of ampicillin sodium and sulbactam sodium 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 ampicillin sodium and sulbactam sodium. Infections and Infestations: Clostridioides difficile- associated diarrhea (see WARNINGS section). 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 Ampicillin and Sulbactam for injection, as with other beta-lactam antibacterials. Gastrointestinal Disorders: Abdominal pain, cholestatic hepatitis, cholestasis, hyperbilirubinemia, jaundice, abnormal hepatic function, melena, gastritis, stomatitis, dyspepsia, and black “hairy” tongue (see CONTRAINDICATIONS and WARNINGS sections). General Disorders and Administration Site Conditions: Injection site reaction Immune System Disorders: Serious and fatal hypersensitivity (anaphylactic) reactions (See WARNINGS section), Acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction. Metabolism and Nutrition Disorders: Hypokalemia Nervous System Disorders: Convulsion and dizziness. Renal and Urinary Disorders: Tubulointerstitial nephritis. Musculoskeletal and Connective Tissue Disorders: Arthralgia Respiratory, Thoracic and Mediastinal Disorders: Dyspnea Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS),angioedema, Acute generalised exanthematous pustulosis (AGEP), erythema multiforme, exfoliative dermatitis, urticaria (see CONTRAINDICATIONS and WARNINGS sections), and linear IgA bullous dermatosis. To report SUSPECTED ADVERSE REACTIONS, contact Onesource (1-888-217-8103) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.