VANCOMYCIN HYDROCHLORIDE

1 INDICATIONS AND USAGE Vancomycin Injection is a glycopeptide antibacterial indicated for the treatment of the following infections in adult and pediatric patients for whom appropriate dosing with this formulation can be achieved: • Septicemia ( 1.1 ) • Infective Endocarditis ( 1.2 ) • Skin and Skin Structure Infections ( 1.3 ) • Bone Infections ( 1.4 ) • Lower Respiratory Tract Infections ( 1.5 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin Injection and other antibacterial drugs, Vancomycin Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.6 ) 1.1 Septicemia Vancomycin Injection is indicated in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2) and Use in Specific Populations (8.4) ] for the treatment of septicemia due to: • Susceptible isolates of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase negative staphylococci. • Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.2 Infective Endocarditis Vancomycin Injection is indicated in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2) and Use in Specific Populations (8.4) ] for the treatment of infective endocarditis due to: • Susceptible isolates of MRSA. • Viridans group streptococci or Streptococcus gallolyticus (previously known as Streptococcus bovis ) and Enterococcus species and Corynebacterium species. For enterococcal endocarditis ( e.g., E. faecalis ), use Vancomycin Injection in combination with an aminoglycoside. • Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. Vancomycin Injection is indicated in adults and pediatric patients for the treatment of early-onset prosthetic valve endocarditis caused by Staphylococcus epidermidis in combination with rifampin and an aminoglycoside. 1.3 Skin and Skin Structure Infections Vancomycin Injection is indicated in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2) and Use in Specific Populations (8.4) ] for the treatment of skin and skin structure infections due to: • Susceptible isolates of MRSA and coagulase negative staphylococci. • Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.4 Bone Infection Vancomycin Injection is indicated in adults and pediatric patients (and older) for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2) and Use in Specific Populations (8.4) ] for the treatment of bone infections due to: • Susceptible isolates of MRSA and coagulase negative staphylococci. • Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.5 Lower Respiratory Tract Infections Vancomycin Injection is indicated in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2) and Use in Specific Populations (8.4) ] for the treatment of lower respiratory tract infections due to: • Susceptible isolates of MSRA. • Methicillin-susceptible staphylococci in penicillin-allergic patients, or those patients who cannot receive or who have failed to respond to other drugs, including penicillins or cephalosporins. 1.6 Usage To reduce the development of drug-resistant bacteria a …

2 DOSAGE AND ADMINISTRATION • If a dose of Vancomycin Injection is required that does not equal 500 mg, 750 mg, 1 g, 1.25 g or 1.5 g, this product is not recommended for use and an alternative formulation of vancomycin should be considered. ( 2.1 ) • For Intravenous use only. Do not administer orally. ( 2.1 ). • Administer Vancomycin Injection by intravenous infusion over 60 minutes or greater to reduce the risk of infusion reactions. ( 2.1 ). • Recommended Dosage in Adult Patients with Normal Renal Function: 2 g divided either as 0.5 grams (g) every 6 hours or 1 g every 12 hours. ( 2.2 ) • Recommended Dosage in Pediatric Patients with Normal Renal Function: 10 mg/kg per dose given every 6 hours. ( 2.3 ) • Recommended Dosage in Patients with Renal Impairment: See full prescribing information for recommended doses in patients with renal impairment. ( 2.4 ) • See full prescribing information for further important preparation and administration instructions. ( 2.1 , 2.5 ) 2.1 Important Administration Instructions • If a dose of Vancomycin Injection is required that does not equal 500 mg, 750 mg, 1 g, 1.25 g or 1.5 g, this product is not recommended for use and an alternative formulation of vancomycin should be considered. • Vancomycin Injection is intended for intravenous use only. • Vancomycin Injection is not to be administered orally. • To reduce the risk of infusion related adverse reactions, administer Vancomycin Injection by intravenous infusion over 60 minutes or greater [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . An infusion rate of 10 mg/min or less is associated with fewer infusion-related adverse reactions [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Infusion related adverse reactions may occur, however, at any rate or concentration. • Drug additives should not be made to this solution. • Vancomycin Injection concentrations of no more than 5 mg/mL are recommended in adults [see Dosage and Administration (2.2) ] . See also age-specific recommendations [see Dosage and Administration (2.3) ]. • Administer Vancomycin by a secure intravenous route of administration to reduce the risk of local irritation and phlebitis reactions [see Warnings and Precautions (5.8) ]. • Administer Vancomycin Injection prior to intravenous anesthetic agents to reduce the risk of infusion related adverse reactions [see Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage in Adult Patients with Normal Renal Function The usual daily intravenous dosage of Vancomycin Injection is 2 grams (g) divided either as 500 mg every 6 hours or 1 g every 12 hours. Administer each dose by intravenous infusion over a period of 60 minutes or greater. Other patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose. The initial daily dose should be no less than 15 mg/kg. 2.3 Recommended Dosage in Pediatric Patients with Normal Renal Function If a dose of Vancomycin Injection is required that does not equal 500 mg, 750 mg, 1 g, 1.25 g or 1.5 g, this product is not recommended for use and an alternative formulation of vancomycin should be considered [see Use in Specific Populations (8.4) ]. Pediatric Patients (Aged 1 Month and Older) The usual intravenous dosage of vancomycin is 10 mg/kg per dose given every 6 hours. Each dose should be administered over a period of at least 60 minutes. Close monitoring of serum concentrations of vancomycin may be warranted in these patients. Pediatric Patients (Younger than 1 Month Old) In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1 st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be …

3 DOSAGE FORMS AND STRENGTHS Injection: Vancomycin Injection USP, is a frozen, iso-osmotic, sterile, nonpyrogenic premixed solution available in the following strengths: • 500 mg/100 mL (5 mg/mL); Each 100 mL single-dose GALAXY container contains 500 mg Vancomycin (as Vancomycin hydrochloride) in 5% Dextrose or 0.9% Sodium Chloride. • 750 mg/150 mL (5 mg/mL); Each 150 mL single-dose GALAXY container contains 750 mg Vancomycin (as Vancomycin hydrochloride) in 5% Dextrose or 0.9% Sodium Chloride. • 1 g/200 mL (5 mg/mL); Each 200 mL single-dose GALAXY container contains 1 g Vancomycin (as Vancomycin hydrochloride) in 5% Dextrose or 0.9% Sodium Chloride. • 1.25 g/250 mL (5 mg/mL): Each 250 mL single-dose GALAXY container contains 1.25 g of Vancomycin (as Vancomycin hydrochloride) in 5 % Dextrose. • 1.5 g/300 mL (5 mg/mL): Each 250 mL single-dose GALAXY container contains 1.5 g of Vancomycin (as Vancomycin hydrochloride) in 5 % Dextrose. • Injection: Vancomycin Injection (in 5% Dextrose) 500 mg/100 mL; 750 mg/150 mL; 1 g/200 mL; 1.25 g/250 mL; 1.5 g/300 mL (5 mg/mL) in single-dose GALAXY container. ( 3 ) • Injection: Vancomycin Injection (in 0.9% Sodium Chloride) 500 mg/100 mL; 750 mg/150 mL; 1 g/200 mL (5 mg/mL) in single dose GALAXY container. ( 3 )

4 CONTRAINDICATIONS • Vancomycin Injection is contraindicated in patients with known hypersensitivity to vancomycin. • Solutions containing dextrose including Vancomycin Injection, may be contraindicated in patients with a known allergy to corn or corn products. Hypersensitivity to vancomycin ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Infusion Reactions [see Warnings and Precautions (5.1) ] • Nephrotoxicity [see Warnings and Precautions (5.2) ] • Ototoxicity [see Warnings and Precautions (5.3) ] • Severe Dermatologic Reactions [see Warnings and Precautions (5.4) ] • Clostridioides Difficile -Associated Diarrhea [see Warnings and Precautions (5.5) ] • Hemorrhagic Occlusive Retinal Vasculitis [see Warnings and Precautions (5.6) ] • Neutropenia [see Warnings and Precautions (5.7) ] • Phlebitis and Other Administration Site Reactions [see Warnings and Precautions (5.8) ]. The most common adverse reactions are anaphylaxis, “vancomycin infusion reaction”, acute kidney injury, hearing loss, neutropenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions associated with the use of vancomycin were identified in clinical trials: Immune System Disorders: Anaphylaxis and “vancomycin infusion reaction” Renal and urinary Disorders: Acute kidney injury and interstitial nephritis Ear and Labyrinth Disorders: Hearing loss, vertigo, and tinnitus Skin and subcutaneous tissue disorders : Rashes including exfoliative dermatitis, and Stevens-Johnson syndrome (SJS) Gastrointestinal Disorders: Clostridioides difficile colitis, nausea Blood and Lymphatic System Disorders: Agranulocytosis, neutropenia, pancytopenia, leukopenia, thrombocytopenia, eosinophilia Cardiac Disorders: Cardiac arrest, chest pain General Disorders and Administration Site Conditions : General discomfort, drug fever, chills, phlebitis, injection site irritation, injection site pain and necrosis following intramuscular injection, chemical peritonitis following intraperitoneal administration (Vancomycin Injection is not approved for intramuscular and intraperitoneal administration) Laboratory Abnormalities: Elevated blood urea nitrogen, elevated serum creatinine Musculoskeletal and connective tissue disorders: Muscle pain Nervous system disorders: Dizziness Respiratory, thoracic and mediastinal disorders: Wheezing, dyspnea Vascular disorders: Hypotension, shock, vasculitis 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of vancomycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction. Skin and Subcutaneous Tissue Disorders: Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD). Blood and lymphatic system disorders : Hemolytic anemia

7 DRUG INTERACTIONS • Anesthetic Agents: Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing. ( 2.1 , 7.1 ) • Piperacillin/Tazobactam: Increased incidence of acute kidney injury in patients receiving concomitant piperacillin/tazobactam and vancomycin as compared to vancomycin alone. Monitor kidney function in patients. ( 7.2 ) 7.1 Anesthetic Agents Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ]. 7.2 Piperacillin-Tazobactam Studies have detected an increased incidence of acute kidney injury in patients administered concomitant piperacillin/tazobactam and vancomycin as compared to vancomycin alone. Monitor kidney function in patients receiving concomitant piperacillin/tazobactam and Vancomycin Injection. No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin. 7.3 Ototoxic and/or Nephrotoxic Drugs Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs with Vancomycin Injection requires more frequent monitoring of renal function.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data over several decades of vancomycin use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Vancomycin did not show adverse developmental effects when administered intravenously to pregnant rats and rabbits during organogenesis at doses less than or equal to the recommended maximum human dose (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data A published study evaluated hearing loss and nephrotoxicity in infants of 10 pregnant intravenous drug users treated with intravenously administered vancomycin for suspected or documented methicillin-resistant Staphylococcus-aureus (MRSA) in the second or third trimester. The comparison groups were 10 non-intravenous drug-dependent patients who received no treatment, and 10 untreated intravenous drug-dependent patients who served as substance abuse controls. No infant in the vancomycin exposed group had abnormal sensorineural hearing at 3 months of age or nephrotoxicity. A published prospective study assessed outcomes in 55 pregnant women with a positive Group B streptococcus (GBS) culture and a high-risk penicillin allergy with resistance to clindamycin or unknown sensitivity who were administered vancomycin at the time of delivery. Vancomycin dosing ranged from the standard 1 g intravenously every 12 hours to 20 mg/kg intravenous every 8 hours (maximum individual dose 2 g). No major adverse reactions were recorded either in the mothers or their newborns. None of the newborns had sensorineural hearing loss. Neonatal renal function was not examined, but all of the newborns were discharged in good condition. Animal Data Vancomycin did not cause fetal malformations when administered during organogenesis to pregnant rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18) at the equivalent recommended maximum human dose (based on body surface area comparisons) of 200 mg/kg/day IV to rats or 120 mg/kg/day IV to rabbits. No effects on fetal weight or development were seen in rats at the highest dose tested or in rabbits given 80 mg/kg/day (approximately 1 and 0.8 times the recommended maximum human dose based on body surface area, respectively). Maternal toxicity was observed in rats (at doses 120 mg/kg and above) and rabbits (at 80 mg/kg and above). 1 8.2 Lactation Risk Summary Vancomycin is present in human milk following intravenous administration, however, there are insufficient data to inform the levels. There are no data on the effects of vancomycin on the breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for vancomycin and any potential adverse effects on the breastfed infant from vancomycin or from the underlying maternal condition. 8.4 Pediatric Use Vancomycin Injection is indicated in pediatric patients for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections and lower respiratory tract infections for whom appropriate dosing with this formulation can be achieved [see Indications and Usage (1.1 to 1.5 ) and Dosage and Administration (2.1 , 2.3 )]. Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of Vancomycin Injection, and to avoid unintentional overdose, this product is not recommended for use if a dose of Vancomycin Injection that does not equal 500 mg, 750 mg, 1 g, 1.25 g or 1.5 g is required, and an alternative formula …

12.1 Mechanism of Action Vancomycin is an antibacterial drug [see Microbiology (12.4) ].

11 DESCRIPTION Vancomycin Injection USP, in the GALAXY plastic container contains vancomycin, added as Vancomycin Hydrochloride USP. It is a tricyclic glycopeptide antibacterial derived from Amycolatopsis orientalis (formerly Nocardia orientalis ). The chemical name of vancomycin hydrochloride is (Sa)-(3S, 6R, 7R, 22R, 23S, 26S, 36R, 38aR)-44-[[2-O-(3-Amino-2, 3, 6-trideoxy-3-Cmethyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyl]oxy]-3-(carbamoylmethyl)- 10,19dichloro 2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6[(2R)-4-methyl-2-(methylamino) valeramido]-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno23, 36-(iminomethano)-13, 16:31, 35-dimetheno-1H, 16H-[l, 6, 9] oxadiazacyclohexadecino [4, 5-m] [10, 2, 16]-benzoxadiazacyclotetracosine-26-carboxylic acid, monohydrochloride. The molecular formula is C 66 H 75 Cl 2 N 9 O 24 ·HCl and the molecular weight is 1,485.71. Vancomycin hydrochloride has the following structural formula: Vancomycin Injection, USP in the GALAXY container is a frozen, iso-osmotic, sterile, nonpyrogenic, premixed single-dose formulation. The composition of Vancomycin Injection, USP, available in the following strengths are: • 500 mg/100 mL (5 mg/mL): containing 500 mg of vancomycin (equivalent to 513 mg of vancomycin hydrochloride); approximately 5 g of dextrose hydrous or 0.9 g of sodium chloride (equivalent to 354 mg total sodium content) • 750 mg/150 mL (5 mg/mL): containing 750 mg of vancomycin (equivalent to 769 mg of vancomycin hydrochloride); approximately 7.5 g of dextrose hydrous or 1.35 g of sodium chloride (equivalent to 531 mg total sodium content) • 1 g/200 mL (5 mg/mL): containing 1 g of vancomycin (equivalent to 1.025 g of vancomycin hydrochloride); approximately 10 g of dextrose hydrous or 1.8 g of sodium chloride (equivalent to 708 mg total sodium content) • 1.25 g/250 mL (5 mg/mL): containing 1.25 g of vancomycin (equivalent to 1.281 g of vancomycin hydrochloride); approximately 12.5 g of dextrose hydrous. • 1.5 g/300 mL (5 mg/mL): containing 1.5 g of vancomycin (equivalent to 1.538 g of vancomycin hydrochloride); approximately 15 g of dextrose hydrous. The pH of the solution may have been adjusted with hydrochloric acid and/or sodium hydroxide. Thawed solutions have a pH in the range of 3.0 to 5.0. After thawing to room temperature, this solution is intended for intravenous use only. This GALAXY container is fabricated from a specially designed multilayer plastic. Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Vancomycin Structural Formula

10 OVERDOSAGE Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed by dialysis. Hemofiltration and hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance. For current information on the management of overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Vancomycin Injection, USP is supplied as a frozen, iso-osmotic, premixed solution packaged in a single-dose GALAXY plastic container and is available as follows: Supply Information for Vancomycin Injection, in 5% Dextrose Strength Number of Containers/ Carton NDC 500 mg of vancomycin / 100 mL (5 mg/mL) 12 count 0338-3551-48 750 mg of vancomycin / 150 mL (5 mg/mL) 6 count 0338-3580-48 1 g of vancomycin / 200 mL (5mg/mL) 6 count 0338-3552-48 1.25 g of vancomycin / 250 mL (5 mg/mL) 4 count 0338-0122-04 1.5 g of vancomycin / 300 mL (5 mg/mL) 4 count 0338-0124-04 Supply Information for Vancomycin Injection, in 0.9% Sodium Chloride Strength Number of Containers/ Carton NDC 500 mg of vancomycin / 100 mL (5 mg/mL) 12 count 0338-3581-01 750 mg vancomycin / 150 mL (5 mg/mL) 6 count 0338-3582-01 1 g of vancomycin / 200 mL (5mg/mL) 6 count 0338-3583-01 Storage Store Vancomycin Injection at or below -20°C (-4°F) or Store in a freezer capable of maintaining a temperature at or below -20°C (-4°F). Storage of the thawed solution is described elsewhere in the labeling [see Dosage and Administration (2.5) ] Handling Handle frozen product containers with care. Product containers may be fragile in the frozen state.