VANCOMYCIN HYDROCHLORIDE

Vancomycin Hydrochloride for Injection contains the hydrochloride salt of vancomycin, a tricyclic glycopeptide antibacterial derived from Amycolatopsis orientalis (formerly Nocardia orientalis ). The chemical name for vancomycin hydrochloride is ( S a)-(3 S ,6 R ,7 R ,22 R ,23 S , 26 S ,36 R ,38a R )-44-[[2- O -(3-Amino-2,3,6-trideoxy-3- C -methyl-α-L-lyxo-hexopyranosyl)-β-Dglucopyranosyl]oxy]-3-(carbamoylmethyl)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38atetradecahydro-7,22,28,30,32-pentahydroxy-6-[(2 R )-4-methyl-2-(methylamino)valeramido]2,5,24,38,39-pentaoxo-22 H -8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno1 H ,16 H -[l,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]-benzoxadiazacyclotetracosine-26carboxylic 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 Hydrochloride for Injection, 5 g and 10 g, in Pharmacy Bulk Package, is a sterile, preservative-free, white, almost white to tan to brown, spray-dried powder, for preparing intravenous (IV) infusions, in vials. Each 5 g vial contains 5 g vancomycin (equivalent to 5.13 g vancomycin hydrochloride), 1.25 g trehalose, 0.5 mg polysorbate 80, and hydrochloric acid used to adjust the pH. Each 10 g vial contains 10 g vancomycin (equivalent to 10.25 g vancomycin hydrochloride), 2.5 g trehalose, 1 mg polysorbate 80, and hydrochloric acid used to adjust the pH. The spray-dried powder is reconstituted with Sterile Water for Injection which forms a clear solution and subsequently diluted prior to intravenous or oral administration [see Dosage and Administration ( 2.5 , 2.8 )] . A pharmacy bulk package is a sterile dosage form containing many single doses. The contents of this pharmacy bulk package are intended for use by a pharmacy admixture service for addition to suitable parenteral fluids in the preparation of admixtures for intravenous infusion. Vancomycin Hydrochloride for Injection is for intravenous or oral administration. Vancomycin Hydrochloride for Injection must be diluted with an appropriate diluent prior to intravenous administration [see Dosage and Administration ( 2.5 )] . Vancomycin Hydrochloride for Injection may also be diluted with a sweetening agent for oral administration [see Dosage and Administration ( 2.8 )] . structure

Vancomycin Hydrochloride for Injection is a glycopeptide antibacterial indicated in adult and pediatric patients less than 18 years of age as follows: Vancomycin Hydrochloride for Injection administered intravenously is indicated for the treatment of: o Septicemia ( 1.1 ) o Infective Endocarditis ( 1.2 ) o Skin and Skin Structure Infections ( 1.3 ) o Bone Infections ( 1.4 ) o Lower Respiratory Tract Infections ( 1.5 ) Vancomycin Hydrochloride for Injection administered orally is indicated for the treatment of: o Clostridioides difficile -associated diarrhea ( 1.6 ) o Enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) ( 1.7 ) Limitations of Use ( 1.8 ) Vancomycin Hydrochloride for Injection administered intravenously is not approved for the treatment of C. difficile -associated diarrhea and enterocolitis caused by susceptible isolates of Staphylococcus aureus because it is not effective. Vancomycin Hydrochloride for Injection administered orally is not approved for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections and lower respiratory tract infections because it is not effective. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin Hydrochloride for Injection and other antibacterial drugs, Vancomycin Hydrochloride for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.9 ) 1.1 Septicemia Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age 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 Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of infective endocarditis due to: Susceptible isolates of MRSA. Viridans group streptococci Streptococcus gallolyticus (previously known as Streptococcus bovis ), Enterococcus species and Corynebacterium species. For enterococcal endocarditis, use Vancomycin Hydrochloride for 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 Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age 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 Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age 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 Infections Vancomycin Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age 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 Hydrochloride for Injection administered intravenously is indicated in adults and pediatric patients less than 18 years of age for the treatment of lower respiratory tract infections due to: Susceptible isolates of MRSA 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 Clostridioides difficile -Associated Diarrhea Vancomycin Hydrochloride for Injection administered orally is indicated for the treatment of C. difficile -associated diarrhea (CDAD) in adult and pediatric patients less than 18 years of age. 1.7 Enterocolitis Caused by S. aureus (including methicillin-resistant strains) Vancomycin Hydrochloride for Injection administered orally is indicated for the treatment of enterocolitis caused by susceptible isolates of Staphylococcus aureus in adults and pediatric patients less than 18 years of age. 1.8 Limitations of Use Vancomycin Hydrochloride for Injection administered intravenously is not approved for the treatment of the following conditions because it is not effective: C. difficile -Associated Diarrhea Enterocolitis caused by susceptible isolates of Staphylococcus aureus Vancomycin Hydrochloride for Injection administered orally is not approved for the treatment of the following conditions because it is not effective: Septicemia due to susceptible isolates of MRSA or methicillin-susceptible staphylococci Infective endocarditis due to susceptible isolates of MRSA, methicillin susceptible staphylococci, Viridans group streptococci Streptococcus gallolyticus , Enterococcus species and Corynebacterium species, or for the treatment of early-onset prosthetic valve endocarditis caused by Staphylococcus epidermidis in combination with rifampin and an aminoglycoside Skin and skin structure infections due to susceptible isolates of MRSA and methicillin susceptible staphylococci Bone infections due to susceptible isolates of MRSA and lower respiratory tract infections due to susceptible isolates of MRSA and methicillin susceptible staphylococci 1.9 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin Hydrochloride for Injection and other antibacterial drugs, Vancomycin Hydrochloride for Injection 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.

Pharmacy Bulk Package. Not for direct intravenous infusion See full prescribing information for important information on intravenous and oral administration, preparation and storage instructions ( 2.1 , 2.5 , 2.8 ). Recommended Dosage and Administration Intravenous Use: o Administer Vancomycin Hydrochloride for Injection in a diluted solution by intravenous infusion over 60 minutes or greater to reduce the risk of infusion reactions. o Adult Patients: 2 grams (g) divided either as 0.5 g every 6 hours or 1 g every 12 hours ( 2.2 ) o Pediatric Patients (1 month and older): 10 mg/kg per dose given every 6 hours ( 2.2 ) o Pediatric Patients (younger than 1 month of age): See full prescribing information for recommended dosage ( 2.2 ) o Patients with Renal Impairment: See full prescribing information for recommended dosage in patients with renal impairment ( 2.4 ) Oral use: Adult Patients (18 years of age or greater): o C. difficile Associated Diarrhea: 125 mg administered orally 4 times daily for 10 days ( 2.3 ). o Staphylococcal enterocolitis: 500 mg to 2 grams administered orally in 3 or 4 divided doses for 7 to 10 days ( 2.3 ) Pediatric Patients (less than 18 years of age): o For both C. difficile -associated diarrhea and staphylococcal enterocolitis: 40 mg/kg in 3 or 4 divided doses for 7 days to 10 days. The total daily dosage should not exceed 2 g ( 2.3 ) 2.1 Important Administration Instructions for Intravenous Use Vancomycin Hydrochloride for Injection is supplied in pharmacy bulk packages. A pharmacy bulk package is a sterile dosage form containing many single doses. The contents of Vancomycin Hydrochloride for Injection pharmacy bulk package are intended for use by a pharmacy admixture service for addition to suitable parenteral fluids in the preparation of admixtures for intravenous infusion. The Pharmacy Bulk Package is NOT for direct infusion. Further dilution is required before use [see Dosage and Administration ( 2.4 )] . To reduce the risk of infusion related adverse reactions, administer diluted Vancomycin Hydrochloride for Injection by intravenous infusion over 60 minutes or greater [see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6.1 )] . Diluted Vancomycin Hydrochloride for 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 ( 2.2 , 2.3 )] . In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used. Infusion related events may occur, however, at any rate or concentration [see Warnings and Precautions ( 5.5 )] . Other drugs should not be added to the Vancomycin Hydrochloride for Injection Pharmacy Bulk Package or the diluted Vancomycin Hydrochloride for Injection [see Dosage and Administration ( 2.7 )] . Administer diluted Vancomycin Hydrochloride for Injection prior to intravenous anesthetic agents to reduce the risk of infusion related adverse reactions [see Warnings and Precautions ( 5.5 )] . Administer diluted Vancomycin Hydrochloride for Injection by a secure intravenous route of administration to avoid local irritation and phlebitis reactions [see Warnings and Precautions ( 5.6 )] . 2.2 Intravenous Dosage in Adult and Pediatric Patients with Normal Renal Function Dosage in Adult Patients The usual daily intravenous dose 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. Dosage in 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. Dosage in Pediatric Patients Younger than 1 Month of Age 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 pediatric patients in the 1st 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 necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients. 2.3 Orally Administered Dosage in Adult and Pediatric Patients Dosage in Adult Patients C. difficile -associated diarrhea: The recommended dose is 125 mg administered orally 4 times daily for 10 days. Staphylococcal enterocolitis: Total daily dosage is 500 mg to 2 g administered orally in 3 or 4 divided doses for 7 days to 10 days. Dosage in Pediatric Patients (Less than 18 years of age) For both C. difficile -associated diarrhea and staphylococcal enterocolitis, the usual daily dosage is 40 mg/kg in 3 or 4 divided doses for 7 days to 10 days. The total daily dosage should not exceed 2 g. 2.4 Intravenous Dosage in Patients with Renal Impairment Dosage adjustment must be made in adult and pediatric patients with renal impairment. The initial dose should be no less than 15 mg/kg, in adult patients with any degree of renal impairment. In premature infants and the elderly, greater dosage reductions than expected may be necessary because of decreased renal function. Measure trough vancomycin serum concentrations to guide therapy, especially in seriously ill patients with changing renal function. For functionally anephric patients, an initial dose of 15 mg/kg of body weight should be given to achieve prompt therapeutic serum concentration. A dose of 1.9 mg/kg/24 hr should be given after the initial dose of 15 mg/kg. 2.5 Directions for the Preparation, Dilution and Storage of the Pharmacy Bulk Package for Intravenous Use Preparation Vancomycin Hydrochloride for Injection pharmacy bulk package is not for direct intravenous infusion . Prior to intravenous administration, contents of the Vancomycin Hydrochloride for Injection pharmacy bulk package must be reconstituted and further diluted . No preservative is present in this product. Aseptic technique must be used in the preparation of final IV solution. Prepare Vancomycin Hydrochloride for Injection pharmacy bulk packages for use in a pharmacy admixture service only in a suitable work area, such as a laminar flow hood. They should be hung by the integral hanger provided and suspended as a unit in the laminar flow hood. Using aseptic technique, penetrate the container closure only one time utilizing a suitable sterile dispensing set or transfer device which allows measured distribution dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. Swab bottle stopper with an antiseptic solution prior to inserting the dispensing set into the bottle using aseptic technique. Once the sterile dispensing set has been inserted into the container, withdrawal of the contents from the Vancomycin Hydrochloride for Injection pharmacy bulk package should be accomplished without delay immediately. However, if this is not possible, a maximum time of 4 hours from the initial closure entry may be permitted to complete fluid transfer operations. Discard the container and any unused portion in the container no later than 4 hours after initial closure puncture the container closure has been penetrated. Reconstitution and Dilution 5 g Pharmacy Bulk Package Vial At the time of use, reconstitute by adding 47 mL of Sterile Water for Injection to the 5 g vial of dry, sterile vancomycin powder following the reconstitution steps below. The resultant solution will contain vancomycin equivalent to about 100 mg/mL. After reconstitution, further dilution is required using one of the compatible intravenous diluents listed below [see Dosage and Administration ( 2.6 )] , prior to intravenous administration. Reconstituted solutions of vancomycin (100 mg/mL) must be further diluted. A dose of 500 mg (5 mL) must be diluted with at least 100 mL of a suitable infusion. For doses of 1 gram (10 mL), at least 200 mL of solution must be used. The desired dose diluted in this manner should be administered by intermittent IV infusion over a period of at least 60 minutes. 10 g Pharmacy Bulk Package Vial At the time of use, reconstitute by adding 94 mL of Sterile Water for Injection to the 10 g vial of dry, sterile vancomycin powder following the reconstitution steps below. The resultant solution will contain vancomycin equivalent to about 100 mg/mL. After reconstitution, further dilution is required using one of the compatible intravenous diluents listed below [see Dosage and Administration ( 2.6 )] , prior to intravenous administration. Reconstituted solutions of vancomycin (100 mg/mL) must be further diluted. A dose of 500 mg (5 mL) must be diluted with at least 100 mL of a suitable infusion solution. For doses of 1 gram (10 mL), at least 200 mL of solution must be used. The desired dose diluted in this manner should be administered by intermittent IV infusion over a period of at least 60 minutes. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution steps: Shake the vial to loosen the powder. Remove the flip-off cap and transfer sterile water for injection into the vial using a syringe. When injecting the sterile water for injection into the vial, adjust the syringe needle angle pointing towards the vial wall, to disperse the powder and to prevent powder clump at the bottom. After the sterile water for injection transfer, within 1 minute begin to shake the vial vigorously, continuing for up to 3 minutes or until a uniform solution is obtained. 2.6 Compatibility with Intravenous Fluids for Intravenous Use The following diluents are physically and chemically compatible with approximately 4.5 mg/mL of vancomycin hydrochloride: 5% Dextrose Injection, USP 5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP 5% Dextrose and Lactated Ringer’s Injection, USP 0.9% Sodium Chloride Injection, USP 2.7 Incompatibilities for Intravenous Use Vancomycin Hydrochloride for Injection reconstituted solution has a low pH and may cause chemical or physical instability when it is mixed with other compounds. Mixtures of solutions of vancomycin and beta-lactam antibacterial drugs have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous lines between the administration of these antibacterial drugs. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less. 2.8 Preparation of Vancomycin Hydrochloride for Injection for Oral Administration Preparation of the Pharmacy Bulk Package for Oral Use Reconstitute Vancomycin Hydrochloride for Injection to 100 mg/mL by adding the appropriate amount of sterile water for injection: Table 1: Reconstitution-Volume of Sterile Water for Injection to be Added Vancomycin Hydrochloride for Injection Strength per Vial Volume of Sterile Water for Injection to be added to achieve 100 mg/mL Vancomycin Hydrochloride Solution 5 g 47 mL 10 g 94 mL Sweeteners may be added to this solution to improve the taste for oral administration following the steps outlined in Instructions for How to Prepare and Add Sweeteners below. Instructions for How to Prepare and Add Sweeteners 1. Prepare the sweetening agent separately from the reconstituted Vancomycin hydrochloride solution in a plastic-container following one of the preparation options below: Mix sucrose and sterile water for injection in a 1:2 ratio (e.g., 10 g sucrose and 20 mL sterile water for injection) OR Mix agave nectar with an equal volume of sterile water for injection 2. Mix the sweetening agent with the reconstituted Vancomycin hydrochloride solution in a 3:1 ratio (e.g., 30 mL sweetening agent with 10 mL vancomycin solution) to obtain a sweetened solution containing 25 mg/mL of vancomycin that is suitable for oral administration. The diluted solution may be administered orally or via a nasogastric tube [see Dosage and Administration ( 2.3 )] . 2.9 Storage of Reconstituted and Diluted Vancomycin Hydrochloride for Injection for Intravenous or Oral Administration Intravenous Administration: Administer the compounded mixtures within 4 hours after preparation when storing at room temperature and 6 days when stored refrigerated (14 days for solutions made with 0.9% sodium chloride and 5% dextrose). Oral Administration: Store the diluted solution for oral use in a plastic container refrigerated at 2 °C to 8 °C (36°F to 46°F) for up to 10 days.

Vancomycin Hydrochloride for Injection is contraindicated in patients with known hypersensitivity to vancomycin and polysorbate 80. Hypersensitivity to vancomycin, and polysorbate 80 ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Nephrotoxicity [see Warnings and Precautions ( 5.1 )] Ototoxicity [see Warnings and Precautions ( 5.2 )] Severe Dermatologic Reactions [see Warnings and Precautions ( 5.3 )] Neutropenia [see Warnings and Precautions ( 5.4 )] Infusion Reactions [see Warnings and Precautions ( 5.5 )] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.7 )] The common adverse reactions following i ntravenously, and orally administered vancomycin were acute kidney injury, hearing loss, neutropenia, anaphylaxis, vancomycin infusion reaction. ( 6.1 ) The most common adverse reaction of orally administered vancomycin (> 10%) were nausea, abdominal pain, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Injectables USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatc h . 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. Adverse Reactions in Patients Receiving Intravenously and Orally Administered Vancomycin The following adverse reactions associated with the use of intravenously and orally administered vancomycin were identified in clinical trials: Renal and urinary disorders: Acute kidney injury and interstitial nephritis [see Warnings and Precautions ( 5.1 )] Ear and labyrinth disorders: Tinnitus, hearing loss, vertigo [see Warnings and Precautions ( 5.2 )] Skin and subcutaneous tissue disorders: Erythema (especially of the face, neck and upper torso) and pruritus which are manifestations of rashes including exfoliative dermatitis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), Linear IgA bullous dermatosis (LABD) [see Warnings and Precautions ( 5.3 )] . Blood and lymphatic system disorders: Agranulocytosis, neutropenia, pancytopenia, leukopenia, thrombocytopenia, eosinophilia [see Warnings and Precautions ( 5.4 )] Immune system disorders: Hypersensitivity reactions including anaphylaxis and vancomycin infusion reaction [see Warnings and Precautions ( 5.5 )] General disorders and administration site conditions: General discomfort, fever, chills, phlebitis, injection site irritation, injection site pain and necrosis following intramuscular injection, chemical peritonitis following intraperitoneal administration. Vancomycin Hydrochloride for Injection is not approved for intramuscular and intraperitoneal administration [see Warnings and Precautions ( 5.6 )] Gastrointestinal disorders: Pseudomembranous colitis [see Warnings and Precautions ( 5.7 )] Cardiac disorders: Cardiac arrest, chest pain 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 Adverse Reactions in Patients Receiving Oral Administration of Vancomycin Hydrochloride Capsules The data described below reflect exposure to vancomycin hydrochloride capsules in 260 adult subjects in two Phase 3 clinical trials for the treatment of diarrhea associated with C. difficile . In both trials, subjects received vancomycin hydrochloride capsules 125 mg orally four times daily. The mean duration of treatment was 9.4 days. The median age of patients was 67, ranging between 19 and 96 years of age. Patients were predominantly Caucasian (93%) and 52% were male. Adverse reactions occurring in ≥5% of vancomycin hydrochloride capsules-treated subjects are shown in Table 2. The most common adverse reactions associated with vancomycin hydrochloride capsules (≥10%) were nausea, abdominal pain, and hypokalemia. Table 2: Common (≥5%) Adverse Reactions a for Vancomycin Hydrochloride Capsules Reported in Clinical Trials for Treatment of Diarrhea Associated with C. difficile System/Organ Class Adverse Reaction Vancomycin Hydrochloride Capsule % (N=260) Gastrointestinal disorders Nausea Abdominal pain Vomiting Diarrhea Flatulence 17 15 9 9 8 General disorders and administration site conditions Pyrexia Edema peripheral Fatigue 9 6 5 Infections and infestations Urinary tract infection 8 Metabolism and nutrition disorders Hypokalemia 13 Musculoskeletal and connective tissue disorders Back pain 6 Nervous system disorders Headache 7 a Adverse reaction rates were derived from the incidence of treatment-emergent adverse events. Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) occurred in 5% of subjects treated with vancomycin hydrochloride capsules. Nephrotoxicity following vancomycin hydrochloride capsules typically first occurred within one week after completion of treatment (median day of onset was Day 16). Nephrotoxicity following vancomycin hydrochloride capsules occurred in 6% of subjects >65 years of age and 3% of subjects ≤65 years of age. The incidences of hypokalemia, urinary tract infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension were higher among subjects >65 years of age than in subjects ≤65 years of age. Discontinuation of study drug due to adverse events occurred in 7% of subjects treated with vancomycin hydrochloride capsules. The most common adverse events leading to discontinuation of vancomycin hydrochloride capsules were C. difficile colitis (<1%), nausea (<1%), and vomiting (<1%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of vancomycin (administered orally and intravenously). 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. Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions ( 5.3 )] . Ototoxicity: Cases of hearing loss associated with intravenously administered vancomycin have been reported. Most of these patients had kidney dysfunction or a preexisting hearing loss or were receiving concomitant treatment with an ototoxic drug [see Warnings and Precautions ( 5.2 )] . Vertigo, dizziness, and tinnitus have been reported. Hematopoietic: Reversible neutropenia, usually starting 1 week or more after onset of intravenous therapy with vancomycin or after a total dose of more than 25 g, has been reported for several dozen patients. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has been reported. Miscellaneous: Patients have been reported to have had anaphylaxis, drug fever, chills, nausea, eosinophilia, and cases of vasculitis in association with the administration of vancomycin. A condition has been reported with oral vancomycin that is similar to the intravenous vancomycin-induced syndrome with symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (“vancomycin infusion reaction”), pain and muscle spasm of the chest and back [see Warnings and Precautions ( 5.5 )] . These reactions usually resolve within 20 minutes but may persist for several hours.

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 administered 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 ( 5.5 ) 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 Hydrochloride for 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 requires more frequent monitoring of renal function.