Vancomycin Hydrochloride

1 INDICATIONS AND USAGE Vancomycin Hydrochloride for Injection is a glycopeptide antibacterial indicated in adult and pediatric patients (neonates and older) for the treatment of: • 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 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. ( 1.6 ) 1.1 Septicemia Vancomycin Hydrochloride for Injection is indicated in adults and pediatric patients (neonates and older) 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 is indicated in adults and pediatric patients (neonates and older) 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 is indicated in adults and pediatric patients (neonates and older) 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 is indicated in adults and pediatric patients (neonates and older) 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 is indicated in adults and pediatric patients (neonates and older) 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 is indicated in adults and pediatric patients (neonates and older) 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 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 …

2 DOSAGE AND ADMINISTRATION • Administer Vancomycin Hydrochloride for Injection in a diluted solution over 60 minutes or greater to reduce the risk of infusion reactions. • See full prescribing information for further important administration and preparation instructions ( 2.1 , 2.5 ) • Adult Patients: 2 g divided either as 0.5 grams (g) every 6 hours or 1 g every 12 hours ( 2.2 ) • Pediatric Patients (1 month and older): 10 mg/kg per dose given every 6 hours ( 2.3 ) • Neonates: See full prescribing information for recommended doses in neonates ( 2.3 ) • Patients with renal impairment: See full prescribing information for recommended doses in patients with renal impairment ( 2.4 ) 2.1 Important Administration Instructions To reduce the risk of infusion related adverse reactions, administer Vancomycin Hydrochloride for Injection in a diluted solution over 60 minutes or greater [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . 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 (2.3) ] . In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used [see Warnings and Precautions (5.1) ] . Administer Vancomycin Hydrochloride for Injection prior to intravenous anesthetic agents to reduce the risk of infusion related adverse reactions [see Warnings and Precautions (5.1) ]. Administer Vancomycin Hydrochloride by a secure intravenous route of administration to avoid local irritation and phlebitis reactions [ see Warnings and Precautions (5.8) ] . The supplied lyophilized powder must be reconstituted and subsequently diluted prior to intravenous use [see Dosage and Administration (2.5) ]. 2.2 Dosage in Adult Patients With Normal Renal Function The usual daily intravenous dose is 2 grams divided either as 500 mg every 6 hours or 1 g every 12 hours. Administer each dose 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. 2.3 Dosage in Pediatric Patients With Normal Renal Function 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. Neonates (Up to 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 necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients. 2.4 Dosage in Patients With Renal Impairment Dosage adjustment must be made in patients with renal impairment. The initial dose should be no less than 15 mg/kg, in 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 Preparation of Vancomycin Hydrochloride for Injection for Intravenous Administration and Storage Instructions Vancomycin Hydrochloride for Injection must be reconstituted and further …

5 WARNINGS AND PRECAUTIONS • Infusion Reactions : Hypotension, including shock and cardiac arrest, wheezing, dyspnea, urticaria, muscular, chest pain and “vancomycin infusion reaction” which manifests as pruritus and erythema that involves the face, neck and upper torso may occur with rapid intravenous administration. To reduce the risk of infusion reactions, administer Vancomycin Hydrochloride for Injection in a diluted solution over a period of 60 minutes or greater and also prior to intravenous anesthetic agents. ( 2.1 , 5.1 ) • Nephrotoxicity : Systemic vancomycin exposure may result in acute kidney injury (AKI) including acute renal failure, mainly due to interstitial nephritis or less commonly acute tubular necrosis. Monitor serum vancomycin concentrations and renal function. ( 5.2 ) • Ototoxicity : Ototoxicity has occurred in patients receiving vancomycin hydrochloride. Monitor for signs and symptoms of ototoxicity during therapy. Monitor serum vancomycin concentrations and renal function. Assessment of auditory function may be appropriate in some instances. ( 5.3 ) • Severe Dermatologic Reactions: Discontinue Vancomycin Hydrochloride for Injection at the first appearance of skin rashes, mucosal lesions, or blisters ( 5.4 ). • Clostridioides difficile -Associated Diarrhea : Evaluate patients if diarrhea occurs. ( 5.5 ) • Neutropenia : Periodically monitor leukocyte count. ( 5.7 ) • Phlebitis: To reduce the risk of local irritation and phlebitis administer Vancomycin Hydrochloride for Injection by a secure intravenous route of administration. ( 5.8 ) • Development of Drug-Resistant Bacteria: Prescribing Vancomycin Hydrochloride for Injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria. ( 5.9 ) 5.1 Infusion Reactions Hypotension, including shock and cardiac arrest, wheezing, dyspnea, urticaria, muscular and chest pain may occur with rapid Vancomycin Hydrochloride for Injection administration. The reactions may be more severe in younger patients, particularly children, and in patients receiving concomitant muscle relaxant anesthetics. Rapid intravenous administration of Vancomycin Hydrochloride for Injection may also be associated with “vancomycin infusion reaction”, which manifests as pruritus and erythema that involves the face, neck and upper torso. Infusion-related adverse reactions are related to both the concentration and the rate of administration of vancomycin. Infusion-related adverse reactions may occur, however, at any rate or concentration. Administer Vancomycin Hydrochloride for Injection in a diluted solution over a period of 60 minutes or greater to reduce the risk of infusion-related adverse reactions. In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used; use of such higher concentrations may increase the risk of infusion-related adverse reactions. Administer prior to intravenous anesthetic agents when feasible. Stop the infusion if a reaction occurs. 5.2 Nephrotoxicity Vancomycin Hydrochloride for Injection can result in acute kidney injury (AKI), including acute renal failure, mainly due to interstitial nephritis or less commonly acute tubular necrosis. AKI is manifested by increasing blood urea nitrogen (BUN) and serum creatinine (Cr). The risk of AKI increases with higher vancomycin serum levels, prolonged exposure, concomitant administration of other nephrotoxic drugs, concomitant administration of piperacillin-tazobactam [see Drug Interactions (7.2) ] , volume depletion, pre-existing renal impairment and in critically ill patients and patients with co-morbid conditions that predispose to renal impairment. Monitor serum vancomycin concentrations and renal function in all patients receiving Vancomycin Hydrochloride for Injection. More frequent monitoring is recommended in patients with comorbidities that predispose to impairm…

4 CONTRAINDICATIONS Vancomycin Hydrochloride for Injection is contraindicated in patients with known hypersensitivity to vancomycin. Hypersensitivity to vancomycin ( 4 )

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. 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.

8.1 Pregnancy Risk Summary There are no available data on vancomycin use in pregnant women to inform a drug associated risk of major birth defects or miscarriage. Available published data on vancomycin use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related 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 based on body surface area (see Data ) . 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 pregnant intravenous drug users treated with vancomycin for suspected or documented methicillin-resistant Staphylococcus-aureus 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).

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) ] • 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) ] The common adverse reactions are anaphylaxis, “vancomycin infusion reaction”, acute kidney Injury, hearing loss, neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 Hydrochloride for Injection were identified in clinical trials: Immune system disorders: Hypersensitivity reactions including anaphylaxis and “vancomycin infusion reaction” [see Warnings and Precautions (5.1) ] 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 (5.4) ]. Renal and urinary disorders: Acute kidney injury and interstitial nephritis Ear and Labyrinth Disorders: Tinnitus, hearing loss, vertigo Blood and Lymphatic System Disorders: Agranulocytosis, neutropenia, pancytopenia, leukopenia, thrombocytopenia, eosinophilia Gastrointestinal Disorders: Pseudomembranous colitis [see Warnings and Precautions (5.5) ] Cardiac Disorders: Cardiac arrest, chest pain 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 (5.7) ] 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 post approval 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. Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions (5.4) ].