Vancomycin Hydrochloride

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) ].

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

11 DESCRIPTION Vancomycin Hydrochloride for Injection, USP, contains the hydrochloride salt of vancomycin, a tricyclic glycopeptide antibacterial derived from Amycolatopsis orientalis (formerly Nocardia orientalis ). The chemical name for vancomycin hydrochloride, USP 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-D-glucopyranosyl]oxy]-3-(carbamoylmethyl)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-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-dimetheno-1 H ,16 H -[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, USP has the following structural formula: Vancomycin Hydrochloride for Injection, USP is a sterile off-white to light tan colored lyophilized plug or powder for injection. Vancomycin Hydrochloride for Injection, USP is supplied in single-dose vials, containing 256 mg, 769 mg, 1.28 g, or 1.54 g of vancomycin hydrochloride, USP equivalent to 250 mg, 750 mg, 1.25 g, or 1.5 g of vancomycin base. The lyophilized powder is reconstituted with Sterile Water for Injection, USP which forms a clear, colorless or light to dark tan solution and subsequently diluted prior to intravenous administration [see Dosage and Administration (2.5) ]. Chemical structure

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 diluted. Reconstitution of the Lyophilized Powder and further dilution At the time of use, reconstitute the vials of Vancomycin Hydrochloride for Injection (lyophilized powder) with Sterile Water for Injection to a concentration of 50 mg of vancomycin/mL then further dilute with an infusion solution to a final concentration of 5 mg/mL (see Table 1 for the appropriate volumes). Discard any reconstituted solution remaining in the vial. Table 1 Volume of Sterile Water for Injection to be Added for Reconstitution and Volume of Infusion Solution to be Used for Further Dilution Vancomycin Strength per Vial Volume of Sterile Water for Injection for reconstitution a Volume of infusion solution b to further dilute to a final concentration of 5 mg/mL 250 mg 5 mL 50 mL 750 mg 15 mL 150 mL 1.25 g 25 mL 250 mL 1.5 g 30 mL 300 mL a After reconstitution, the vials may be stored in a refrigerator for 14 days without significant loss of potency. b Use an infusion solution from the list of the compatible infusion solutions below [see Dosage and Administration (2.6) ] . The desired dose diluted in this manner should be administered by intermittent IV infusion over a period of 60 minutes or greater. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard reconstituted and diluted solutions 14 days after initial reconstitution. 2.6 Compatibility with Intravenous Fluids The following diluents are physically and chemically compatible with 5 g/L vancomycin hydrochloride: 5% Dextrose Injection, USP 5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP Lactated Ringer’s and 5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP Storage of Diluted Solutions: Solutions that are diluted with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be stored in a refrigerator for 14 days without significant loss of potency. Solutions that are diluted with the following infusion fluids may be stored in a refrigerator for 96 hours: 5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP Lactated Ringer’s and 5% Dextrose Injection, USP 2.7 Incompatibilities for Intravenous Use Vancomycin 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.

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 the empiric selection of therapy.

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 .

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vancomycin is an antibacterial drug [see Microbiology (12.4) ] . 12.2 Pharmacodynamics The pharmacodynamics of vancomycin is unknown. 12.3 Pharmacokinetics In subjects with normal kidney function, multiple intravenous dosing of 1 g of vancomycin (15 mg/kg) infused over 60 minutes produces mean plasma concentrations of approximately 63 mcg/mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg/mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg/mL 11 hours after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mcg/mL at the completion of infusion, mean plasma concentrations of about 19 mcg/mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg/mL 6 hours after infusion. The plasma concentrations during multiple dosing are like those after a single dose. Distribution The volume of distribution ranges from 0.3 to 0.43 L/kg after intravenous administration. Vancomycin is approximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg/mL. After intravenous administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin does not readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid occurs. Elimination Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In anephric patients, the mean elimination half-life is 7.5 days. Total body and renal clearance of vancomycin may be reduced in the elderly. Metabolism There is no apparent metabolism of the vancomycin. Excretion In the first 24 hours after intravenous administration, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Renal impairment slows excretion of vancomycin. About 60% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of about 10 mcg/mL are achieved by intraperitoneal injection of 30 mg/kg of vancomycin. However, the safety and efficacy of the intraperitoneal use of vancomycin has not been established in adequate and well-controlled trials [see Warnings and Precautions (5.7) ] . 12.4 Microbiology Mechanism of Action The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. Resistance Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi. There is no cross-resistance between vancomycin and other antibacterials. Interaction With Other Antimicrobials The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many isolates of Staphylococcus aureus , Streptococcus gallolyticus ( previously known as Streptococcus bovis) , enterococcus spp, and the viridans group streptococci. Antimicrobial Activity Vancomycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ]. Aerobic Gram-Positive Bacteria Corynebacterium spp. Enterococcus spp. (including Enterococcus faecalis ) Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates) Coagulase negative staphylococci (including S. epidermidis and methicillin-resistant isolates) Streptococcus gallolyticus ( previously known as Streptococcus bovis) Viridans group streptococci The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for vancomycin against isolates of similar genus or organism group. However, the efficacy of vancomycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic Gram-Positive Bacteria Listeria monocytogenes Streptococcus pyogenes Streptococcus pneumoniae Streptococcus agalactiae Anaerobic Gram-Positive Bacteria Actinomyces species Lactobacillus species Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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

12.2 Pharmacodynamics The pharmacodynamics of vancomycin is unknown.

12.3 Pharmacokinetics In subjects with normal kidney function, multiple intravenous dosing of 1 g of vancomycin (15 mg/kg) infused over 60 minutes produces mean plasma concentrations of approximately 63 mcg/mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg/mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg/mL 11 hours after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mcg/mL at the completion of infusion, mean plasma concentrations of about 19 mcg/mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg/mL 6 hours after infusion. The plasma concentrations during multiple dosing are like those after a single dose. Distribution The volume of distribution ranges from 0.3 to 0.43 L/kg after intravenous administration. Vancomycin is approximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg/mL. After intravenous administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin does not readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid occurs. Elimination Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In anephric patients, the mean elimination half-life is 7.5 days. Total body and renal clearance of vancomycin may be reduced in the elderly. Metabolism There is no apparent metabolism of the vancomycin. Excretion In the first 24 hours after intravenous administration, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Renal impairment slows excretion of vancomycin. About 60% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of about 10 mcg/mL are achieved by intraperitoneal injection of 30 mg/kg of vancomycin. However, the safety and efficacy of the intraperitoneal use of vancomycin has not been established in adequate and well-controlled trials [see Warnings and Precautions (5.7) ] .

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3 DOSAGE FORMS AND STRENGTHS Vancomycin Hydrochloride for Injection, USP is a sterile lyophilized powder for injection supplied as an off-white to light tan colored plug or powder in single-dose vials containing vancomycin hydrochloride, USP equivalent to 250 mg, 750 mg, 1.25 g, or 1.5 g of vancomycin base. Vancomycin Hydrochloride for Injection is a sterile lyophilized powder for injection in single-dose vials containing vancomycin hydrochloride, USP equivalent to 250 mg, 750 mg, 1.25 g, or 1.5 g of vancomycin base ( 3 )

Vancomycin Hydrochloride Vancomycin Hydrochloride VANCOMYCIN HYDROCHLORIDE VANCOMYCIN Vancomycin Hydrochloride Vancomycin Hydrochloride VANCOMYCIN HYDROCHLORIDE VANCOMYCIN Vancomycin Hydrochloride Vancomycin Hydrochloride VANCOMYCIN HYDROCHLORIDE VANCOMYCIN Vancomycin Hydrochloride Vancomycin Hydrochloride VANCOMYCIN HYDROCHLORIDE VANCOMYCIN

13.2 Animal Toxicology and/or Pharmacology In animal studies, hypotension and bradycardia occurred in dogs receiving an intravenous infusion of vancomycin hydrochloride 25 mg/kg, at a concentration of 25 mg/mL and an infusion rate of 13.3 mL/min.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no mutagenic potential of Vancomycin Hydrochloride for Injection was found in standard laboratory tests. No definitive fertility studies have been performed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no mutagenic potential of Vancomycin Hydrochloride for Injection was found in standard laboratory tests. No definitive fertility studies have been performed. 13.2 Animal Toxicology and/or Pharmacology In animal studies, hypotension and bradycardia occurred in dogs receiving an intravenous infusion of vancomycin hydrochloride 25 mg/kg, at a concentration of 25 mg/mL and an infusion rate of 13.3 mL/min.

NDA209481

Vancomycin Hydrochloride

Vancomycin Hydrochloride

67457-824

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 67457-822-99 Vancomycin Hydrochloride for Injection, USP 250 mg*/vial For Intravenous Use AFTER RECONSTITUTION MUST BE FURTHER DILUTED. SEE PACKAGE INSERT. Sterile Powder Rx only Mylan 10 x 250 mg Single-Dose Vials Carton 250 mg

17 PATIENT COUNSELING INFORMATION Infusion Reactions During or After Intravenous Use Advise patients that generalized skin redness, skin rash, itching, flushing, muscle pain, chest pain, shortness of breath, wheezing, or dizziness may occur during intravenous infusion of Vancomycin Hydrochloride for Injection. These reactions can be lessened or prevented by infusing the drug over at least 60 minutes [see Warnings and Precautions (5.1) ] . Acute Kidney Injury Advise patients that Vancomycin Hydrochloride for Injection can result in kidney damage and that blood tests are required to monitor vancomycin blood levels and kidney function during therapy [see Warnings and Precautions (5.2) ] . Hearing Loss or Balance Problems Advise patients that Vancomycin Hydrochloride for Injection may result in decreased hearing and to report hearing loss or balance problems to their healthcare provider [see Warnings and Precautions (5.3) ] . Severe Dermatologic Reactions Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop Vancomycin Hydrochloride for Injection immediately and promptly seek medical attention at the first signs or symptoms of skin rash, mucosal lesions or blisters [see Warnings and Precautions (5.4) ] . Antibacterial Resistance Patients should be counseled that antibacterial drugs including Vancomycin Hydrochloride for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Vancomycin Hydrochloride for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Vancomycin Hydrochloride for Injection or other antibacterial drugs in the future. Diarrhea Diarrhea is a common problem caused by antibacterial drugs, including vancomycin, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.5) ] . The brands listed are trademarks of their respective owners. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited Bangalore, India

15 REFERENCES 1. Byrd RA., Gries CL, Buening M.: Developmental Toxicology Studies of Vancomycin Hydrochloride Administered Intravenously to Rats and Rabbits. Fundam Appl Toxicol 1994; 23: 590-597.

8.5 Geriatric Use Vancomycin Hydrochloride for Injection is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection [see Dosage and Administration (2.2) ] , and it may be useful to monitor renal function [see Warnings and Precautions (5.2) ] .

8.4 Pediatric Use Vancomycin Hydrochloride for Injection is indicated in pediatric patients (neonates and older). In pediatric patients, monitor vancomycin serum concentration and renal function when administering Vancomycin Hydrochloride for Injection [see Dosage and Administration (2.2 , 2.3) and Warnings and Precautions (5.2) ] . More severe infusion related reactions related to vancomycin administration may occur in pediatric patients. Concomitant administration of vancomycin and intravenous anesthetic agents has been associated with erythema and histamine-like flushing in all patients including pediatric patients [see Warnings and Precautions (5.1) ] .

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).

8 USE IN SPECIFIC POPULATIONS 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). 8.2 Lactation Risk Summary There are insufficient data to inform the levels of vancomycin in human milk. 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 Hydrochloride for Injection is indicated in pediatric patients (neonates and older). In pediatric patients, monitor vancomycin serum concentration and renal function when administering Vancomycin Hydrochloride for Injection [see Dosage and Administration (2.2 , 2.3) and Warnings and Precautions (5.2) ] . More severe infusion related reactions related to vancomycin administration may occur in pediatric patients. Concomitant administration of vancomycin and intravenous anesthetic agents has been associated with erythema and histamine-like flushing in all patients including pediatric patients [see Warnings and Precautions (5.1) ] . 8.5 Geriatric Use Vancomycin Hydrochloride for Injection is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection [see Dosage and Administration (2.2) ] , and it may be useful to monitor renal function [see Warnings and Precautions (5.2) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied: Vancomycin Hydrochloride for Injection, USP is a sterile lyophilized powder for injection supplied as an off-white to light tan colored powder or plug in single-dose flip top vials that contain vancomycin hydrochloride, USP equivalent to 250 mg, 750 mg, 1.25 g, or 1.5 g of vancomycin base. They are available as follows: NDC No. 67457-822-99: Vancomycin Hydrochloride for Injection, USP equivalent to 250 mg vancomycin in a 5 mL flip top vial with an ash gray seal, in packages of 10 vials. NDC No. 67457-705-75: Vancomycin Hydrochloride for Injection, USP equivalent to 750 mg vancomycin in a 20 mL flip top vial with an ash gray seal, in packages of 10 vials. NDC No. 67457-823-99: Vancomycin Hydrochloride for Injection, USP equivalent to 1.25 g vancomycin in a 30 mL flip top vial with an ash gray seal, in packages of 10 vials. NDC No. 67457-824-99: Vancomycin Hydrochloride for Injection, USP equivalent to 1.5 g vancomycin in a 30 mL flip top vial with a golden brown seal, in packages of 10 vials. Storage: Prior to reconstitution, store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]