Vancomycin

Boxed Warning 10/2021 Warnings and Precautions, Severe Dermatologic Reactions ( 5.5 ) 5/2021 Warnings and Precautions, Potential Risk of Exposure to Excipients During the First or Second Trimester of Pregnancy ( 5.1 ) 10/2021

1 INDICATIONS AND USAGE Vancomycin Injection is a glycopeptide antibacterial indicated in adult and pediatric patients (1 month 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 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 susceptible bacteria. ( 1.6 ) 1.1 Septicemia Vancomycin Injection is indicated in adults and pediatric patients (1 month 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 Injection is indicated in adults and pediatric patients (1 month 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 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 (1 month 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 Injection is indicated in adults and pediatric patients (1 month 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 Injection is indicated in adults and pediatric patients (1 month 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 Injection is indicated in adults and pediatric patients (1 month 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 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 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.

2 DOSAGE AND ADMINISTRATION Use this formulation of Vancomycin Injection only in patients who require the entire (500 mg, 750 mg, 1 g, 1.25 g, 1.5 g, 1.75 g or 2 g) dose and not any fraction thereof. ( 2.1 ) For intravenous use only. Do Not administer orally. Administer Vancomycin Injection by intravenous infusion over 60 minutes or greater to reduce the risk of infusion reactions ( 2.1 ) 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 ) 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 administration and preparation instructions ( 2.1 , 2.5 ) 2.1 Important Administration Instructions Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with Vancomycin Injection [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ]. Use this formulation of Vancomycin Injection only in patients who require the entire (500 mg, 750 mg, 1 g, 1.25 g, 1.5 g, 1.75 g or 2 g) dose and not any fraction thereof. Vancomycin Injection in transparent single-dose flexible bags are intended for intravenous use only. Do NOT administer 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 (5.2) and Adverse Reactions (6.1) ] . An infusion rate of 10 mg/min or less is associated with fewer infusion-related events [see Warnings and Precautions (5.2) ] . Infusion related events 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 Injection prior to intravenous anesthetic agents to reduce the risk of infusion related adverse reactions [see Warnings and Precautions (5.2) ] . Administer Vancomycin Injection by a secure intravenous route of administration to avoid local irritation and phlebitis reactions [see Warnings and Precautions (5.9) ] . 2.2 Dosage in Adult Patients with Normal Renal Function The usual daily intravenous dose is 2 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 Dosage in Pediatric Patients (1 Month and Older) with Normal Renal Function Use this formulation of Vancomycin Injection only in pediatric patients (1 month and older) who require the entire dose (500 mg, 750 mg, 1 g, 1.25 g, 1.5 g, 1.75 g or 2 g) of this single-dose flexible bag and not any fraction of it [see Dosage Forms and Strengths (3) ]. 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. 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 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 h should …

3 DOSAGE FORMS AND STRENGTHS Vancomycin Injection, USP is a ready to use clear, colorless to light brown solution in single-dose flexible bags containing 500 mg vancomycin in 100 mL, 750 mg vancomycin in 150 mL, 1 g vancomycin in 200 mL, 1.25 g vancomycin in 250 mL, 1.5 g vancomycin in 300 mL, 1.75 g vancomycin in 350 mL and 2 g vancomycin in 400 mL of liquid [see Description (11) ] . The flexible bags are supplied in sealed aluminum overpouches. Vancomycin Injection, USP: Single-dose flexible bags containing 500 mg vancomycin in 100 mL, 750 mg vancomycin in 150 mL, 1 g vancomycin in 200 mL, 1.25 g vancomycin in 250 mL, 1.5 g vancomycin in 300 mL, 1.75 g vancomycin in 350 mL and 2 g vancomycin in 400 mL of liquid. ( 3 )

4 CONTRAINDICATIONS Vancomycin Injection is contraindicated in patients with known hypersensitivity to vancomycin. 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 (5.2) ] Nephrotoxicity [see Warnings and Precautions (5.3) ] Ototoxicity [see Warnings and Precautions (5.4) ] Severe Dermatologic Reactions [see Warnings and Precautions (5.5) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.6) ] Hemorrhagic Occlusive Retinal Vasculitis [see Warnings and Precautions (5.7) ] Neutropenia [see Warnings and Precautions (5.8) ] The common adverse reactions are anaphylaxis, "red man syndrome", acute kidney injury, hearing loss, neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xellia Pharmaceuticals USA, LLC at 1-833-295-6953 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: Hypersensitivity reactions including anaphylaxis and "red man syndrome" [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 (5.5) ] . 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 (5.6) ] 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 Injection is not approved for intramuscular and intraperitoneal administration) [see Warnings and Precautions (5.9) ] 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 Post Marketing 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. Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions (5.5) ] .

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 (5.2) 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary This formulation of Vancomycin Injection is not recommended for use during the first or second trimester of pregnancy because it contains the excipients, PEG 400 and NADA, which caused fetal malformations in animal reproduction studies (see Data ) . Advise pregnant women of the potential risk to the fetus. If therapy with Vancomycin Injection is needed during the first or second trimester of pregnancy, use other available formulations of vancomycin, free of PEG 400 and NADA. The available data on use of this formulation of Vancomycin Injection (with the excipients PEG 400 and NADA) in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available published data on vancomycin (without the excipients PEG 400 and NADA) use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes (see Data ) . There are no available data on first trimester use of vancomycin in pregnant women to assess the risk of major birth defects or miscarriage. Vancomycin alone 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 ) . Reproduction studies in rabbits with intravenous doses of PEG 400 at approximately 8 times the maximum daily human dose based on systemic exposures of PEG 400 during organogenesis resulted in fetal spinal malformations. Reproduction studies in rabbits and rats using intravenous doses of NADA at approximately 32 and 20 times the maximum daily human dose, respectively, based on systemic exposures of NADA resulted in maternal toxicity and fetal spinal and cardiovascular malformations in rabbits, and maternal toxicity with no adverse embryo-fetal effects in rats. Vancomycin alone 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 Available data from postmarketing cases on use of this formulation of vancomycin injection (with the excipients PEG 400 and NADA) in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or infant outcomes. There are no available data on first trimester use of vancomycin (without the excipients PEG 400 and NADA); however, available published data on use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes. A published study evaluated hearing loss and nephrotoxicity in infants of 10 pregnant intravenous drug users treated with vancomycin (formulation did not include the excipients PEG 400 and NADA) for suspected or documented methicillin-resistant Staphylococcus aureus in the second or third trimester. The comparison groups were 10 uninfected non-intravenous drug-dependent patients, and 10 uninfected 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 (formulation did not include the excipients PEG 400 and NADA) at the time of delivery. Vancomyc …

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

11 DESCRIPTION Vancomycin Injection, USP, in single-dose flexible bags contain vancomycin as vancomycin hydrochloride. It is a tricyclic glycopeptide antibacterial drug derived from Amycolatopsis orientalis (formerly Nocardia orientalis ). The molecular formula is C 66 H 75 Cl 2 N 9 O 24 ∙HCl and the molecular weight is 1,485.71. The chemical name is (Sa)-(3S,6R,7R,22R,23S,26S,36R,38aR)-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-[(2R)-4-methyl-2-(methylamino]valeramido]-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36(iminometha-no)-13,16:31,35-dimetheno-1H,16H-[1,6,9]-oxadiazacyclohexadecino-[4,5-m][10,2,16]-benzoxa-diazacyclotetracosine-26-carboxylic acid, monohydrochloride. Vancomycin hydrochloride has the following structural formula: Vancomycin Injection, USP, in single-dose flexible bags are sterile, nonpyrogenic premixed 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 350 mL or 400 mL solution containing 500 mg, 750 mg, 1 g, 1.25 g, 1.5 g, 1.75 g or 2 g vancomycin, respectively, as vancomycin hydrochloride. Each 100 mL of solution contains 1.8 mL polyethylene glycol 400, 1.36 g N-acetyl-D-alanine, 1.26 g L-lysine hydrochloride (monochloride) in water for injection. Hydrochloric acid and sodium hydroxide are used for pH adjustment. The pH is 4.5 to 5.5 and the osmolarity is 350 to 475 mOsmol/L. Chemical Structure

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 16.1 How Supplied Vancomycin Injection, USP is supplied as a ready to use clear, colorless to light brown solution in single-dose flexible bags containing 500 mg, 750 mg, 1 g, 1.25 g, 1.5 g, 1.75 g and 2 g vancomycin in 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 350 mL and 400 mL of liquid (consists of water and PEG together with the excipients NADA and lysine) [see Description (11) ] . The flexible bags are supplied in sealed aluminum overpouches. The bags are supplied in the following packages: 16.2 Storage NDC number Packaging configuration 70594-041-02 Carton of six 500 mg/100 mL bags 70594-041-03 Carton of twelve 500 mg/100 mL bags 70594-056-02 Carton of six 750 mg/150 mL bags 70594-056-03 Carton of twelve 750 mg/150 mL bags 70594-042-02 Carton of six 1 g/200 mL bags 70594-042-03 Carton of twelve 1 g/200 mL bags 70594-057-02 Carton of six 1.25 g/250 mL bags 70594-043-02 Carton of six 1.5 g/300 mL bags 70594-058-02 Carton of six 1.75 g/350 mL bags 70594-044-02 Carton of six 2 g/400 mL bags Store below 25°C (77oF), in original package. Product should be used within 28 days of removal from aluminum overpouch.