1 INDICATIONS AND USAGE 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.

6 ADVERSE REACTIONS 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.