Vancomycin Hydrochloride

Vancomycin hydrochloride for injection is a glycopeptide antibacterial indicated in adult and pediatric patients (neonates and older) for the treatment of:

• Septicemia (
  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.
  )
• Infective Endocarditis (
  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.
  )
• Skin and Skin Structure Infections (
  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.
  )
• Bone Infections (
  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.
  )
• Lower Respiratory Tract Infections (
  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.
  )

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. (

• 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 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)]

  .
  ,
  2.5 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

  aAfter reconstitution, the vials may be stored in a refrigerator for 14 days without significant loss of potency. bUse an infusion solution from the list of the compatible infusion solutions below [see Dosage and Administration (2.6)] .
  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
  1.25 g	25 mL	250 mL
  1.5 g	30 mL	300 mL

  The desired dose diluted in this manner should be administered by intermittent intravenous 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.
  )
• Adult Patients: 2 g divided either as 0.5 grams (g) every 6 hours or 1 g every 12 hours (
  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 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.
  )
• Pediatric Patients (1 month and older): 10 mg/kg per dose given every 6 hours (
  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^stweek 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.
  )
• Neonates: See full prescribing information for recommended doses in neonates (
  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^stweek 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.
  )
• Patients with renal impairment: See full prescribing information for recommended doses in patients with renal impairment (
  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.
  )

Vancomycin hydrochloride for injection, USP is a sterile lyophilized powder for injection supplied as an white or off-white to light tan colored cake or powder in single-dose vials containing vancomycin hydrochloride, USP equivalent to 1.25 g or 1.5 g of vancomycin base.

• 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 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)]

  .
  ,
  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.
  )
• 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 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 impairment in renal function or are concomitantly receiving other nephrotoxic drugs, in critically ill patients, in patients with changing renal function, and in patients requiring higher therapeutic vancomycin levels. If acute kidney injury occurs, discontinue vancomycin hydrochloride for injection or reduce the dose.
  )
• 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 Ototoxicity

  Ototoxicity has occurred in patients receiving vancomycin hydrochloride for injection. It may be transient or permanent. Ototoxicity manifests as tinnitus, hearing loss, dizziness or vertigo. The risk is higher in older patients, patients who are receiving higher doses, who have an underlying hearing loss, who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside or who have underlying renal impairment. Monitor for signs and symptoms of ototoxicity during therapy. Monitor serum vancomycin concentrations and renal function in all patients receiving parenteral vancomycin. Discontinue vancomycin hydrochloride for injection if ototoxicity occurs. Dosage of vancomycin hydrochloride for injection must be adjusted for patients with renal impairment

  [see Dosage and Administration (2.3)]

  . Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity.
  )
• Severe Dermatologic Reactions
  : Discontinue vancomycin hydrochloride for injection at the first appearance of skin rashes, mucosal lesions, or blisters (
  5.4 Severe Dermatologic Reactions

  Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD) have been reported in association with the use of vancomycin. Cutaneous signs or symptoms reported include skin rashes, mucosal lesions, and blisters.
  
  
  
  Discontinue vancomycin hydrochloride for injection at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD.
  ).
• Clostridioides difficile-

  Associated Diarrhea
  : Evaluate patients if diarrhea occurs. (
  5.5

  Clostridioides difficile-

  Associated Diarrhea

  Clostridioides difficile

  -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including vancomycin hydrochloride for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of

  C. difficile

  .
  
  
  
  

  C. difficile

  produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of

  C. difficile

  cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
  
  
  
  If CDAD is suspected or confirmed, ongoing antibacterial use not directed against

  C. difficile

  may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of

  C. difficile

  , and surgical evaluation should be instituted as clinically indicated.
  
  
  
  Clinically significant serum concentrations have been reported in some patients being treated for active

  C. difficile

  -induced pseudomembranous colitis after multiple oral doses of vancomycin.
  
  
  
  Prolonged use of vancomycin hydrochloride for injection may result in the overgrowth of nonsusceptible microorganisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. In rare instances, there have been reports of pseudomembranous colitis due to

  C. difficile

  developing in patients who received intravenous vancomycin hydrochloride for injection.
  )
• Neutropenia
  : Periodically monitor leukocyte count. (
  5.7 Neutropenia

  Reversible neutropenia has been reported in patients receiving vancomycin hydrochloride for injection

  [see Adverse Reactions (6.1)]

  . Patients who will undergo prolonged therapy with vancomycin hydrochloride for injection or those who are receiving concomitant drugs which may cause neutropenia should have periodic monitoring of the leukocyte count.
  )
• Phlebitis
  : To reduce the risk of local irritation and phlebitis administer vancomycin hydrochloride for injection by a secure intravenous route of administration. (
  5.8 Phlebitis and Other Administration Site Reactions

  Inflammation at the site of injection of vancomycin hydrochloride for injection has been reported. vancomycin hydrochloride for injection is irritating to tissue and must be given by a secure intravenous route of administration to reduce the risk of local irritation and phlebitis.
  
  
  
  Administration of vancomycin hydrochloride for injection by intramuscular (IM), intraperitoneal, intrathecal (intralumbar or intraventricular), or intravitreal routes has not been approved and is not recommended. The safety and efficacy of vancomycin administered by the intrathecal (intralumbar or intraventricular) route or by the intraperitoneal route have not been established by adequate and well controlled trials.
  
  
  
  Pain, tenderness, and necrosis occur with intramuscular injection of vancomycin hydrochloride for injection or with inadvertent extravasation. Thrombophlebitis may occur, the frequency and severity of which can be minimized by administering the drug slowly as a dilute solution (2.5 to 5 g/L) and by rotation of venous access sites.
  
  
  
  Intraperitoneal administration during continuous ambulatory peritoneal dialysis (CAPD) can result in chemical peritonitis. Manifestations range from cloudy dialysate alone to a cloudy dialysate accompanied by variable degrees of abdominal pain and fever. This syndrome appears to be resolve after discontinuation of intraperitoneal vancomycin.
  )
• 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 Development of Drug-Resistant Bacteria

  Prescribing vancomycin hydrochloride for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
  )