Vancomycin Hydrochloride

DOSAGE AND ADMINISTRATION Infusion-related events are related to both the concentration and the rate of administration of vancomycin. Concentrations of no more than 5 mg/mL and rates of no more than 10 mg/min, are recommended in adults (see also age-specific recommendations). 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 events. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS ). Infusion-related events may occur, however, at any rate or concentration.

1 INDICATIONS AND USAGE These highlights do not include all the information needed to use VANCOMYCIN HYDROCHLORIDE FOR INJECTION safely and effectively. See full prescribing information for VANCOMYCIN HYDROCHLORIDE FOR INJECTION. VANCOMYCIN HYDROCHLORIDE for injection, for intravenous use Initial U.S. Approval: 1958 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 b …

DOSAGE AND ADMINISTRATION: Infusion-related events are related to both the concentration and the rate of administration of vancomycin. Concentrations of no more than 5 mg/mL and rates of no more than 10 mg/min are recommended in adults (see also age-specific recommendations). 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 events. Infusion-related events may occur, however, at any rate or concentration. Patients with Normal Renal Function Adults The usual daily dose is 2 g divided either as 500 mg every six hours or 1 g every 12 hours. Each dose should be administered at no more than 10 mg/min, or over a period of at least 60 minutes, whichever is longer. Other patients factors, such as age or obesity, may call for modification of the usual intravenous daily dose. Children 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. Infants and Neonates In neonates and young infants, the total daily IV dosage may be lower. In both neonates and infants, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the first week of life and every eight hours thereafter up to the age of one month. Each dose should be administered over 60 minutes. Close monitoring of serum concentrations of vancomycin may be warranted in these patients. Patients with Impaired Renal Function and Elderly Patients Dosage adjustment must be made in patients with impaired renal function. In premature infants and the elderly, greater dosage reductions than expected may be necessary because of decreased renal function. Measurement of vancomycin serum concentrations can be helpful in optimizing therapy, especially in seriously ill patients with changing renal function. Vancomycin serum concentrations can be determined by use of microbiologic assay, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay or high-pressure liquid chromatography. If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following table. The dosage of vancomycin per day in mg is about 15 times the glomerular filtration rate in mL/min (see following table). DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION (Adapted from Moellering et al. 3 ) Creatinine Clearance Vancomycin Dose _______mL/min mg/24 hr_____ 100 1,545 90 1,390 80 1,235 70 1,080 60 925 50 770 40 620 30 465 20 310 10 155 The initial dose should be no less than 15 mg/kg, even in patients with mild to moderate renal insufficiency. The table is not valid for functionally anephric patients. For such patients, an initial dose of 15 mg/kg of body weight should be given to achieve prompt therapeutic serum concentrations. The dose required to maintain stable concentrations is 1.9 mg/kg/24 hr. In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1,000 mg once every several days rather than administering the drug on a daily basis. In anuria, a dose of 1,000 mg every 7 to 10 days has been recommended. When only serum creatinine is known, the following formula (based on sex, weight and age of the patient) may be used to calculate creatinine clearance. Calculated creatinine clearances (mL/min) are only estimates. The creatinine clearance should be measured promptly. Men: Weight (kg) x (140 – age in years) 72 x serum creatinine concentration (mg/dL) Women: 0.85 x above value The serum creatinine must represent a steady state of renal function or the estimated value for creatinine clearance will not be valid. Such a calculated clearance is an overestimate of actual clearance in patients with conditions: (1) characterized by decreasing renal function, such as shock, severe heart failure or oliguria; (2) in …

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, 1.5 g, 1.75 g or 2 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, 1.5 g, 1.75 g or 2 g of vancomycin base ( 3 )

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

ADVERSE REACTIONS: Infusion-Related Events During or soon after rapid infusion of vancomycin, patients may develop anaphylactoid reactions, including hypotension (see ANIMAL PHARMACOLOGY ), wheezing, dyspnea, urticaria, or pruritus. Rapid infusion may also cause flushing of the upper body (“red neck”) or pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours. Such events are infrequent if vancomycin is given by a slow infusion over 60 minutes. In studies of normal volunteers, infusion-related events did not occur when vancomycin was administered at a rate of 10 mg/min or less. Nephrotoxicity Renal failure, principally manifested by increased serum creatinine or BUN concentrations, especially in patients administered large doses of vancomycin, has been reported rarely. Cases of interstitial nephritis have also been reported rarely. Most of these have occurred in patients who were given aminoglycosides concomitantly or who had pre-existing kidney dysfunction. When vancomycin was discontinued, azotemia resolved in most patients. Gastrointestinal Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS ). Ototoxicity A few dozen cases of hearing loss associated with vancomycin have been reported. Most of these patients had kidney dysfunction or a pre-existing hearing loss or were receiving concomitant treatment with an ototoxic drug. Vertigo, dizziness, and tinnitus have been reported rarely. Hematopoietic Reversible neutropenia, usually starting 1 week or more after onset of therapy with vancomycin or after a total dosage of more than 25 g, has been reported for several dozen patients. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has rarely been reported. Although a causal relationship has not been established, reversible agranulocytosis (granulocytes <500/mm 3 ) has been reported rarely. Phlebitis Inflammation at the injection site has been reported. Miscellaneous Infrequently, patients have been reported to have had anaphylaxis, drug fever, nausea, chills, eosinophilia, rashes including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and vasculitis in association with administration of vancomycin. Chemical peritonitis has been reported following intraperitoneal administration of vancomycin (see PRECAUTIONS ). Post Marketing Reports 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 Rash with Eosinophilia and Systemic Symptoms (DRESS)

Infusion-Related Events During or soon after rapid infusion of vancomycin, patients may develop anaphylactoid reactions, including hypotension (see ANIMAL PHARMACOLOGY ), wheezing, dyspnea, urticaria, or pruritus. Rapid infusion may also cause flushing of the upper body (“red neck”) or pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours. Such events are infrequent if vancomycin is given by a slow infusion over 60 minutes. In studies of normal volunteers, infusion-related events did not occur when vancomycin was administered at a rate of 10 mg/min or less.

Nephrotoxicity Renal failure, principally manifested by increased serum creatinine or BUN concentrations, especially in patients administered large doses of vancomycin, has been reported rarely. Cases of interstitial nephritis have also been reported rarely. Most of these have occurred in patients who were given aminoglycosides concomitantly or who had pre-existing kidney dysfunction. When vancomycin was discontinued, azotemia resolved in most patients.

Gastrointestinal Onset of pseudomembranous …

7 DRUG INTERACTIONS 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) ] . 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 ) See 17 for PATIENT COUNSELING INFORMATION. 7.1 Anesthetic Agents Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] . 7.2 Piperacillin-Tazobactam Studies have detected an increased incidence of acute kidney injury in patients administered concomitant piperacillin/tazobactam and vancomycin as compared to vancomycin alone. Monitor kidney function in patients receiving concomitant piperacillin/tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin. 7.3 Ototoxic and/or Nephrotoxic Drugs Concurrent and/or sequential systemic or topical use of other potentially, neurotoxic and/or nephrotoxic drugs requires more frequent monitoring of renal function.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on vancomycin hydrochloride use in pregnant women to inform a drug associated risk of major birth defects or miscarriage. Available published data on vancomycin hydrochloride use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes (see Data ) . Vancomycin hydrochloride 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 hydrochloride 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 hydrochloride at the time of delivery. Vancomycin hydrochloride 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 hydrochloride 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 intravenous to rats or 120 mg/kg/day intravenous 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 hydrochloride administration may occur in pediatric patients. Concomitant administration of vancomycin hydrochloride 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) ] …

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

DESCRIPTION Vancomycin Hydrochloride for Injection USP, Pharmacy Bulk Package bag SmartPak ® should not be used in patients who require less than a 500 mg dose of vancomycin. Vancomycin Hydrochloride for Injection, USP is a white to almost white to brownish lyophilized powder for preparing intravenous (I.V.) infusions, in bags containing the equivalent of 100 grams vancomycin base. 500 mg of the base are equivalent to 0.34 mmol. When reconstituted with Sterile Water for Injection to a concentration of 100 mg/mL, a clear, brownish-yellow solution is formed with the pH of the solution between 2.5 and 4.5. This product is oxygen sensitive. Vancomycin Hydrochloride for Injection, USP should be administered intravenously in diluted solution (see DOSAGE AND ADMINISTRATION ). AFTER RECONSTITUTION FURTHER DILUTION IS REQUIRED BEFORE USE. Each SmartPak ® Pharmacy Bulk Package contains Vancomycin Hydrochloride for Injection, USP equivalent to 100 grams of vancomycin activity and is intended for intravenous infusion only following further dilution. A Pharmacy Bulk Package is a sterile dosage form containing many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. VANCOMYCIN HYDROCHLORIDE FOR INJECTION PHARMACY BULK PACKAGE BAG SMARTPAK ® SHOULD NOT BE USED IN PATIENTS WHO REQUIRE LESS THAN A 500 MG DOSE OF VANCOMYCIN. BEFORE ADMINISTRATION, THIS PHARMACY BULK PACKAGE REQUIRES RECONSTITUTION USING STERILE WATER FOR INJECTION, USP TO A CONCENTRATION OF 100 MG PER ML AND FURTHER DILUTION IN 100 ML OF A COMPATIBLE SOLUTION AND INFUSED INTRAVENOUSLY. THIS PRODUCT IS NOT INTENDED TO BE USED IN PEDIATRIC AND RENALLY IMPAIRED PATIENTS WHO REQUIRE LESS THAN A 500 MG DOSE. Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopasis orientalis (formerly Nocardia orientalis ). The chemical name for vancomycin hydrochloride is [3S- [3 R *,6 S *( S *),7 S *,22 S *,23 R *,26 R *,36 S *,38a S *]]-3-(2-Amino-2-oxoethyl)-44-[[2-O-(3-amino- 2,3,6-trideoxy-3-C-methyl-α-L-lyxo-hexopyranosyl)-ß-D-glucopyranosyl]oxy]-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-[[4-methyl- 2-(methylamino)-1-oxopentyl]amino]-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 -[1,6,9]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 1,485.74. Vancomycin Hydrochloride has the following structural formula: image description

OVERDOSAGE The intent of the pharmacy bulk package for this product is for preparation of solutions for intravenous infusion only. 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. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice. To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

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, 1.5 g, 1.75 g or 2 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. NDC No. 72078-065-50: Vancomycin Hydrochloride for Injection, USP equivalent to 1.75 g vancomycin in a 50 mL flip top vial with a grey seal, in packages of 1 vial. NDC No. 72078-065-99: Vancomycin Hydrochloride for Injection, USP equivalent to 1.75 g vancomycin in a 50 mL flip top vial with a grey seal, in packages of 10 vials. NDC No. 72078-066-50: Vancomycin Hydrochloride for Injection, USP equivalent to 2 g vancomycin in a 50 mL flip top vial with a pink seal, in packages of 1 vial. NDC No. 72078-066-99: Vancomycin Hydrochloride for Injection, USP equivalent to 2 g vancomycin in a 50 mL flip top vial with a pink 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.]