Label: VANCOMYCIN HYDROCHLORIDE injection, powder, lyophilized, for solution

Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of vancomycin hydrochloride for injection, USP and other antibacterial drugs, vancomycin hydrochloride for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Vancomycin hydrochloride for injection, USP is a white or off-white to light tan sterile, lyophilized powder or cake, for preparing intravenous (IV) infusions, in Pharmacy Bulk Package bottles containing the equivalent of 5 g or 10 g vancomycin base. 500 mg of the base are equivalent to 0.34 mmol. When reconstituted with Sterile Water for Injection to a concentration of 50 mg/mL for the 5 g Pharmacy Bulk Package bottle and 100 mg/mL for the 10 g Pharmacy Bulk Package bottle, the pH of the solution is between 2.5 and 4.5. Vancomycin hydrochloride for injection, USP should be administered intravenously in diluted solution (see DOSAGE AND ADMINISTRATION).

Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis (formerly Nocardia orientalis). Vancomycin hydrochloride USP is a white or almost white, hygroscopic powder. The chemical name for vancomycin hydrochloride is 3S-[3R*,6S*(S*),7S*,22S*,23R*,26R*,36S*,38aS*]]-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-22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-1H,16H-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]-benzoxadiazacyclotetracosine-26-carboxylic acid, monohydrochloride. The molecular formula is C66H75Cl2N9O24 • HCl and the molecular weight is 1,485.74. Vancomycin hydrochloride has the following structural formula:

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 IV infusion. AFTER RECONSTITUTION FURTHER DILUTION IS REQUIRED BEFORE USE.

Vancomycin is poorly absorbed after oral administration.

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 similar to those after a single dose.

The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In the first 24 hours, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. Renal dysfunction slows excretion of vancomycin. In anephric patients, the average half-life of elimination is 7.5 days. The distribution coefficient is from 0.3 to 0.43 L/kg. There is no apparent metabolism of the drug. 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 PRECAUTIONS).

Total systemic and renal clearance of vancomycin may be reduced in the elderly. Vancomycin is approximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg/mL. After IV 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.

MICROBIOLOGY

The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

Synergy

The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many strains of Staphylococcus aureus, Streptococcus bovis, enterococci, and the viridans group streptococci.

Vancomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive microorganisms

Diphtheroids

Enterococci (e.g., Enterococcus faecalis)

Staphylococci, including Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains)

Streptococcus bovis

Viridans group streptococci

The following in vitro data are available, but their clinical significance is unknown.

Vancomycin exhibits in vitro MIC's of 1 mcg/mL or less against most (≥90%) strains of streptococci listed below and MIC's of 4 mcg/mL or less against most (≥90%) strains of other listed microorganisms; however, the safety and effectiveness of vancomycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Listeria monocytogenes

Streptococcus pyogenes

Streptococcus pneumoniae (including penicillin-resistant strains)

Streptococcus agalactiae

Anaerobic gram-positive microorganisms

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.

Vancomycin hydrochloride for injection, USP is indicated for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (β-lactam-resistant) staphylococci. It is indicated for penicillin-allergic patients, for patients who cannot receive or who have failed to respond to other drugs, including the penicillins or cephalosporins, and for infections caused by vancomycin-susceptible organisms that are resistant to other antimicrobial drugs. Vancomycin hydrochloride for injection, USP is indicated for initial therapy when methicillin-resistant staphylococci are suspected, but after susceptibility data are available, therapy should be adjusted accordingly.

Vancomycin hydrochloride for injection, USP is effective in the treatment of staphylococcal endocarditis. Its effectiveness has been documented in other infections due to staphylococci, including septicemia, bone infections, lower respiratory tract infections, skin and skin structure infections. When staphylococcal infections are localized and purulent, antibiotics are used as adjuncts to appropriate surgical measures.

Vancomycin hydrochloride for injection, USP has been reported to be effective alone or in combination with an aminoglycoside for endocarditis caused by S. viridans or S. bovis. For endocarditis caused by enterococci (e.g., E. faecalis), vancomycin has been reported to be effective only in combination with an aminoglycoside.

Vancomycin hydrochloride for injection, USP has been reported to be effective for the treatment of diphtheroid endocarditis. Vancomycin hydrochloride for injection, USP has been used successfully in combination with either rifampin, an aminoglycoside, or both in early-onset prosthetic valve endocarditis caused by S. epidermidis or diphtheroids.

Specimens for bacteriologic cultures should be obtained in order to isolate and identify causative organisms and to determine their susceptibilities to vancomycin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of vancomycin hydrochloride for injection, USP and other antibacterial drugs, vancomycin hydrochloride for injection, USP 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.

The parenteral form of vancomycin hydrochloride may be administered orally for treatment of antibiotic-associated pseudomembranous colitis produced by C. difficile and for staphylococcal enterocolitis. Parenteral administration of vancomycin hydrochloride alone is of unproven benefit for these indications. Vancomycin is not effective by the oral route for other types of Infection.

Vancomycin hydrochloride for injection is contraindicated in patients with known hypersensitivity to this antibiotic.

Rapid bolus administration (e.g., over several minutes) may be associated with exaggerated hypotension, including shock and rarely cardiac arrest.

Vancomycin hydrochloride for injection should be administered in a diluted solution over a period of not less than 60 minutes to avoid rapid-infusion-related reactions. Stopping the infusion usually results in prompt cessation of these reactions.

Ototoxicity has occurred in patients receiving vancomycin hydrochloride for injection. It may be transient or permanent. It has been reported mostly in patients who have been given excessive doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside. Vancomycin should be used with caution in patients with renal insufficiency because the risk of toxicity is appreciably increased by high, prolonged blood concentrations.

Dosage of vancomycin hydrochloride for injection must be adjusted for patients with renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Clostridium 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Infusion-Related Events

During or soon after rapid infusion of vancomycin hydrochloride for injection, 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 hydrochloride for injection is given by a slow infusion over 60 minutes. In studies of normal volunteers, infusion-related events did not occur when vancomycin hydrochloride for injection 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 preexisting 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 preexisting 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/mm3) 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, linear IgA bullous dermatosis, Stevens-Johnson syndrome, toxic epidermal necrolysis and vasculitis in association with the administration of vancomycin.

Chemical peritonitis has been reported following intraperitoneal administration (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)

To report SUSPECTED ADVERSE EVENTS, contact Northstar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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.

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.

Patients With Normal Renal Function

Adults

The usual daily intravenous dose is 2 g divided either as 500 mg every 6 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 patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric patients

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

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 1st 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.

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 hydrochloride for injection per day in mg is about 15 times the glomerular filtration rate in mL/min (see following table).

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.

The serum creatinine must represent a steady state of renal function. Otherwise, the estimated value for creatinine clearance is not 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 which a normal relationship between muscle mass and total body weight is not present, such as in obese patients or those with liver disease, edema, or ascites; and (3) accompanied by debilitation, malnutrition, or inactivity. The safety and efficacy of vancomycin administration by the intrathecal (intralumbar or intraventricular) routes have not been established. Intermittent infusion is the recommended method of administration.

Compatibility with Other Drugs and IV Fluids

The following diluents are physically and chemically compatible (with 4 g/L vancomycin hydrochloride):

5% Dextrose Injection, USP
5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP
Lactated Ringer’s Injection, USP
5% Dextrose and Lactated Ringer’s Injection
Normosol®-M and 5% Dextrose
0.9% Sodium Chloride Injection, USP
Isolyte® E

Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

Vancomycin solution has a low pH and may cause physical instability of other compounds.

PREPARATION AND STABILITY

Directions for Proper Use of a Pharmacy Bulk Package

Not for direct infusion. The pharmacy bulk package is for use in the Pharmacy Admixture Service only in a suitable work area such as a laminar flow hood. Using aseptic technique, the closure may be penetrated only one time after reconstitution using a suitable sterile transfer device or dispensing set, which allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. After entry use entire contents of the Pharmacy Bulk Package bottle promptly. The entire contents of the Pharmacy Bulk Package bottle should be dispensed within 4 hours after initial entry. A maximum time of 4 hours from the initial entry may be allowed to complete fluid aliquoting/transferring operations. Discard the container no later than 4 hours after initial closure puncture. This time limit should begin with the introduction of solvent or diluent into the Pharmacy Bulk Package bottle.

Preparation and Stability

5 g Pharmacy Bulk Package bottle

At the time of use, reconstitute by adding 100 mL of Sterile Water for Injection to the 5 g Pharmacy Bulk Package bottle of dry, sterile vancomycin powder. The resultant solution will contain vancomycin equivalent to 500 mg/10 mL. FURTHER DILUTION IS REQUIRED. Reconstituted solutions of vancomycin (500 mg/10 mL) must be further diluted in at least 100 mL of a suitable infusion solution. Doses of 1 gram/20 mL must be further diluted in at least 200 mL of a suitable infusion solution. The desired dose diluted in this manner should be administered by intermittent intravenous infusion over a period of at least 60 minutes.

10 g Pharmacy Bulk Package bottle

At the time of use, reconstitute by adding 95 mL of Sterile Water for Injection, USP to the 10 g bottle of dry, sterile vancomycin powder. The resultant solution will contain vancomycin equivalent to 500 mg/5 mL (1 g/10 mL). AFTER RECONSTITUTION, FURTHER DILUTION IS REQUIRED.

Reconstituted solutions of vancomycin (500 mg/5 mL) must be further diluted in at least 100 mL of a suitable infusion solution. For doses of 1 gram (10 mL), at least 200 mL of solution must be used. The desired dose diluted in this manner should be administered by intermittent IV infusion over a period of at least 60 minutes.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

For Oral Administration

Oral vancomycin is used in treating antibiotic-associated pseudomembranous colitis caused by C. difficile and for staphylococcal enterocolitis. Vancomycin is not effective by the oral route for other types of infections. The usual adult total daily dosage is 500 mg to 2 g given in 3 or 4 divided doses for 7 to 10 days. The total daily dose in children is 40 mg/kg of body weight in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g. The appropriate dose may be diluted in 1 oz of water and given to the patients to drink. Common flavoring syrups may be added to the solution to improve the taste for oral administration. The diluted solution may be administered via a nasogastric tube.

Vancomycin hydrochloride for injection, USP is a white or off-white to light tan lyophilized powder or cake and is supplied as follows:

5 grams

Pharmacy Bulk Package Bottles,
packaged individually                                                          NDC 16714-517-01

10 grams

Pharmacy Bulk Package Bottles,
packaged individually                                                           NDC 16714-699-01

Store dry powder at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Sterile, Nonpyrogenic, Preservative free

This container closure is not made with natural rubber latex.

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.

1.  Moellering RC, Krogstad DJ, Greenblatt DJ: Vancomycin therapy in patients with impaired renal function: A nomogram for dosage. Ann Inter Med 1981;94:343.

All brands listed are the trademarks of their respective owners and are not trademarks of Eugia Pharma Specialities Limited.

Manufactured for:
Northstar Rx LLC
Memphis, TN 38141.

Manufactured by:
Eugia Pharma Specialities Limited
IDA, Pashamylaram - 502307
TS., India.

Issued December 2021

                              Rx Only
NDC 16714-517-01
 Vancomycin
Hydrochloride for Injection, USP
5 grams*
per Pharmacy Bulk Package
PHARMACY BULK PACKAGE -
NOT FOR DIRECT INFUSION
For Intravenous Infusion After Dilution.
AFTER RECONSTITUTION MUST BE FURTHER DILUTED.
NOT TO BE DISPENSED AS A UNIT.
Lyophilized

NORTHSTARX®

                        Rx only

NDC 16714-517-01

Vancomycin
Hydrochloride for Injection, USP
5 grams*
per Pharmacy Bulk Package

PHARMACY BULK PACKAGE -
NOT FOR DIRECT INFUSION

For Intravenous Infusion
After Dilution.

AFTER RECONSTITUTION
MUST BE FURTHER DILUTED.
NOT TO BE DISPENSED AS A UNIT.

One Pharmacy Bulk Package Bottle

Lyophilized

NORTHSTARX®

                                                Rx only
NDC 16714-699-01
Vancomycin
Hydrochloride for Injection, USP
10 grams*
per Pharmacy Bulk Package
PHARMACY BULK PACKAGE -
NOT FOR DIRECT INFUSION
For Intravenous Infusion After Dilution.
AFTER RECONSTITUTION MUST BE FURTHER DILUTED.
NOT TO BE DISPENSED AS A UNIT.
Lyophilized
NORTHSTARX®

                        Rx only

NDC 16714-699-01

Vancomycin
Hydrochloride for Injection, USP
10 grams*
per Pharmacy Bulk Package

PHARMACY BULK PACKAGE -
NOT FOR DIRECT INFUSION

For Intravenous Infusion
After Dilution.

AFTER RECONSTITUTION
MUST BE FURTHER DILUTED.
NOT TO BE DISPENSED AS A UNIT.

One Pharmacy Bulk Package Bottle

Lyophilized

NORTHSTARX®