Prescription Drug Information: Vancomycin Hydrochloride

VANCOMYCIN HYDROCHLORIDE- vancomycin hydrochloride injection, powder, lyophilized, for solution
Meitheal Pharmaceuticals Inc.

meitheal® Rx only

PHARMACY BULK PACKAGE — NOT FOR DIRECT INFUSION

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.

DESCRIPTION

Vancomycin Hydrochloride for Injection, USP, is a white or off-white to light tan-colored lyophilized powder or cake, for preparing intravenous (IV) infusions, in Pharmacy Bulk Package bottles containing the equivalent of 5 grams or 10 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 50 mg per mL for the 5 gram Pharmacy Bulk Package bottle and 100 mg per mL for the 10 gram Pharmacy Bulk Package bottle, the pH of the solution is 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 .

Vancomycin is a tricyclic glycopeptide antibiotic derived from Amycolatopasis orientalis (formerly Nocardia orientalis). 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)-β-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 C66 H7 5 Cl2 N9 O24 • HCl and the molecular weight is 1,485.71. Vancomycin hydrochloride has the following structural formula:

structure
(click image for full-size original)

A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses. The contents of this pharmacy bulk package are intended for use by a pharmacy admixture service for addition to suitable parenteral fluids in the preparation of admixtures for intravenous infusion (see DOSAGE AND ADMINISTRATION, Directions for Proper Use of Pharmacy Bulk Package ). FURTHER DILUTION IS REQUIRED. NOT FOR DIRECT INFUSION.

CLINICAL PHARMACOLOGY

Vancomycin hydrochloride is poorly absorbed after oral administration.


In subjects with normal kidney function, multiple intravenous dosing of 1 gram of vancomycin hydrochloride (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 hydrochloride 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 hydrochloride 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 hydrochloride. However, the safety and efficacy of the intraperitoneal use of vancomycin hydrochloride 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 intravenous administration of vancomycin hydrochloride, 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 hydrochloride results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin hydrochloride alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin hydrochloride and other antibiotics. Vancomycin hydrochloride is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.


Synergy

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

Vancomycin hydrochloride 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 hydrochloride 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 hydrochloride 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.

INDICATIONS AND USAGE

Vancomycin Hydrochloride for Injection 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 hydrochloride-susceptible organisms that are resistant to other antimicrobial drugs. Vancomycin Hydrochloride for Injection 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 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 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 Hydrochloride for Injection has been reported to be effective only in combination with an aminoglycoside.


Vancomycin Hydrochloride for Injection has been reported to be effective for the treatment of diphtheroid endocarditis. Vancomycin Hydrochloride for Injection 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 hydrochloride.


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.


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 hydrochloride is not effective by the oral route for other types of infections.

CONTRAINDICATIONS

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

WARNINGS

Infusion Reactions


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.


Nephrotoxicity


Systemic vancomycin exposure may result in acute kidney injury (AKI). The risk of AKI increases as systemic exposure/serum levels increase. Monitor renal function in all patients, especially patients with underlying renal impairment, patients with co-morbidities that predispose to renal impairment, and patients receiving concomitant therapy with a drug known to be nephrotoxic.


Ototoxicity


Ototoxicity has occurred in patients receiving vancomycin hydrochloride. 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 hydrochloride 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).

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 hydrochloride. 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.


Clostridium Difficile Associated Diarrhea (CDAD)


Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including vancomycin hydrochloride, 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.


Hemorrhagic Occlusive Retinal Vasculitis (HORV)


Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin hydrochloride during or after cataract surgery. The safety and efficacy of vancomycin hydrochloride administered by the intracameral or the intravitreal route have not been established by adequate and well-controlled trials. Vancomycin hydrochloride is not indicated for the prophylaxis of endophthalmitis.

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