​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.

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.

Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity.

Reversible neutropenia has been reported in patients receiving vancomycin hydrochloride for injection (see ADVERSE REACTIONS). 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.

Vancomycin hydrochloride for injection is irritating to tissue and must be given by a secure IV route of administration. Pain, tenderness, and necrosis occur with intramuscular (IM) 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 grams/L) and by rotation of the venous access sites.

There have been reports that the frequency of infusion-related events (including hypotension, flushing, erythema, urticaria, and pruritus) increases with the concomitant administration of anesthetic agents. Infusion-related events may be minimized by the administration of vancomycin as a 60-minute infusion prior to anesthetic induction.  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.

Reports have revealed that administration of sterile vancomycin by the intraperitoneal route during continuous ambulatory peritoneal dialysis (CAPD) has resulted in a syndrome of chemical peritonitis.  To date, this syndrome has ranged from cloudy dialysate alone to a cloudy dialysate accompanied by variable degrees of abdominal pain and fever.  This syndrome appears to be short-lived after discontinuation of intraperitoneal vancomycin.

Prescribing vancomycin hydrochloride for injection, USP 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.

Drug Interactions

Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing (see PRECAUTIONS, Pediatric Use) and anaphylactoid reactions (see ADVERSE REACTIONS).

Monitor renal function in patients receiving vancomycin and concurrent and/or sequential systemic or topical use of other potentially, neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin, or cisplatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no mutagenic potential of vancomycin hydrochloride for injection was found in standard laboratory tests.  No definitive fertility studies have been performed.

Pregnancy

Teratogenic Effects

Animal reproduction studies have not been conducted with vancomycin.  It is not known whether vancomycin can affect reproduction capacity.  In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were evaluated when the drug was administered to pregnant women for serious staphylococcal infections complicating intravenous drug abuse.  Vancomycin was found in cord blood.  No sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted.  One infant whose mother received vancomycin in the third trimester experienced conductive hearing loss that was not attributed to the administration of vancomycin.  Because the number of patients treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not known whether vancomycin causes fetal harm.  Vancomycin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Vancomycin hydrochloride for injection is excreted in human milk. Caution should be exercised when vancomycin hydrochloride for injection is administered to a nursing woman. Because of the potential for adverse events, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Vancomycin Hydrochloride for Injection USP, Pharmacy Bulk Package bag SmartPak® should not be used in pediatric patients who require less than a 500 mg dose of vancomycin.  In pediatric patients, it may be appropriate to confirm desired vancomycin serum concentrations. Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing in pediatric patients (see PRECAUTIONS). 

Geriatric Use

The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage is not adjusted. Vancomycin dosage schedules should be adjusted in elderly patients (see DOSAGE AND ADMINISTRATION).

Information for Patients

Patients should be counseled that antibacterial drugs including vancomycin hydrochloride for injection, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When vancomycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by vancomycin hydrochloride for injection or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.  Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.  If this occurs, patients should contact their physician as soon as possible.

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/minute or less.

Nephrotoxicity

Systemic vancomycin exposure may result in acute kidney injury (AKI).  The risk of AKI increases as systemic exposure/serum levels increase.  Additional risk factors for AKI in patients receiving vancomycin include receipt of concomitant drugs known to be nephrotoxic, in patients with pre-existing renal impairment, or with co-morbidities that predispose to renal impairment.  Interstitial nephritis has also been reported in patients receiving vancomycin.

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 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)

To report SUSPECTED ADVERSE EVENTS, contact Samson Medical Technologies, L.L.C. at 1-877-418-3600 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

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/minute are recommended in adults (see also age-specific recommendations).  In selected patients in need of fluid restriction, a concentration of 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

Patients with Impaired Renal Function and Elderly Patients

Vancomycin Hydrochloride for Injection USP, Pharmacy Bulk Package SmartPak® should not be used in patients with renal impairment who require less than a 500 mg dose of vancomycin.

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/minute (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 concentration 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 Intravenous Fluids

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

         5% Dextrose Injection, USP

         0.9% Sodium Chloride Injection, USP

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.

Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible.  The likelihood of precipitation increases with higher concentrations of vancomycin.  It is recommended to adequately flush the intravenous lines between the administration of these antibiotics.  It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less.

Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles.  The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity.

Preparation of Solution

Vancomycin Hydrochloride for Injection USP, Pharmacy Bulk Package SmartPak® should not be used in patients who require less than a 500 mg dose of vancomycin.

Directions for Proper Use of a Pharmacy Bulk Package

Following is a table provided for convenience in reconstituting Vancomycin Hydrochloride for Injection SmartPak® Pharmacy Bulk Package for intravenous administration:

• NOT FOR DIRECT INFUSION.  The Pharmacy Bulk Package is for use in the hospital pharmacy admixture service only in a suitable work area, such as a laminar flow hood.  Using aseptic technique, the container closure may be penetrated only one time after reconstitution using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents.  Use of a syringe and needle is not recommended as it may cause leakage.  The withdrawal of container contents should be accomplished without delay.  However, should this not be possible, a maximum time of 4 HOURS from initial reconstitution port closure entry is permitted to complete fluid transfer operations.  This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package.  Discard any unused portion after 4 HOURS.  This pharmacy bulk package is not intended to be dispensed as a unit.

• PRIOR TO RECONSTITUTION: Visually examine outer (natural foil) bag for damage. IF THE SEAL IS BROKEN OR DAMAGE IS OBSERVED, DO NOT OPEN THE OUTER BAG. STERILITY OF THE INNER BAG SURFACE MAY BE COMPROMISED. DISCARD BOTH BAGS IMMEDIATELY. DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT, IF THE DRY POWDER IS BROWN, IF THE SEALS ARE NOT INTACT, OR IF THERE IS ANY OTHER DAMAGE TO THE BAG.  IN SUCH CASES, DISCARD THE BAG IMMEDIATELY.

• After initial reconstitution port entry, use entire contents of the Pharmacy Bulk Package promptly.  Any unused portion must be discarded after 4 HOURS.

• Gather the following items prior to the reconstitution of the product: Appropriate number of bags of Sterile Water for Injection and, depending upon the method of filling, appropriate sterile tubing and adapters.

INSTRUCTION FOR RECONSTITUTION OF THE PHARMACY BULK PACKAGE BAG SmartPak®

The entire contents of the bag and the preparation process (reconstitution and dilution) should be completed within 4 hours of initial entry.

• Document the date and time reconstitution starts in the designated place on the container label. The entire contents of the bag must be used within 4 hours from the time of initial entry.

• Remove the translucent unthreaded cap from the reconstitution (smaller) port and discard it.

• Reconstitute the powder through the reconstitution (smaller) port, using Sterile Water for Injection according to the table shown under Preparation of Solution.

• After reconstitution is complete, remove the transfer needle from the reconstitution port.

• Place the bag on a flat surface of a laminar flow hood and mix for at least 20 minutes by rocking gently from side to side. CAUTION: To avoid possible leakage caused by the heavy weight of the added water, do not shake vigorously or pull strongly on the bag.

• When foam dissipates, visually inspect the bag to verify the solution is clear, colorless to pale yellow and free of particulate matter. DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT.

• Unscrew the clear threaded cap from the transfer (larger) port and discard it. Attach sterile tubing and filling adapter unit to the transfer port.

• Reconstituted solution can now be transferred using the transfer port and the filling adapter.

It should be noted that the spike placed into the transfer port of the Pharmacy Bulk Package SmartPak® is NEVER removed during this procedure and that the reconstitution port is self-sealing.

Dilution

• Hang the bag from two eyelets.

• Following reconstitution, transfer 5 mL of the reconstituted solution into transfusion bags, each containing 100 mL, of one of the compatible solutions below.

         Compatible solutions for dilution are the following:

               0.9% Sodium Chloride Injection, USP

               5% Dextrose Injection, USP

• Dilution should be completed within the 4 hour preparation process.

• Reconstituted solutions containing 500 mg/5 mL (100 mg/mL) must be diluted in at least 100 mL of a suitable infusion solution. The desired dose, diluted in this manner, should be administered by intermittent IV infusion over a period of at least 60 minutes.
• Solutions that are diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection may be stored in a refrigerator for 14 days without significant loss of potency.

Administration

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.