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Document Name: QEN-2888v3.qxp EN-2888

EN-2888 Vancomycin Hydrochloride for Injection, USP Hydrochloride for Injection, USP ADD-Vantage™ Vials Rx only ADD-Vantage™ Vials Rx only

Hospira, Inc., Lake Forest, IL 60045 USA 60045 IL Forest, Lake Inc., , To reduce the development of drug-resistant and maintain the effectiveness of vancomycin and other antibacterial drugs,

Printed in USA in Printed vancomycin should be used only to treat or prevent that are proven or strongly suspected to be caused by bacteria. DESCRIPTION Vancomycin Hydrochloride for Injection, USP, intravenous, is a chromatographically purified tricyclic glycopeptide derived from Amycolatopsis orientalis (formerly Nocardia orientalis) and has the molecular formula C66H75Cl2N9O24 • HCl. The molecular weight is 1485.74; 500 mg of the base is equivalent to 0.34 mmol, 750 mg of the base is equivalent to 0.51 mmol, and 1 g of the base is equivalent to 0.67 mmol. Vancomycin Hydrochloride has the following structural formula:

OH HO

O H2N O OH CH2OH H C O 3 O CH3 CI O O HO CI H C H H H O C H C O H OH • HCI N C O C C H C N C N CH3 O C H C N C O HN H H C NH NH C H CH2 H C H HO C C O C CH2 OH H2N O O HC CH3 OH OH CH3 The ADD-Vantage™ vials contain sterile vancomycin hydrochloride equivalent to either 500 mg, 750 mg, or 1 g vancomycin activity for reconstitution in the ADD-Vantage flexible diluent container containing 5% dextrose injection or 0.9% sodium chloride injection. Vancomycin Hydrochloride is a white to tan lyophilized powder. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. When reconstituted in water, it forms a clear, light to dark tan solution with a pH of 4.0 (2.5 to 4.5). This product is oxygen sensitive. The solutions contain no bacteriostat, antimicrobial agent (except vancomycin) or buffer and are intended for use only as a single- dose injection only with the ADD-Vantage Flexible Diluent Container. FURTHER DILUTION IS REQUIRED BEFORE USE (see DOSAGE AND ADMINISTRATION). CLINICAL PHARMACOLOGY Vancomycin Hydrochloride for Injection, USP is administered intravenously for therapy of systemic infections. 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 two hours after infusion, and mean plasma concentrations of approximately 8 mcg/mL Revised: 09/2011 Revised: eleven 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 two hours after infusion, and

1981;94:343.

Ann Inter Med Inter Ann mean plasma concentrations of about 10 mcg/mL six hours after infusion. The plasma concentrations during multiple dosing are

.

4. Moellering RC, Krogstad DJ, Greenblatt DJ: Vancomycin therapy in patients with impaired renal function: A nomogram for dosage for nomogram A function: renal impaired with patients in therapy Vancomycin DJ: Greenblatt DJ, Krogstad RC, Moellering 4. similar to those after a single dose.

Clinical and Laboratory Standards Institute. Wayne, PA. January, 2009. January, PA. Wayne, Institute. Standards Laboratory and Clinical The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In the first

3. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 10th ed., CLSI document M02-A10. document CLSI ed., 10th – Standard Approved Tests; Susceptibility Disk Antimicrobial for Standards Performance 3. 24 hours, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Mean plasma clearance is

Clinical and Laboratory Standards Institute. Wayne, PA. January, 2011. January, PA. Wayne, Institute. Standards Laboratory and Clinical about 0.058 L/kg/hr, and mean renal clearance is about 0.048 L/kg/hr. Renal dysfunction slows of vancomycin. In anephric

2. Performance Standards for Antimicrobial Susceptibility Testing; 21st Informational Supplement, CLSI document M100-S21. document CLSI Supplement, Informational 21st Testing; Susceptibility Antimicrobial for Standards Performance 2. 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

document M07-A8. Clinical and Laboratory Standards Institute. Wayne, PA. January, 2009. January, PA. Wayne, Institute. Standards Laboratory and Clinical M07-A8. document metabolism of the drug. About 60% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is absorbed

1. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard – 8th ed., CLSI ed., 8th – Standard Approved Aerobically; Grow That Bacteria for Tests Susceptibility Antimicrobial Dilution for Methods 1. systemically in six hours. Serum concentrations of about 10 mcg/mL are achieved by intraperitoneal injection of 30 mg/kg of

REFERENCES vancomycin.

concentration of 25 mg/mL and an infusion rate of 13.3 mL/min. 13.3 of rate infusion an and mg/mL 25 of concentration However, the safety and efficacy of the intraperitoneal use of vancomycin has not been established in adequate and well-

In animal studies, and bradycardia occurred in dogs receiving an intravenous infusion of vancomycin, 25 mg/kg, at a at mg/kg, 25 vancomycin, of infusion intravenous an receiving dogs in occurred bradycardia and hypotension studies, animal In controlled trials (see PRECAUTIONS). ANIMAL PHARMACOLOGY ANIMAL Total systemic and renal clearance of vancomycin may be reduced in the elderly.

Vancomycin is approximately 55% serum bound as measured by ultrafiltration at vancomycin serum concentrations of Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Room Controlled USP [See 77°F). to (68 25°C to 20 at Store 10 to 100 mcg/mL. After I.V. 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 hydrochloride does not

0409-6535-01 1 g 10 ADD-Vantage™ Vials ADD-Vantage™ 10 g 1 0409-6535-01 readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid

0409-6531-01 750 mg 10 ADD-Vantage™ Vials ADD-Vantage™ 10 mg 750 0409-6531-01 occurs.

0409-6534-01 500 mg 10 ADD-Vantage™ Vials ADD-Vantage™ 10 mg 500 0409-6534-01 Microbiology

NDC Number Fill Units per Carton per Units Fill Number NDC The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters

500 mg, 750 mg or 1 g. 1 or mg 750 mg, 500 bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other .

r

Vancomycin Hydrochloride for Injection, USP is supplied as a sterile powder in single-dose ADD-Vantage vials that contain eithe contain that vials ADD-Vantage single-dose in powder sterile a as supplied is USP Injection, for Hydrochloride Vancomycin Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi. HOW SUPPLIED HOW Synergy

The combination of vancomycin and an acts synergistically in vitro against many strains of ,

WARNING: Do not use flexible containers in series connections. series in containers flexible use not Do WARNING: Streptococcus bovis, enterococci, and the viridans group streptococci.

10. Regulate rate of administration with flow control clamp. control flow with administration of rate Regulate 10. Vancomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical

9. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. make and prime indwelling, not is device If device. venipuncture to set Attach 9. infections as described in the INDICATIONS AND USAGE section.

8. Open flow control clamp and clear air from set. Close clamp. Close set. from air clear and clamp control flow Open 8. Gram-positive bacteria

7. Squeeze and release drip chamber to establish proper fluid level in chamber. in level fluid proper establish to chamber drip release and Squeeze 7. Diphtheroids

the upright position, then suspend container from hanger. from container suspend then position, upright the Enterococci (e.g., faecalis)

t in t

6. Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock i lock to outward loop the Bend strings. tie two the breaking vial, the of bottom the on loop hanger the of end free the Lift 6. Staphylococci, including Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous -resistant

on administration set carton. set administration on strains) in adequate and well-controlled clinical trials.

NOTE:

See full directions full See

5. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. seated. firmly is pin the until motion twisting a with port into set administration of pin piercing Insert 5. Gram-positive bacteria

4. Remove cover from outlet port at bottom of container. of bottom at port outlet from cover Remove 4. monocytogenes

3. Close flow control clamp of administration set. administration of clamp control flow Close 3. Streptococcus pyogenes

2. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired. be may sterility as unit discard found, are leaks If firmly. container squeezing by leaks for Check 2. Streptococcus pneumoniae (including -resistant strains)

1. Confirm the activation and admixture of vial contents. vial of admixture and activation the Confirm 1.

(Use Aseptic Technique) Aseptic (Use Anaerobic Gram-positive bacteria Preparation for Administration: for Preparation Actinomyces species species Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on dilution method1,2 (broth, agar or microdilution) or equivalent using standardized inoculum and concentrations of vancomycin powder. The MIC values should be interpreted according to the criteria in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of

bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations.

Fig. 5 Fig. 6 Fig. 5 Fig. This procedure uses paper disks impregnated with 30-mcg of vancomycin to test the susceptibility of microorganisms to vancomycin.

4. Mix container contents thoroughly and use within the specified time. specified the within use and thoroughly contents container Mix 4. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for vancomycin.

diluent to mix. to diluent Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg vancomycin disk should

and

3. Pull the inner cap from the drug vial. (See Figure 6.) Verify that the rubber stopper has been pulled out, allowing the drug drug the allowing out, pulled been has stopper rubber the that Verify 6.) Figure (See vial. drug the from cap inner the Pull 3. be interpreted according to the following criteria in Table 1.

the vial through the walls of the container. (See Figure 5.) Figure (See container. the of walls the through vial the Table 1: Susceptibility Test Interpretive Criteria for Vancomycin of cap inner the Grasp container. the of walls the telescoping container the into down vial drug the push hand, other the With 2.

al.

1. Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vi drug the of end the surrounding container the of portion the inflate to gently container diluent the of bottom the Squeeze 1. Minimum Inhibitory Concentrations Disk Diffusion Diameters To Reconstitute the Drug: the Reconstitute To (mcg/mL) (mm)

Susceptible Intermediate Resistant Susceptible Intermediate Resistant Pathogen (S) (I) (R) (S) (I) (R)

Enterococci a ≤ 4 8 – 16 ≥ 32 ≥ 17b 15 –16b ≤ 14b

Staphylococcus ≤ 2 4 – 8 ≥ 16 –– –– –– aureus Coagulase- negative ≤ 4 8 – 16 ≥ 32 –– –– –– staphylococci Streptococci other than ≤ 1c,d –– –– ≥ 17c,e –– –– S. pneumoniae a A ß-lactamase test using an inoculum ≥ 107 CFU/mL or direct colony growth and a nitrocefin-based substrate should be performed to detect

Fig. 3 Fig. 4 Fig. 3 Fig. either or penicillin resistance due to ß-lactamase production.

b Plates should be held for a full 24 hours and examined using transmitted light. The presence of a haze or any growth within the zone of

4. Label appropriately. Label 4. inhibition indicates resistance. Those enterococci with intermediate zones of inhibition should be tested by a standardized procedure based

3. Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly. of direction the in further it turn to trying by tight is it that assure to vial the Recheck 3. on a dilution method1,2 (broth or agar) or equivalent.

NOTE: Once vial is seated, do not attempt to remove. (See Figure 4.) Figure (See remove. to attempt not do seated, is vial Once

vial must be turned as far as it will go. go. will it as far as turned be must vial c The current absence of resistant isolates precludes defining results other than “Susceptible”. Isolates yielding results suggestive of

the

occurs approximately 1/2 turn (180°) after the first audible click. (See Figure 4.) The clicking sound does not assure a seal; seal; a assure not does sound clicking The 4.) Figure (See click. audible first the after (180°) turn 1/2 approximately occurs “Nonsusceptible” should be submitted to a reference laboratory for further testing.

2. Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This SEAL. A ASSURE TO TIGHTLY IN SCREWED BE MUST VIAL THE further. no go will it until port vial the into vial the Screw 2. d Interpretative criteria applicable only to tests performed by broth microdilution method using cationadjusted Mueller-Hinton broth with 2 to 5%

cover. (See Figure 3.) Figure (See cover. lysed horse blood1,2.

he b. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the tie membrane, then pull back to remove t remove to back pull then membrane, tie the break to up pull ring, pull the on tab the grasp cover, port vial the remove To b. e Interpretative criteria applicable only to tests performed by disk diffusion method using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO23. A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard

Fig. 1 Fig. 2 Fig. 1 Fig. vancomycin powder should provide MIC values provided below. For the diffusion technique, the 30 mcg vancomycin disk should

provide the following zone diameters with the quality control strains: NOTE: Do not access vial with syringe. with vial access not Do 2.) Figure (See cap. the remove to up straight pull then 1.), Figure (See

a. To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening the start to enough far down pull and vial the of top the over ring pull the swing cap, vial breakaway the remove To a. Table 2. In Vitro Susceptibility Test Quality Control Ranges for Vancomycin

1. Remove the protective covers from the top of the vial and the vial port on the diluent container as follows: as container diluent the on port vial the and vial the of top the from covers protective the Remove 1. Organism (ATTC #) MIC range (mcg/mL) Disk diffusion range (mm)

(Use Aseptic Technique) Aseptic (Use

To Assemble Vial and Flexible Diluent Container: Diluent Flexible and Vial Assemble To (29212) 1 – 4 Not applicable

gradually. Staphylococcus aureus (29213) 0.5 – 2 Not applicable

nish dimi will opacity The safety. or quality solution the affect not does and normal is This observed. be may process sterilization

Peel overwrap at corner and remove solution container. Some opacity of the plastic due to moisture absorption during the during absorption moisture to due plastic the of opacity Some container. solution remove and corner at overwrap Peel Staphylococcus aureus (25923) Not applicable 17 – 21

To Open: To

To Use Vial in ADD-Vantage Flexible Diluent Container Diluent Flexible ADD-Vantage in Vial Use To Streptococcus pneumoniae (49619)a 0.12 – 0.5 20 – 27

INSTRUCTIONS FOR USE FOR INSTRUCTIONS

administration, whenever solution or container permits. container or solution whenever administration, a Interpretative criteria applicable only to tests performed using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood1. Disk

o

Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration prior t prior discoloration and matter particulate for visually inspected be should products drug parenteral administration, to Prior diffusion interpretive criteria applicable only to tests performed using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in

dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity. visual of improvement with and months two over cavity vitreous the of clearing complete with gradually, dissolved 5% CO2. of vancomycin and for using different syringes and needles. The precipitates The needles. and syringes different using endophthalmitis for ceftazidime and vancomycin of injection intravitreal

r Although intravitreal injection is not an approved for vancomycin, precipitation has been reported afte reported been has precipitation vancomycin, for administration of route approved an not is injection intravitreal Although INDICATIONS AND USAGE

between the administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less. or mg/mL 5 to vancomycin of solutions dilute to recommended also is It antibiotics. these of administration the between Vancomycin hydrochloride is indicated for the treatment of serious or severe infections caused by susceptible strains of methicillin-

s of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous line intravenous the flush adequately to recommended is It vancomycin. of concentrations higher with increases precipitation of resistant (beta-lactam-resistant) staphylococci. It is indicated for penicillin-allergic patients, for patients who cannot receive or who

Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood The incompatible. physically be to shown been have antibiotics beta-lactam and vancomycin of solutions of Mixtures have failed to respond to other drugs, including the or , and for infections caused by vancomycin-

Vancomycin solution has a low pH and may cause physical instability of other compounds. compounds. other of instability physical cause may and pH low a has solution Vancomycin susceptible organisms that are resistant to other antimicrobial drugs. Vancomycin hydrochloride is indicated for initial therapy when

manner should be administered by intravenous infusion over a period of at least 60 minutes. 60 least at of period a over infusion intravenous by administered be should manner methicillin-resistant staphylococci are suspected, but after susceptibility data are available, therapy should be adjusted accordingly.

1 g ADD-Vantage vial should be joined joined be should vial ADD-Vantage g 1 to a 250 mL ADD-Vantage flexible diluent container. The desired dose diluted in this in diluted dose desired The container. diluent flexible ADD-Vantage mL 250 a to only Vancomycin hydrochloride is effective in the treatment of staphylococcal . It’s effectiveness has been documented in

The 500 mg ADD-Vantage vial should be joined with at least a 100 mL ADD-Vantage flexible diluent container, the 750 mg and the and mg 750 the container, diluent flexible ADD-Vantage mL 100 a least at with joined be should vial ADD-Vantage mg 500 The other infections due to staphylococci, including septicemia, bone infections, lower respiratory tract infections, skin and skin-

Intermittent infusion is the recommended method of administration. of method recommended the is infusion Intermittent structure infections. When staphylococcal infections are localized and purulent, antibiotics are used as adjuncts to appropriate

the time of preparation. Admixtures should be prepared as close to the time of administration as is reasonable. is as administration of time the to close as prepared be should Admixtures preparation. of time the surgical measures.

ll after ll potency. However, this information is not intended to suggest that it is acceptable practice to administer such an admixture we admixture an such administer to practice acceptable is it that suggest to intended not is information this However, potency. Vancomycin hydrochloride has been reported to be effective alone or in combination with an aminoglycoside for endocarditis

oss of oss sodium chloride injection may be stored for 24 hours at room temperature or in a refrigerator for 14 days without significant l significant without days 14 for refrigerator a in or temperature room at hours 24 for stored be may injection chloride sodium caused by Streptococcus viridans or S. bovis. For endocarditis caused by enterococci (e.g., E. faecalis), vancomycin hydrochloride

Chemical Stability: Chemical It has been shown that after reconstitution, the admixture solution prepared in either dextrose injection or injection dextrose either in prepared solution admixture the reconstitution, after that shown been has It has been reported to be effective only in combination with an aminoglycoside.

INSTRUCTIONS FOR USE FOR INSTRUCTIONS chloride injection) (see (see injection) chloride ). Vancomycin hydrochloride has been reported to be effective for the treatment of diphtheroid endocarditis. Vancomycin

Vancomycin Hydrochloride ADD-Vantage vials should be used only with approved diluents (5% dextrose injection or 0.9% sodium 0.9% or injection dextrose (5% diluents approved with only used be should vials ADD-Vantage Hydrochloride Vancomycin hydrochloride has been used successfully in combination with either rifampin, an aminoglycoside, or both in early-onset prosthetic PREPARATION AND STABILITY AND PREPARATION 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

Intermittent infusion is the recommended method of administration. of method recommended the is infusion Intermittent their susceptibilities to vancomycin hydrochloride.

assessed. To reduce the development of drug-resistant bacteria and maintain the effectiveness of vancomycin and other antibacterial drugs,

The safety and efficacy of vancomycin administration by the intrathecal (intralumbar or intraventricular) route have not been not have route intraventricular) or (intralumbar intrathecal the by administration vancomycin of efficacy and safety The vancomycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible

by debilitation, malnutrition, or inactivity. or malnutrition, debilitation, by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial

nied

and total body weight is not present, such as in obese patients or those with liver disease, edema, or ascites; and (3) accompa (3) and ascites; or edema, disease, liver with those or patients obese in as such present, not is weight body total and therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of

mass

decreasing renal function, such as shock, severe heart failure, or oliguria; (2) in which a normal relationship between muscle muscle between relationship normal a which in (2) oliguria; or failure, heart severe shock, as such function, renal decreasing therapy. not valid. Such a calculated clearance is an overestimate of actual clearance in patients with conditions: (1) characterized by characterized (1) conditions: with patients in clearance actual of overestimate an is clearance calculated a Such valid. not

s The serum creatinine must represent a steady state of renal function. Otherwise, the estimated value for creatinine clearance i clearance creatinine for value estimated the Otherwise, function. renal of state steady a represent must creatinine serum The CONTRAINDICATION Vancomycin Hydrochloride for Injection, USP is contraindicated in patients with known to this antibiotic.

Women: 0.85 x above value above x 0.85 Women: WARNINGS

72 x serum creatinine concentration (mg/dL) concentration creatinine serum x 72 Rapid bolus administration (e.g., over several minutes) may be associated with exaggerated hypotension, including shock, and,

Men: Weight (kg) x (140 - age in years) in age - (140 x (kg) Weight Men: rarely, cardiac arrest.

should be measured promptly. measured be should Vancomycin hydrochloride should be administered in a dilute solution over a period of not less than 60 minutes to avoid rapid-

used to calculate creatinine clearance. Calculated creatinine clearances (mL/min) are only estimates. The creatinine clearance creatinine The estimates. only are (mL/min) clearances creatinine Calculated clearance. creatinine calculate to used infusion-related reactions. Stopping the infusion usually results in a prompt cessation of these reactions.

When only serum creatinine concentration is known, the following formula (based on sex, weight, and age of the patient) may be may patient) the of age and weight, sex, on (based formula following the known, is concentration creatinine serum only When has occurred in patients receiving vancomycin hydrochloride. It may be transient or permanent. It has been reported

days rather than administering the drug on a daily basis. In anuria, a dose of 1000 mg every 7 to 10 days has been recommended. been has days 10 to 7 every mg 1000 of dose a anuria, In basis. daily a on drug the administering than rather days mostly in patients who have been given excessive doses, who have an underlying , or who are receiving concomitant

ral In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1000 mg once every seve every once mg 1000 to 250 of doses maintenance give to convenient more be may it impairment, renal marked with patients In therapy with another ototoxic agent, such as an aminoglycoside. Vancomycin should be used with caution in patients with renal

. given to achieve prompt therapeutic serum concentrations. The dose required to maintain stable concentrations is 1.9 mg/kg/24 h mg/kg/24 1.9 is concentrations stable maintain to required dose The concentrations. serum therapeutic prompt achieve to given insufficiency because the risk of toxicity is appreciably increased by high, prolonged blood concentrations.

be The table is not valid for functionally anephric patients. For such patients, an initial dose of 15 mg/kg of body weight should weight body of mg/kg 15 of dose initial an patients, such For patients. anephric functionally for valid not is table The Dosage of vancomycin hydrochloride must be adjusted for patients with renal dysfunction (see PRECAUTIONS and DOSAGE AND The initial dose should be no less than 15 mg/kg, even in patients with mild to moderate renal insufficiency. renal moderate to mild with patients in even mg/kg, 15 than less no be should dose initial The ADMINISTRATION).

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

0155 10 Vancomycin Hydrochloride for Injection, USP, and may range in severity from mild diarrhea to fatal . Treatment with

0310 20 antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

0465 30 C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile

0620 40 cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

0770 50 CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary

0925 60 since CDAD has been reported to occur over two months after the administration of antibacterial agents.

01080 70 If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

01235 80 Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation 01390 90 should be instituted as clinically indicated.

0 1545 100 PRECAUTIONS

mL/min mg/24 h mg/24 mL/min General

Creatinine Clearance Vancomycin Dose Vancomycin Clearance Creatinine Prolonged use of vancomycin may result in the overgrowth of nonsusceptible microorganisms. Careful observation of the patient is

(Adapted from Moellering et al) et Moellering from (Adapted

4 essential. If occurs during therapy, appropriate measures should be taken. In rare instances, there have been reports

IN PATIENTS WITH IMPAIRED RENAL FUNCTION RENAL IMPAIRED WITH PATIENTS IN of pseudomembranous colitis due to C. difficile developing in patients who received intravenous vancomycin.

DOSAGE TABLE FOR VANCOMYCIN FOR TABLE DOSAGE In order to minimize the risk of when treating patients with underlying renal dysfunction or patients receiving

filtration rate in mL/min: in rate filtration concomitant therapy with an aminoglycoside, serial monitoring of renal function should be performed and particular care should be

calculated using the following table. The dosage of vancomycin hydrochloride per day in mg is about 15 times the glomerular the times 15 about is mg in day per hydrochloride vancomycin of dosage The table. following the using calculated taken in following appropriate dosing schedules (see DOSAGE AND ADMINISTRATION).

If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be can impairment renal with patients most for dosage the accurately, estimated or measured be can clearance creatinine If Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity.

or high-pressure liquid chromatography. liquid high-pressure or Reversible has been reported in patients receiving vancomycin hydrochloride (see ADVERSE REACTIONS). Patients

determined by use of microbiologic assay, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay, fluorescence immunoassay, polarization fluorescence radioimmunoassay, assay, microbiologic of use by determined who will undergo prolonged therapy with vancomycin hydrochloride or those who are receiving concomitant drugs which may cause

optimizing therapy, especially in seriously ill patients with changing renal function. Vancomycin serum concentrations can be can concentrations serum Vancomycin function. renal changing with patients ill seriously in especially therapy, optimizing neutropenia should have periodic monitoring of the leukocyte count.

may be necessary because of decreased renal function. Measurement of vancomycin serum concentrations can be helpful in helpful be can concentrations serum vancomycin of Measurement function. renal decreased of because necessary be may Vancomycin hydrochloride is irritating to tissue and must be given by a secure intravenous route of administration. Pain,

d

Dosage adjustment must be made in patients with impaired renal function. In the elderly, greater dosage reductions than expecte than reductions dosage greater elderly, the In function. renal impaired with patients in made be must adjustment Dosage tenderness, and necrosis occur with inadvertent extravasation. may occur, the frequency and severity of which

Patients with Impaired Renal Function and Elderly Patients Elderly and Function Renal Impaired with Patients can be minimized by administering the drug slowly as a dilute solution (2.5 to 5 g/L) and by rotating the sites of infusion.

monitoring of serum concentrations of vancomycin is recommended in these patients. these in recommended is vancomycin of concentrations serum of monitoring There have been reports that the frequency of infusion-related events (including hypotension, flushing, , urticaria, and

decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close infants. premature in necessary be may intervals dosing longer Therefore, decreases. age postconceptional as decreases pruritus) increases with the concomitant administration of agents. Infusion-related events may be minimized by the

up to the age of one month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance vancomycin infants, premature In minutes. 60 over administered be should dose Each month. one of age the to up administration of vancomycin hydrochloride as a 60-minute infusion prior to anesthetic induction.

eafter

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 ther hours eight every and life of week first the in neonates for hours 12 every mg/kg 10 by followed suggested, is mg/kg 15 of The safety and efficacy of vancomycin administration by the intrathecal (intralumbar or intraventricular) route or by intraperitoneal

Neonates:

In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose initial an neonates, In lower. be may dosage intravenous daily total the month, 1 of age the to up patients pediatric In route have not been established by adequate and well-controlled trials.

recommended in these patients. these in recommended Reports have revealed that administration of Vancomycin Hydrochloride for Injection, USP by the intraperitoneal route during

dose should be administered over a period of at least 60 minutes. Close monitoring of serum concentrations of vancomycin is vancomycin of concentrations serum of monitoring Close minutes. 60 least at of period a over administered be should dose continuous ambulatory peritoneal dialysis (CAPD) has resulted in a syndrome of chemical peritonitis. To date, this syndrome has

Pediatric Patients: Pediatric

The usual intravenous dosage of vancomycin hydrochloride is 10 mg/kg per dose given every six hours. Each hours. six every given dose per mg/kg 10 is hydrochloride vancomycin of dosage intravenous usual The ranged from a cloudy dialysate alone to a cloudy dialysate accompanied by variable degrees of abdominal pain and fever. This

age or obesity, may call for modification of the usual daily dose. daily usual the of modification for call may obesity, or age syndrome appears to be short-lived after discontinuation of intraperitoneal vancomycin.

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administered at no more than 10 mg/min, or over a period of at least 60 minutes, whichever is longer. Other patient factors, su factors, patient Other longer. is whichever minutes, 60 least at of period a over or mg/min, 10 than more no at administered Prescribing vancomycin in the absence of a proven or strongly suspected bacterial or a prophylactic indication is

Adults:

The usual daily intravenous dose is 2 g divided either as 500 mg every six hours or 1 g every 12 hours. Each dose should be should dose Each hours. 12 every g 1 or hours six every mg 500 as either divided g 2 is dose intravenous daily usual The unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Patients with Normal Renal Function Renal Normal with Patients Information for Patients

REQUIRE DOSES OF LESS THAN 500 MG. 500 THAN LESS OF DOSES REQUIRE Patients should be counseled that antibacterial drugs including vancomycin should only be used to treat bacterial infections. They

VIALS OF VANCOMYCIN HYDROCHLORIDE SHOULD NOT BE USED IN NEONATES, INFANTS, OR PEDIATRIC PATIENTS WHO PATIENTS PEDIATRIC OR INFANTS, NEONATES, IN USED BE NOT SHOULD HYDROCHLORIDE VANCOMYCIN OF VIALS do not treat viral infections (e.g., the common cold). When vancomycin is prescribed to treat a bacterial infection, the patient should

750 mg or 1 g are determined to be inappropriate, conventional vials of vancomycin hydrochloride should be used. ADD-VANTAGE used. be should hydrochloride vancomycin of vials conventional inappropriate, be to determined are g 1 or mg 750 be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

00 mg, 00

Patient factors, such as renal function and age, are critical in calculating correct dosage regimens (see below). If doses of 5 of doses If below). (see regimens dosage correct calculating in critical are age, and function renal as such factors, Patient Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2)

The use of ADD-Vantage vials of vancomycin hydrochloride is indicated only when doses of 500 mg, 750 mg or 1 g are appropriate. are g 1 or mg 750 mg, 500 of doses when only indicated is hydrochloride vancomycin of vials ADD-Vantage of use The increase the likelihood that bacteria will develop resistance and will not be treatable by vancomycin or other antibacterial drugs in

may increase the risk of infusion-related events. Infusion-related events may occur, however, at any rate or concentration. or rate any at however, occur, may events Infusion-related events. infusion-related of risk the increase may the future.

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In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used; use of such higher concentration higher such of use used; be may mg/mL 10 to up concentration a restriction, fluid of need in patients selected In Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after

5 mg/mL and rates of no more than 10 mg/min are recommended in adults (see also age-specific recommendations). age-specific also (see adults in recommended are mg/min 10 than more no of rates and mg/mL 5 starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even

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Infusion-related events are related to both concentration and rate of administration of vancomycin. Concentrations of no more t more no of Concentrations vancomycin. of administration of rate and concentration both to related are events Infusion-related as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician

DOSAGE AND ADMINISTRATION AND DOSAGE as soon as possible.

ient.

overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your pat your in kinetics drug unusual and drugs, among interaction overdoses, drug multiple of possibility the consider overdosage, Drug Interactions

Center. Telephone numbers of certified poison control centers are listed in the the in listed are centers control poison certified of numbers Telephone Center. . In managing In .

Physicians’ Desk Reference (PDR) Reference Desk Physicians’ Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Poison Regional certified your is resource good a overdose, of treatment the about information up-to-date obtain To (see Pediatric Use under PRECAUTIONS) and anaphylactoid reactions (see ADVERSE REACTIONS).

intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice. in mg/kg 400 and rats in mg/kg 319 is dose intravenous Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as

hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance. The median lethal median The clearance. vancomycin increased in result to reported been have resin polysulfone with hemoperfusion , , , B, , viomycin, or cisplatin, when indicated, requires careful

and

Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed by dialysis. Hemofiltration dialysis. by removed poorly is Vancomycin filtration. glomerular of maintenance with advised, is care Supportive monitoring. OVERDOSAGE Carcinogenesis, Mutagenesis, Impairment of Fertility

Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no mutagenic potential of

To report SUSPECTED ADVERSE EVENTS, contact FDA at 1-800-FDA-1088 or www.fda.gov. www.fda.gov. or 1-800-FDA-1088 at FDA contact EVENTS, ADVERSE SUSPECTED report To Vancomycin Hydrochloride for Injection, USP was found in standard laboratory tests. No definitive fertility studies have been

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Symptoms Systemic and Eosinophilia with Rash Drug performed.

Skin and Subcutaneous Tissue Disorders Tissue Subcutaneous and Skin Pregnancy: Teratogenic Effects, Category C — Animal reproduction studies have not been conducted with Vancomycin

relationship to the drug exposure. drug the to relationship hydrochloride. It is not known whether Vancomycin hydrochloride can affect reproduction capacity. In a controlled clinical study, the

a causal a

reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish establish or frequency their estimate reliably to possible not is it size, uncertain of population a from voluntarily reported potential ototoxic and nephrotoxic effects of Vancomycin hydrochloride on infants were evaluated when the drug was administered

The following adverse reactions have been identified during post-approval use of vancomycin. Because these reactions are reactions these Because vancomycin. of use post-approval during identified been have reactions adverse following The to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. Vancomycin hydrochloride was

Post Marketing Reports Marketing Post found in cord blood. No sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. One infant whose mother

PRECAUTIONS Chemical peritonitis has been reported following intraperitoneal administration of vancomycin (see (see vancomycin of administration intraperitoneal following reported been has peritonitis Chemical

). received vancomycin in the third trimester experienced conductive hearing loss that was not attributed to the administration of

vasculitis in association with the administration of vancomycin. of administration the with association in vasculitis vancomycin. Because the number of patients treated in this study was limited and vancomycin was administered only in the second

(including exfoliative dermatitis), linear IgA bullous dermatosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and necrolysis, epidermal toxic syndrome, Stevens-Johnson dermatosis, bullous IgA linear dermatitis), exfoliative (including and third trimesters, it is not known whether vancomycin causes fetal harm. Vancomycin should be given to a pregnant woman only

Miscellaneous: Infrequently, patients have been reported to have had , drug fever, nausea, chills, eosinophilia, rashes eosinophilia, chills, nausea, fever, drug anaphylaxis, had have to reported been have patients Infrequently, if clearly needed.

Phlebitis:

Inflammation at the injection site has been reported. been has site injection the at Inflammation Nursing Mothers

rarely. Vancomycin is excreted in human milk. Caution should be exercised when vancomycin is administered to a nursing woman. Because

Although a causal relationship has not been established, reversible agranulocytosis (granulocytes <500/mm (granulocytes agranulocytosis reversible established, been not has relationship causal a Although

) has been reported been has ) of the potential for adverse events, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into 3

when vancomycin hydrochloride is discontinued. has rarely been reported. been rarely has Thrombocytopenia discontinued. is hydrochloride vancomycin when account the importance of the drug to the mother.

ible after a total dosage of more than 25 g, has been reported for several dozen patients. Neutropenia appears to be promptly revers promptly be to appears Neutropenia patients. dozen several for reported been has g, 25 than more of dosage total a after Pediatric Use

Hematopoietic:

Reversible neutropenia, usually starting one week or more after onset of therapy with vancomycin hydrochloride or hydrochloride vancomycin with therapy of onset after more or week one starting usually neutropenia, Reversible In pediatric patients, it may be appropriate to confirm desired vancomycin serum concentrations. Concomitant administration of

Vertigo, dizziness, and have been reported rarely. reported been have tinnitus and dizziness, Vertigo, vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing in pediatric patients (see

patients had kidney dysfunction or a preexisting hearing loss, or were receiving concomitant treatment with an ototoxic drug. ototoxic an with treatment concomitant receiving were or loss, hearing preexisting a or dysfunction kidney had patients ADVERSE REACTIONS).

Ototoxicity:

A few dozen cases of hearing loss associated with vancomycin hydrochloride have been reported. Most of these of Most reported. been have hydrochloride vancomycin with associated loss hearing of cases dozen few A Geriatrics Use

WARNINGS Gastrointestinal: ).

Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see (see treatment antibiotic after or during occur may symptoms colitis pseudomembranous of Onset The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage

vancomycin hydrochloride was discontinued, azotemia resolved in most patients. most in resolved azotemia discontinued, was hydrochloride vancomycin is not adjusted. Vancomycin dosage schedules should be adjusted in elderly patients (see DOSAGE AND ADMINISTRATION).

have occurred in patients who were given aminoglycosides concomitantly or who had preexisting kidney dysfunction. When dysfunction. kidney preexisting had who or concomitantly aminoglycosides given were who patients in occurred have ADVERSE REACTIONS

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patients given large doses of vancomycin, has been reported. Rare cases of interstitial nephritis have been reported. Most of t of Most reported. been have nephritis interstitial of cases Rare reported. been has vancomycin, of doses large given patients Infusion-Related Events: During or soon after rapid infusion of vancomycin hydrochloride, patients may develop anaphylactoid

Nephrotoxicity:

Rarely, renal failure, principally manifested by increased serum creatinine or BUN concentrations, especially in especially concentrations, BUN or creatinine serum increased by manifested principally failure, renal Rarely, reactions, including hypotension (see ANIMAL PHARMACOLOGY), wheezing, dyspnea, urticaria, or pruritus. Rapid infusion may also

administered at a rate of 10 mg/min or less. or mg/min 10 of rate a at administered cause flushing of the upper body (“red neck”) or pain and muscle spasm of the chest and back. These reactions usually resolve

was infusion over 60 minutes. In studies of normal volunteers, infusion-related events did not occur when vancomycin hydrochloride hydrochloride vancomycin when occur not did events infusion-related volunteers, normal of studies In minutes. 60 over infusion within 20 minutes but may persist for several hours. Such events are infrequent if vancomycin hydrochloride is given by a slow

Reference ID: 3051857