Intravenous Dilution Guidelines

Vibativ™ (telavancin hydrochloride) injection

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Usual Diluents

D5W, NS, LR

Standard Dilution [Amount of drug] [Infusion volume] [Infusion rate]

[150 - 800mg] [100 - 250 ml] [60 minutes]

For doses of 150 to 800 mg, the appropriate volume of reconstituted solution must be further diluted in 100 to 250 mL prior to infusion. Doses less than 150 mg or greater than 800 mg should be further diluted in a volume resulting in a final concentration of 0.6 to 8 mg/mL.

Preparation and Administration (reconstitution):
250 mg vial: Reconstitute the contents of a VIBATIV 250 mg vial with 15 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP. The resultant solution has a concentration of 15 mg/mL (total volume of approximately 17.0 mL).

750 mg vial: Reconstitute the contents of a VIBATIV 750 mg vial with 45 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP, The resultant solution has a concentration of 15 mg/mL (total volume of approximately 50.0 mL).

Dosage and administration...

Stability / Miscellaneous

Stability:
Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparing the final intravenous solution. Studies have shown that the reconstituted solution in the vial should be used within 4 hours when stored at room temperature or within 72 hours under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag should be used within 4 hours when stored at room temperature or used within 72 hours when stored under refrigeration at 2 to 8°C (36 to 46°F). However, the total time in the vial plus the time in the infusion bag should not exceed 4 hours at room temperature and 72 hours under refrigeration at 2 to 8°C (36 to 46°F).

These highlights do not include all the information needed to use VIBATIV safely and effectively. See full prescribing information for VIBATIV.
VIBATIV (telavancin) for injection, for intravenous use- Initial U.S. Approval: 2009.

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

WARNING: FETAL RISK

Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV

Avoid use of VIBATIV during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus

Adverse developmental outcomes observed in 3 animal species at clinically relevant doses raise concerns about potential adverse developmental outcomes in humans

CLINICAL PHARMACOLOGY:
VIBATIV contains telavancin hydrochloride, a lipoglycopeptide antibacterial that is a synthetic derivative of vancomycin.

Pharmacodynamics
The antimicrobial activity of telavancin appears to best correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) forStaphylococcus aureus based on animal models of infection. An exposure-response analysis of 2 cSSSI clinical trials supports the dose of 10 mg/kg every 24 hours.

Pharmacokinetics
Distribution
Telavancin binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The mean binding is approximately 90% and is not affected by renal or hepatic impairment.

Concentrations of telavancin in skin blister fluid were 40% of those in plasma (AUC0-24hr ratio) after 3 daily doses of 7.5 mg/kg VIBATIV in healthy young adults.

Metabolism
No metabolites of telavancin were detected in in vitro studies using human liver microsomes, liver slices, hepatocytes, and kidney S9 fraction. None of the following recombinant CYP 450 isoforms were shown to metabolize telavancin in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 4A11. The clearance of telavancin is not expected to be altered by inhibitors of any of these enzymes.

In a mass balance study in male subjects using radiolabeled telavancin, 3 hydroxylated metabolites were identified with the predominant metabolite (THRX-651540) accounting for <10% of the radioactivity in urine and <2% of the radioactivity in plasma. The metabolic pathway for telavancin has not been identified.

Excretion
Telavancin is primarily eliminated by the kidney. In a mass balance study, approximately 76% of the administered dose was recovered from urine and <1% of the dose was recovered from feces (collected up to 216 hours) based on total radioactivity.

Microbiology -------------------------------------------
Telavancin is a semisynthetic, lipoglycopeptide antibiotic. Telavancin exerts concentration-dependent, bactericidal activity against Gram-positive organisms in vitro, as demonstrated by time-kill assays and MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. In vitro studies demonstrated a telavancin post-antibiotic effect ranging from 1 to 6 hours against S. aureus and other Gram-positive pathogens.

Although telavancin is approximately 90% protein bound, the presence of human serum or human serum albumin has minimal impact on the in vitro activity of telavancin against staphylococci, streptococci, and vancomycin-susceptible enterococci.

Mechanism of Action
Telavancin inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan. Telavancin binds to the bacterial membrane and disrupts membrane barrier function.

Interactions with Other Antibacterials
In vitro investigations demonstrated no antagonism between telavancin and amikacin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, meropenem, oxacillin, piperacillin/tazobactam, rifampin, and trimethoprim/sulfamethoxazole, when tested in various combinations against telavancin susceptible staphylococci, streptococci, and enterococci. This information is not available for other bacteria.

Cross-Resistance
Some vancomycin-resistant enterococci have a reduced susceptibility to telavancin. There is no known cross-resistance between telavancin and other classes of antibiotics.

Antibacterial Activity
Telavancin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections as described in the Indications and Usage section.:

Facultative Gram-Positive Microorganisms
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus pyogenes
Enterococcus faecalis (vancomycin-susceptible isolates only)
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)

Greater than 90% of the following microorganisms exhibit an in vitro MIC less than or equal to the telavancin-susceptible breakpoint for organisms of similar genus shown in Table 7. The safety and effectiveness of telavancin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Facultative Gram-Positive Microorganisms
Enterococcus faecium (vancomycin-susceptible isolates only)
Staphylococcus haemolyticus
Streptococcus dysgalactaie subsp. equisimilis
Staphylococcus epidermidis

INDICATIONS AND USAGE
VIBATIV is a lipoglycopeptide antibacterial indicated for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive bacteria.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of VIBATIV and other antibacterial drugs, VIBATIV should be used only to treat 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.

Complicated Skin and Skin Structure Infections
VIBATIV is indicated for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), or Enterococcus faecalis (vancomycin-susceptible isolates only).

Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative organisms.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to telavancin. VIBATIV may be initiated as empiric therapy before results of these tests are known.

DOSAGE AND ADMINISTRATION

Complicated Skin and Skin Structure Infections:
The recommended dosing for VIBATIV is 10 mg/kg administered over a 60-minute period in patients

18 years of age by intravenous infusion once every 24 hours for 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.

Dosage adjustment in patients with renal impairment.
Because telavancin is eliminated primarily by the kidney, a dosage adjustment is required for patients whose creatinine clearance is

50 mL/min, as listed in Table 1

**Table 1: Dosage Adjustment in Adult Patients with Renal Impairment**
Creatinine Clearance* (mL/min)	VIBATIV Dosage Regimen
>50	10 mg/kg every 24 hours
30 - 50	7.5 mg/kg every 24 hours
10 - <30	10 mg/kg every 48 hours

* As calculated using the Cockcroft-Gault formula

There is insufficient information to make specific dosage adjustment recommendations for patients with end-stage renal disease (CrCl <10 mL/min), including patients undergoing hemodialysis.

Preparation and Administration
250 mg vial: Reconstitute the contents of a VIBATIV 250 mg vial with 15 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP. The resultant solution has a concentration of 15 mg/mL (total volume of approximately 17.0 mL).

750 mg vial: Reconstitute the contents of a VIBATIV 750 mg vial with 45 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP, The resultant solution has a concentration of 15 mg/mL (total volume of approximately 50.0 mL).

The following formula can be used to calculate the volume of reconstituted VIBATIV solution required to prepare a dose:

Telavancin dose (mg) = 10 mg/kg or 7.5 mg/kg x patient weight (in kg) (see Table 1 above).
Volume of reconstituted solution (mL) = Telavancin dose (mg) / (15 mg/mL )

For doses of 150 to 800 mg, the appropriate volume of reconstituted solution must be further diluted in 100 to 250 mL prior to infusion. Doses less than 150 mg or greater than 800 mg should be further diluted in a volume resulting in a final concentration of 0.6 to 8 mg/mL. Appropriate infusion solutions include: 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP. The dosing solution should be administered by intravenous infusion over a period of 60 minutes.

Reconstitution time is generally under 2 minutes, but can sometimes take up to 20 minutes. Mix thoroughly to reconstitute and check to see if the contents have dissolved completely. Parenteral drug products should be inspected visually for particulate matter prior to administration. Discard the vial if the vacuum did not pull the diluent into the vial.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparing the final intravenous solution. Studies have shown that the reconstituted solution in the vial should be used within 4 hours when stored at room temperature or within 72 hours under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag should be used within 4 hours when stored at room temperature or used within 72 hours when stored under refrigeration at 2 to 8°C (36 to 46°F). However, the total time in the vial plus the time in the infusion bag should not exceed 4 hours at room temperature and 72 hours under refrigeration at 2 to 8°C (36 to 46°F).

VIBATIV is administered intravenously. Because only limited data are available on the compatibility of VIBATIV with other IV substances, additives or other medications should not be added to VIBATIV single-use vials or infused simultaneously through the same IV line. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of VIBATIV with 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP.

DOSAGE FORMS AND STRENGTHS
VIBATIV is supplied in single-use vials containing either 250 or 750 mg telavancin as a sterile, lyophilized powder.

CONTRAINDICATIONS
None.

WARNINGS AND PRECAUTIONS

Nephrotoxicity: New onset or worsening renal impairment has occurred. Monitor renal function in all patients.
Decreased efficacy with moderate/severe baseline renal impairment: Consider these data when selecting antibacterial therapy for patients with baseline CrCl 50 mL/min.
Infusion-related reactions: Administer VIBATIV over at least 60 minutes to minimize infusion-related reactions.
Clostridium difficile-associated disease: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs.
QTc prolongation: Avoid use in patients at risk. Use with caution in patients taking drugs known to prolong the QT interval.
Coagulation test interference: Telavancin interferes with some laboratory coagulation tests, including prothrombin time, international normalized ratio, and activated partial thromboplastin time.

ADVERSE REACTIONS
Most common adverse reactions (

10% of patients treated with VIBATIV) include: taste disturbance, nausea, vomiting, and foamy urine.
To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. Pregnancy registry available.
Pediatric patients: Safety and efficacy not demonstrated.

HOW SUPPLIED/STORAGE AND HANDLING:

Cartons of 10 individually packaged 250 mg single-dose vials (NDC 0469-3525-30)
Cartons of 10 individually packaged 750 mg single-dose vials (NDC 0469-3575-50)

Store original packages at refrigerated temperatures of 2 to 8°C (35 to 46 °F). Excursions to ambient temperatures (up to 25 °C (77 °F)) are acceptable. Avoid excessive heat.

Reference(s)