VIBATIV (telavancin hydrochloride) injection®

Telavancin hydrochloride is an off-white to slightly colored amorphous powder with the empirical formula C80H106C12N11O27P•xHCl (where x = 1 to 3) and a free-base molecular weight of 1755.6. It is highly lipophilic and slightly soluble in water.

VIBATIV is a sterile, preservative-free, white to slightly colored lyophilized powder containing telavancin hydrochloride (equivalent to either 250 mg or 750 mg of telavancin as the free base) for intravenous use. The inactive ingredients are Hydroxypropylbetadex, Ph. Eur (hydroxypropyl-beta-cyclodextrin) (2500 mg per 250 mg telavancin, 7500 mg per 750 mg telavancin), mannitol (312.5 mg per 250 mg telavancin, 937.5 mg per 750 mg telavancin), and sodium hydroxide and hydrochloric acid used in minimal quantities for pH adjustment. When reconstituted, it forms a clear to slightly colored solution with a pH of 4.5 (4.0 to 5.0).

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 [see Indications and Usage]:

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

Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative results of the 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.

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.

• 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.

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.

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

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)

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.

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.

Marketed by:
Astellas Pharma US, Inc.
Deerfield, IL 60015

US Patent Nos. 6,635,618 B2; 6,858,584 B2; 6,872,701 B2; 7,008,923 B2; 7,208,471 B2; 7,351,691 B2; 7,531,623 B2; and 7,544,364 B2

VIBATIV is a trademark of Astellas Pharma Inc.