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VIBATIV(telavancin for injection)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VIBATIV ® (telavancin) safely and effectively. See full prescribing information for VIBATIV.
VIBATIV ® (telavancin) for injection, for intravenous use
Initial U.S. Approval: 2009
WARNING: INCREASED MORTALITY IN HABP/VABP PATIENTS WITH PRE-EXISTING MODERATE OR SEVERE RENAL IMPAIRMENT, NEPHROTOXICITY, POTENTIAL ADVERSE DEVELOPMENTAL OUTCOMES
See full prescribing information for the complete boxed warning
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Patients with pre-existing moderate/severe renal impairment (CrCl ≤50 mL/min) who were treated with VIBATIV for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) had increased mortality observed versus vancomycin. Use of VIBATIV in patients with pre-existing moderate/severe renal impairment (CrCl ≤50 mL/min) should be considered only when the anticipated benefit to the patient outweighs the potential risk. (5.1)
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Nephrotoxicity: New onset or worsening renal impairment has occurred. Monitor renal function in all patients. (5.3)
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Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV. (5.4, 8.1)
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Avoid use of VIBATIV during pregnancy unless potential benefit to the patient outweighs potential risk to the fetus. (8.1)
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Adverse developmental outcomes observed in three animal species at clinically relevant doses raise concerns about potential adverse developmental outcomes in humans. (8.1)
INDICATIONS AND USAGE
VIBATIV is a lipoglycopeptide antibacterial drug indicated for the treatment of the following infections in adult patients caused by designated susceptible bacteria:
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Complicated skin and skin structure infections (cSSSI) (1.1)
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Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of Staphylococcus aureus. VIBATIV should be reserved for use when alternative treatments are not suitable. (1.2)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of VIBATIV and other antibacterial drugs VIBATIV should only be used to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
DOSAGE AND ADMINISTRATION
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Complicated skin and skin structure infections (cSSSI):
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10 mg/kg by IV infusion over 60 minutes every 24 hours for 7 to 14 days (2.1)
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Dosage adjustment in patients with renal impairment. (2.3)
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Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP):
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10 mg/kg by IV infusion over 60 minutes every 24 hours for 7 to 21 days (2.2)
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Dosage adjustment in patients with renal impairment. (2.3)
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Creatinine Clearancea (CrCl)
(mL/min) |
VIBATIV Dosage Regimen |
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>50 |
10 mg/kg every 24 hours |
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30-50 |
7.5 mg/kg every 24 hours |
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10-<30 |
10 mg/kg every 48 hours |
DOSAGE FORMS AND STRENGTHS
Single-use vials containing either 250 or 750 mg telavancin. (3)
CONTRAINDICATIONS
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Intravenous Unfractionated Heparin Sodium (4.1, 5.5, 7.1)
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Known hypersensitivity to VIBATIV (4.2, 5.6, 6.2)
WARNINGS AND PRECAUTIONS
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Decreased efficacy among patients treated for skin and skin structure infections with moderate/severe pre-existing renal impairment: Consider these data when selecting antibacterial therapy for patients with baseline CrCl ≤50 mL/min. (5.2)
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Coagulation test interference: Telavancin interferes with some laboratory coagulation tests, including prothrombin time, international normalized ratio, and activated partial thromboplastin time. (5.5, 7.1)
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Hypersensitivity reactions: Serious and potentially fatal hypersensitivity reactions, including anaphylactic reactions, may occur after first or subsequent doses. VIBATIV should be used with caution in patients with known hypersensitivity to vancomycin. (5.6, 6.2)
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Infusion-related reactions: Administer VIBATIV over at least 60 minutes to minimize infusion-related reactions. (5.7)
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Clostridium difficile-associated disease: May range from mild diarrhea to fatal colitis. eva luate if diarrhea occurs. (5.8)
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QTc prolongation: Avoid use in patients at risk. Use with caution in patients taking drugs known to prolong the QT interval. (5.10)
ADVERSE REACTIONS
Most common adverse reaction (≥10% of patients treated with VIBATIV) in the HABP/VABP trials is diarrhea; in the cSSSI trials, the most common adverse reactions (≥10% of patients treated with VIBATIV) include: taste disturbance, nausea, vomiting, and foamy urine. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Theravance Biopharma US, Inc. at 1-855-633-8479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
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Pregnancy: Based on animal data, may cause fetal harm. Pregnancy registry available. (8.1)
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Pediatric patients: Safety and efficacy not demonstrated. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 5/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 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).
1.2 HABP/VABP
VIBATIV is indicated for the treatment of adult patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Staphylococcus aureus (both methicillin-susceptible and -resistant isolates). VIBATIV should be reserved for use when alternative treatments are not suitable.
1.3 USAGE
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.
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.
2 DOSAGE AND ADMINISTRATION
2.1 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 progress.
2.2 Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia (HABP/VABP)
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 21 days. The duration of therapy should be guided by the severity of the infection and the patient's clinical progress.
2.3 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 [see Clinical Pharmacology (12.3)].
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.
2.4 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).
To minimize foaming during product reconstitution, allow the vacuum of the vial to pull the diluent from the syringe into the vial. Do not forcefully inject the diluent into the vial. Do not forcefully shake the vial and do not shake final infusion solution.
The following formula can be used to calculate the volume of reconstituted VIBATIV solution required to prepare a dose:
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Telavancin dose (mg) = 10 mg/kg or 7.5 mg/kg x patient weight (in kg) (see Table 1)
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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 12 hours when stored at room temperature or within 7 days under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag should be used within 12 hours when stored at room temperature or used within 7 days 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 12 hours at room temperature and 7 days under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag can also be stored at -30 to -10°C (-22 to 14°F) for up to 32 days.
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.
3 DOSAGE FORMS AND STRENGTHS
VIBATIV is supplied in single-use vials containing either 250 or 750 mg telavancin as a sterile, lyophilized powder.
4 CONTRAINDICATIONS
4.1 Intravenous Unfractionated Heparin Sodium
Use of intravenous unfractionated heparin sodium is contraindicated with VIBATIV administration because the activated partial thromboplastin time (aPTT) test results are expected to be artificially prolonged for 0 to 18 hours after VIBATIV administration [see Warnings and Precautions (5.5) and Drug Interactions (7.1)].
4.2 Known Hypersensitivity to VIBATIV
VIBATIV is contraindicated in patients with known hypersensitivity to telavancin.
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Patients with HABP/VABP and Pre-existing Moderate to Severe Renal Impairment (CrCl ≤50 mL/min)
In the analysis of patients (classified by the treatment received) in the two combined HABP/VABP trials with pre-existing moderate/severe renal impairment (CrCl ≤50 mL/min), all-cause mortality within 28 days of starting treatment was 95/241 (39%) in the VIBATIV group, compared with 72/243 (30%) in the vancomycin group. All-cause mortality at 28 days in patients without pre-existing moderate/severe renal impairment (CrCl >50 mL/min) was 86/510 (17%) in the VIBATIV group and 92/510 (18%) in the vancomycin group. Therefore, VIBATIV use in patients with baseline CrCl ≤50 mL/min should be considered only when the anticipated benefit to the patient outweighs the potential risk [see Adverse Reactions, Clinical Trials Experience (6.1) and Clinical Trials, HABP/VABP (14.2)].
5.2 Decreased Clinical Response in Patients with cSSSI and Pre-existing Moderate/Severe Renal Impairment (CrCl ≤50 mL/min)
In a subgroup analysis of the combined cSSSI trials, clinical cure rates in the VIBATIV-treated patients were lower in patients with baseline CrCl ≤50 mL/min compared with those with CrCl >50 mL/min (Table 2). A decrease of this magnitude was not observed in vancomycin-treated patients. Consider these data when selecting antibacterial therapy for use in patients with cSSSI and with baseline moderate/severe renal impairment.
5.3 Nephrotoxicity
In both the HABP/VABP trials and the cSSSI trials, renal adverse events were more likely to occur in patients with baseline comorbidities known to predispose patients to kidney dysfunction (pre-existing renal disease, diabetes mellitus, congestive heart failure, or hypertension). The renal adverse event rates were also higher in patients who received concomitant medications known to affect kidney function (e.g., non-steroidal anti-inflammatory drugs, ACE inhibitors, and loop diuretics).
Monitor renal function (i.e., serum creatinine, creatinine clearance) in all patients receiving VIBATIV. Values should be obtained prior to initiation of treatment, during treatment (at 48- to 72-hour intervals or more frequently, if clinically indicated), and at the end of therapy. If renal function decreases, the benefit of continuing VIBATIV versus discontinuing and initiating therapy with an alternative agent should be assessed [see Dosage and Administration (2), Adverse Reactions (6), and Clinical Pharmacology (12.3)].
In patients with renal dysfunction, accumulation of the solubilizer hydroxypropyl-beta-cyclodextrin can occur [see Patients with Renal Impairment (8.6) and Clinical Pharmacology (12.3)].
5.4 Pregnant Women and Women of Childbearing Potential
Avoid use of VIBATIV during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus. VIBATIV caused adverse developmental outcomes in 3 animal species at clinically relevant doses. This raises concern about potential adverse developmental outcomes in humans.
Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV. If not already pregnant, women of childbearing potential should use effective contraception during VIBATIV treatment [see Use in Specific Populations (8.1)].
5.5 Coagulation Test Interference
Although telavancin does not interfere with coagulation, it interfered with certain tests used to monitor coagulation (Table 3), when conducted using samples drawn 0 to 18 hours after VIBATIV administration for patients being treated once every 24 hours. Blood samples for these coagulation tests should be collected as close as possible prior to a patient's next dose of VIBATIV. Blood samples for coagulation tests unaffected by VIBATIV may be collected at any time [see Drug Interactions (7.1)].
For patients who require aPTT monitoring while being treated with VIBATIV, a non phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.
No evidence of increased bleeding risk has been observed in clinical trials with VIBATIV. Telavancin has no effect on platelet aggregation. Furthermore, no evidence of hypercoagulability has been seen, as healthy subjects receiving VIBATIV have normal levels of D-dimer and fibrin degradation products.
5.6 Hypersensitivity Reactions
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur after first or subsequent doses. Discontinue VIBATIV at first sign of skin rash, or any other sign of hypersensitivity. Telavancin is a semi-synthetic derivative of vancomycin; it is unknown if patients with hypersensitivity reactions to vancomycin will experience cross-reactivity to telavancin. VIBATIV should be used with caution in patients with known hypersensitivity to vancomycin [see Postmarketing Experience (6.2)].
5.7 Infusion-related Reactions
VIBATIV is a lipoglycopeptide antibacterial agent and should be administered over a period of 60 minutes to reduce the risk of infusion-related reactions. Rapid intravenous infusions of the glycopeptide class of antimicrobial agents can cause “Red-man Syndrome”-like reactions including: flushing of the upper body, urticaria, pruritus, or rash. Stopping or slowing the infusion may result in cessation of these reactions.
5.8 Clostridium difficile-Associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the flora of the colon and may permit overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hyper-toxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical eva luation should be instituted as clinically indicated.
5.9 Development of Drug-Resistant Bacteria
Prescribing VIBATIV in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
As with other antibacterial drugs, use of VIBATIV may result in overgrowth of nonsusceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.
5.10 QTc Prolongation
In a study involving healthy volunteers, doses of 7.5 and 15 mg/kg of VIBATIV prolonged the QTc interval [see Clinical Pharmacology (12.2)]. Caution is warranted when prescribing VIBATIV to patients taking drugs known to prolong the QT interval. Patients with congenital long QT syndrome, known prolongation of the QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy were not included in clinical trials of VIBATIV. Use of VIBATIV should be avoided in patients with these conditions.
6 ADVERSE REACTIONS
The following serious adverse reactions are also discussed elsewhere in the labeling:
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Nephrotoxicity [see Warnings and Precautions (5.3)]
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Infusion-related reactions [see Warnings and Precautions (5.7)]
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Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.8)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
6.1 Clinical Trials Experience
Complicated Skin and Skin Structure Infections
The two Phase 3 cSSSI clinical trials (Trial 1 and Trial 2) for VIBATIV included 929 adult patients treated with VIBATIV at 10 mg/kg IV once daily. The mean age of patients treated with VIBATIV was 49 years (range 18-96). There was a slight male predominance (56%) in patients treated with VIBATIV, and patients were predominantly Caucasian (78%).
In the cSSSI clinical trials, <1% (8/929) patients who received VIBATIV died and <1% (8/938) patients treated with vancomycin died. Serious adverse events were reported in 7% (69/929) of patients treated with VIBATIV and most commonly included renal, respiratory, or cardiac events. Serious adverse events were reported in 5% (43/938) of vancomycin-treated patients, and most commonly included cardiac, respiratory, or infectious events. Treatment discontinuations due to adverse events occurred in 8% (72/929) of patients treated with VIBATIV, the most common events being nausea and rash (~1% each). Treatment discontinuations due to adverse events occurred in 6% (53/938) of vancomycin-treated patients, the most common events being rash and pruritus (~1% each).
The most common adverse events occurring in ≥10% of VIBATIV-treated patients observed in the VIBATIV Phase 3 cSSSI trials were taste disturbance, nausea, vomiting, and foamy urine.
Table 4 displays the incidence of treatment-emergent adverse drug reactions reported in ≥2% of patients treated with VIBATIV possibly related to the drug.
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