VIBATIV: Package Insert and Label Information (Page 2 of 5)

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 evaluation 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:

  • Nephrotoxicity [see Warnings and Precautions (5.3) ]
  • Infusion-related reactions [see Warnings and Precautions (5.7) ]
  • 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.

Table 4: Incidence of Treatment-Emergent Adverse Drug Reactions Reported in ≥2% of Patients Treated in cSSSI Trial 1 and Trial 2

*Described as metallic or soapy taste.

VIBATIV (N=929) Vancomycin (N=938)
Body as a Whole
Rigors 4% 2%
Digestive System
Nausea 27% 15%
Vomiting 14% 7%
Diarrhea 7% 8%
Metabolic and Nutritional
Decreased appetite 3% 2%
Nervous System
Taste disturbance* 33% 7%
Renal System
Foamy urine 13% 3%

HABP/VABP

Two randomized, double-blind Phase 3 trials (Trial 1 and Trial 2) for VIBATIV included 1,503 adult patients treated with VIBATIV at 10 mg/kg IV once daily or vancomycin at 1 g IV twice daily. The mean age of patients treated with VIBATIV was 62 years (range 18-100) with 69% of the patients white and 65% male. In the combined VIBATIV group, 29% were VAP and 71% were HAP patients.

Table 5 summarizes deaths using Kaplan-Meier estimates at Day 28 as stratified by baseline creatinine clearance categorized into four groups. Patients with pre-existing moderate/severe renal impairment (CrCl 50 mL/min) who were treated with VIBATIV for HABP/VABP had increased mortality observed versus vancomycin in both the trials.

Table 5: 28-Day Mortality* Stratified by Baseline Creatinine Clearance- All-Treated Analysis Population

*(Kaplan-Meier Estimates)

CrCl (mL/min) Trial 1 Trial 2
VIBATIV N (%) Vancomycin N (%) Difference (95% CI) VIBATIV N (%) Vancomycin N (%) Difference (95% CI)
>80 143 (12.2%) 152 (14.1%) -1.8(-9.6, 6.0) 181 (10.5%) 181 (18.7%) -8.2(-15.5, -0.9)
>50-80 88 (27.4%) 88 (17.7%) 9.7(-2.7, 22.1) 96 (25.6%) 90 (27.1%) -1.5(-14.4, 11.3)
30-50 80 (34.7%) 83 (23.1%) 11.5(-2.5, 25.5) 62 (27.7%) 68 (23.7%) 4.0(-11.1, 19.1)
<30 61 (44.3%) 51 (37.3%) 7.0(-11.2, 25.2) 38 (61.1%) 41 (42.1%) 19.0(-2.9, 40.8)

Serious adverse events were reported in 31% of patients treated with VIBATIV and 26% of patients who received vancomycin. Treatment discontinuations due to adverse events occurred in 8% (60/751) of patients who received VIBATIV, the most common events being acute renal failure and electrocardiogram QTc interval prolonged (~1% each). Treatment discontinuations due to adverse events occurred in 5% (40/752) of vancomycin-patients, the most common events being septic shock and multi-organ failure (<1%).

Table 6 displays the incidence of treatment-emergent adverse drug reactions reported in ≥ 5% of HABP/VABP patients treated with VIBATIV possibly related to the drug.

Table 6: Incidence of Treatment Emergent Adverse Drug Reactions Reported in ≥5% of Patients Treated in HABP/VABP Trial 1 and Trial 2
VIBATIV (N=751) Vancomycin (N=752)
Nausea 5% 4%
Vomiting 5% 4%
Renal Failure Acute 5% 4%

Nephrotoxicity

Complicated Skin and Skin Structure Infections

In cSSSI trials, the incidence of renal adverse events indicative of renal impairment (increased serum creatinine, renal impairment, renal insufficiency, and/or renal failure) was 30/929 (3%) of VIBATIV-treated patients compared with 10/938 (1%) of vancomycin-treated patients. In 17 of the 30 VIBATIV-treated patients, these adverse events had not completely resolved by the end of the trials, compared with 6 of the 10 vancomycin-treated patients. Serious adverse events indicative of renal impairment occurred in 11/929 (1%) of VIBATIV-treated patients compared with 3/938 (0.3%) of vancomycin-treated patients. Twelve patients treated with VIBATIV discontinued treatment due to adverse events indicative of renal impairment compared with 2 patients treated with vancomycin.

Increases in serum creatinine to 1.5 times baseline occurred more frequently among VIBATIV-treated patients with normal baseline serum creatinine (15%) compared with vancomycin-treated patients with normal baseline serum creatinine (7%).

Fifteen of 174 (9%) VIBATIV-treated patients ≥65 years of age had adverse events indicative of renal impairment compared with 16 of 755 patients (2%) <65 years of age [see Use in Specific Populations (8.5) ].

Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia

In the HABP/VABP trials, the incidence of renal adverse events (increased serum creatinine, renal impairment, renal insufficiency, and/or renal failure) was 10% for VIBATIV vs. 8% for vancomycin. Of the patients who had at least one renal adverse event, 54% in each treatment group recovered completely, recovered with sequelae, or were improving from the renal AE at the last visit. Three percent of VIBATIV-treated patients and 2% of vancomycintreated patients experienced at least one serious renal adverse event. Renal adverse events resulted in discontinuation of study medication in 14 VIBATIV-treated patients (2%) and 7 vancomycin-treated patients (1%).

Increases in serum creatinine to 1.5 times baseline occurred more frequently among VIBATIV-treated patients (16%) compared with vancomycin-treated patients (10%).

Forty-four of 399 (11.0%) VIBATIV-treated patients ≥ 65 years of age had adverse events indicative of renal impairment compared with 30 of 352 patients (8%) <65 years of age [see Use in Specific Populations (8.5) ].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of VIBATIV. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serious hypersensitivity reactions have been reported after first or subsequent doses of VIBATIV, including anaphylactic reactions. It is unknown if patients with hypersensitivity reactions to vancomycin will experience crossreactivity to telavancin. [see Hypersensitivity Reactions (5.6) ]

7 DRUG INTERACTIONS

7.1 Drug-Laboratory Test Interactions

Effects of Telavancin on Coagulation Test Parameters

Telavancin binds to the artificial phospholipid surfaces added to common anticoagulation tests, thereby interfering with the ability of the coagulation complexes to assemble on the surface of the phospholipids and promote clotting in vitro. These effects appear to depend on the type of reagents used in commercially available assays. Thus, when measured shortly after completion of an infusion of VIBATIV, increases in the PT, INR, aPTT, and ACT have been observed. These effects dissipate over time, as plasma concentrations of telavancin decrease.

Urine Protein Tests

Telavancin interferes with urine qualitative dipstick protein assays, as well as quantitative dye methods (e.g., pyrogallol red-molybdate). However, microalbumin assays are not affected and can be used to monitor urinary protein excretion during VIBATIV treatment.

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