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: Complicated skin and skin structure infections (cSSSI) ( 1.1 ) 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.

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 (vancomycinsusceptible 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.

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.

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 Cumberland Pharmaceuticals Inc.

at 1-877-683-6110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 ) ]