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 [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 )] WARNING: FETAL RISK See full prescribing information for complete boxed warning. • Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV. ( 8.1 ) • Avoid use of VIBATIV during pregnancy unless potential benefit to the patient outweighs potential risk to the fetus. ( 8.1 ) • Adverse developmental outcomes observed in 3 animal species at clinically relevant doses raise concerns about potential adverse developmental outcomes in humans. ( 8.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Nephrotoxicity: New onset or worsening renal impairment has occurred. Monitor renal function in all patients. ( 5.3 ) • Decreased efficacy with moderate/severe baseline renal impairment: Consider these data when selecting antibacterial therapy for patients with baseline CrCl ≤50 mL/min. ( 5.4 ) • Infusion-related reactions: Administer VIBATIV over at least 60 minutes to minimize infusion-related reactions. ( 5.5 ) • Clostridium difficile -associated disease: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. ( 5.6 ) • QTc prolongation: Avoid use in patients at risk. Use with caution in patients taking drugs known to prolong the QT interval. ( 5.8 ) • Coagulation test interference: Telavancin interferes with some laboratory coagulation tests, including prothrombin time, international normalized ratio, and activated partial thromboplastin time. ( 5.9 , 7.1 ) 5.1 Women of Childbearing Potential 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. 5.2 Pregnancy 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 [see Use in Specific Populations ( 8.1 )] . 5.3 Nephrotoxicity 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%). In 30/929 (3.1%) of VIBATIV-treated patients compared to 10/938 (1.1%) of vancomycin-treated patients, renal adverse events indicative of renal impairment occurred, as defined by the following terms: increased serum creatinine, renal impairment, renal insufficiency, and/or renal failure. 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 (1.2%) of VIBATIV-treated patients compared to 3/938 (0.3%) of vancomycin-treated patients. Twelve patients treated with VIBATIV discontinued treatment due to adverse events indicative of renal impairment compared to 2 patients treated with vancomycin. 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 rate was also higher in patients who received concomitant medications known to affect kidney function (eg, non-steroidal anti-inflammatory drugs, ACE inhibitors, and loop diuretics). Fifteen of 174 patients (8.6%) ≥65 years of age had adverse events indicative of renal impairment compared to 16 of 755 patients (1.9%) <65 years of age [see Use in Specific Populations ( 8.5 )] . 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, Clinical Pharmacology ( 2.2 )] . 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 Decreased Efficacy with Moderate/Severe Baseline Renal Impairment In a subgroup analysis of the pooled cSSSI studies, clinical cure rates in the telavancin-treated patients were lower in patients with baseline CrCl ≤50 mL/min compared to 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 baseline moderate/severe renal impairment. Table 2: Clinical Cure by Baseline Renal Function 1 All-treated population - includes all patients randomized, treated, and evaluated for efficacy 2 Clinically evaluable population VIBATIV % (n/N) Vancomycin % (n/N) ATe Population 1 CrCl >50 mL/min 75.3% (565/750) 73.7% (575/780) CrCl ≤50 mL/min 63.1% (70/111) 69.4% (75/108) CE Population 2 CrCl >50 mL/min 87.0% (520/598) 85.9% (524/610) CrCl ≤50 mL/min 67.4% (58/86) 82.7% (67/81) 5.5 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. 5.6 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 over 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. 5.7 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. 5.8 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. 5.9 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 )] . Table 3: Coagulation Tests Affected and Unaffected by Telavancin Affected by Telavancin Unaffected by Telavancin Prothrombin time International normalized ratio Activated partial thromboplastin time Activated clotting time Coagulation based factor Xa tests Thrombin time Whole blood (Lee-White) clotting time Ex vivo platelet aggregation Chromogenic factor Xa assay Functional (chromogenic) factor X assay Bleeding time D-dimer Fibrin degradation products 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.
<table ID="_Reft3" width="100%"><caption>Table 3: Coagulation Tests Affected and Unaffected by Telavancin </caption><col width="45%"/><col width="55%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Affected by Telavancin</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Unaffected by Telavancin</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Prothrombin time International normalized ratio Activated partial thromboplastin time Activated clotting time Coagulation based factor Xa tests </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Thrombin time Whole blood (Lee-White) clotting time Ex vivo platelet aggregation Chromogenic factor Xa assay Functional (chromogenic) factor X assay Bleeding time D-dimer Fibrin degradation products </paragraph></td></tr></tbody></table>
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Nephrotoxicity [ see Warnings and Precautions ( 5.3 ) ] • Infusion-related reactions [ see Warnings and Precautions ( 5.5 ) ] • Clostridium difficile -associated diarrhea [ see Warnings and Precautions ( 5.6 ) ] 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 reactions (≥10% of patients treated with VIBATIV) include: taste disturbance, nausea, vomiting, and foamy urine. ( 6.1 ) 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. 6.1 Clinical Trials Experience 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 reactions 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 (including those reactions known to occur with other glycopeptide antibacterial agents). Table 4: Incidence of Treatment-emergent Adverse Drug Reactions Reported in ≥2% of VIBATIV or Vancomycin Patients Treated in Trial 1 and Trial 2 VIBATIV (N=929) Vancomycin (N=938) 1 Described as a metallic or soapy taste. Body as a Whole Rigors 4% 2% Generalized pruritus 3% 6% Digestive System Nausea 27% 15% Vomiting 14% 7% Diarrhea 7% 8% Abdominal pain 2% 2% Metabolic and Nutritional Decreased appetite 3% 2% Nervous System Taste disturbance 1 33% 7% Dizziness 6% 6% Renal System Foamy urine 13% 3% Skin and Appendages Pruritus 6% 13% Rash 4% 5% Other Infusion site pain 4% 4% Infusion Site erythema 3% 3%