VOTRIENT (Page 2 of 9)

3 DOSAGE FORMS AND STRENGTHS

Tablets: 200 mg, modified capsule-shaped, gray or pink, film-coated with ‘GS JT’ debossed on one side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatic Toxicity

Hepatotoxicity, manifested as increases in ALT, aspartate aminotransferase (AST) and bilirubin, occurred in patients who received VOTRIENT. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations (8.5)]. Transaminase elevations occur early in the course of treatment; 92% of all transaminase elevations of any grade occurred in the first 18 weeks.

In the randomized RCC trial (VEG105192), ALT > 3 × ULN occurred in 18% and ALT > 10 × ULN occurred in 4% of the 290 patients who received VOTRIENT. Concurrent elevation in ALT > 3 × ULN and bilirubin > 2 × ULN in the absence of significant alkaline phosphatase > 3 × ULN occurred in 2%. In the monotherapy trials, 2 patients died with disease progression and hepatic failure.

In the randomized STS trial (VEG110727), ALT > 3 × ULN occurred in 18% and ALT > 8 × ULN occurred in 5% of the 240 patients who received VOTRIENT. Concurrent elevation in ALT > 3 × ULN and bilirubin > 2 × ULN in the absence of significant alkaline phosphatase > 3 × ULN occurred in 2%. One patient died of hepatic failure.

Monitor liver tests at baseline; at Weeks 3, 5, 7, and 9; at Month 3 and Month 4; and then periodically as clinically indicated. Increase to weekly monitoring for patients with elevated ALT until ALT returns to Grade 1 or baseline. Withhold VOTRIENT and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity [see Dosage and Administration (2.2)].

Gilbert’s Syndrome

VOTRIENT is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5)]. In patients with only a mild indirect hyperbilirubinemia known as Gilbert’s syndrome, manage elevation in ALT > 3 × ULN per the recommendations outlined for isolated ALT elevations [see Dosage and Administration (2.2)].

Concomitant Use of Simvastatin

Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

5.2 QT Prolongation and Torsades de Pointes

In the RCC trials, 558/586 patients were subject to routine electrocardiogram (ECG) monitoring and QT prolongation ≥ 500 msec was identified in 2% of these 558 patients. In monotherapy trials, torsades de pointes occurred in < 1% of 977 patients who received VOTRIENT.

In the randomized RCC (VEG105192) and STS (VEG110727) trials, 1% (3/290) and 0.4% (1/240) of patients, respectively, who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction.

Monitor patients who are at significant risk of developing QTc prolongation, including patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease [see Drug Interactions (7.5)]. Monitor ECG and electrolytes (e.g., calcium, magnesium, potassium) at baseline and as clinically indicated. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating VOTRIENT and during treatment.

5.3 Cardiac Dysfunction

Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, occurred in patients who received VOTRIENT.

In the RCC trials, cardiac dysfunction was observed in 0.6% of 586 patients without routine on-study LVEF monitoring. In the randomized RCC trial (VEG105192), myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥ 15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥ 10% compared with baseline that is also below the lower limit of normal. In an RCC trial (COMPARZ), myocardial dysfunction occurred in 13% of the 362 patients on VOTRIENT who had a baseline and post-baseline LVEF measurements. Congestive heart failure occurred in 0.5% of patients.

In the randomized STS trial (VEG110727), myocardial dysfunction occurred in 11% of the 142 patients who had a baseline and a post-baseline LVEF measurements. One percent (3/240) of patients who received VOTRIENT had congestive heart failure, which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload.

Monitor blood pressure and manage as appropriate [see Warnings and Precautions (5.11)]. Monitor for clinical signs or symptoms of congestive heart failure. Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction, including previous anthracycline exposure. Withhold or permanently discontinue VOTRIENT based on severity of cardiac dysfunction [see Dosage and Administration (2.2)].

5.4 Hemorrhagic Events

In the RCC trials, fatal hemorrhage occurred in 0.9% of 586 patients, and cerebral/intracranial hemorrhage was observed in < 1% (2/586) of patients treated with VOTRIENT.

In the randomized RCC trial (VEG105192), 13% of 290 patients treated with VOTRIENT experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events, including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent of patients treated with VOTRIENT died from hemorrhage.

In the randomized STS trial (VEG110727), 22% of 240 patients treated with VOTRIENT experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events occurred in 1% of patients and included intracranial hemorrhage, subarachnoid hemorrhage, and peritoneal hemorrhage.

VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months. Withhold VOTRIENT and resume at reduced dose or permanently discontinue based on severity of hemorrhagic events [see Dosage and Administration (2.2)].

5.5 Arterial Thromboembolic Events

In the RCC trials, fatal arterial thromboembolic events occurred in 0.3% of 586 patients. In the randomized RCC trial (VEG105192), 2% of 290 patients who received VOTRIENT experienced myocardial infarction or ischemia, 0.3% had a cerebrovascular accident, and 1% had an event of transient ischemic attack.

In the randomized STS trial (VEG110727), 2% of 240 patients who received VOTRIENT experienced a myocardial infarction or ischemia and 0.4% had a cerebrovascular accident.

VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue VOTRIENT in case of an arterial thromboembolic event [see Dosage and Administration (2.2)].

5.6 Venous Thromboembolic Events

Venous thromboembolic events (VTEs), including venous thrombosis and fatal pulmonary embolus (PE), occurred in patients who received VOTRIENT.

In the randomized RCC trial (VEG105192), VTEs occurred in 1% of 290 patients who received VOTRIENT. In the randomized STS trial (VEG110727), VTEs were reported in 5% of 240 patients who received VOTRIENT. Fatal PE occurred in 1% (2/240).

Monitor for signs and symptoms of VTE and PE. Withhold VOTRIENT and then resume at same dose or permanently discontinue based on severity of VTE [see Dosage and Administration (2.2)].

5.7 Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), occurred in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued.

Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated.

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