VOTRIENT: Package Insert and Label Information

VOTRIENT- pazopanib hydrochloride tablet, film coated
Novartis Pharmaceuticals Corporation

1 INDICATIONS AND USAGE

1.1 Renal Cell Carcinoma

VOTRIENT^® is indicated for the treatment of adults with advanced renal cell carcinoma (RCC).

1.2 Soft Tissue Sarcoma

VOTRIENT is indicated for the treatment of adults with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Limitations of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of VOTRIENT is 800 mg (four 200 mg tablets) orally once daily without food (at least 1 hour before or 2 hours after a meal) until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)]. The dosage should be modified for hepatic impairment and in patients taking certain concomitant drugs [see Dosage and Administration (2.3, 2.4)].

Swallow tablets whole. Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure [see Clinical Pharmacology (12.3)].

If a dose is missed, it should not be taken if it is < 12 hours until the next dose.

2.2 Dosage Modifications for Adverse Reactions

Table 1 summarizes the recommended dose reductions.

Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

Dose Reduction	For Renal Cell Carcinoma	For Soft Tissue Sarcoma
First	400 mg orally once daily	600 mg orally once daily
Second	200 mg orally once daily	400 mg orally once daily

Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

Table 2 summarizes the recommended dosage modifications for adverse reactions.

Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal.a National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
Adverse Reaction	Severitya	Dosage Modification
Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks.Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
	ALT elevations > 3 × ULN occur concurrently withbilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution.Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
	Grade 4	Permanently discontinue.
Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1).Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
	Grade 3 or 4	Permanently discontinue.
Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
	Grade 4	Permanently discontinue.
Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
	Grade 4	Permanently discontinue.
Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
	Grade 4 or hypertensive crisis	Permanently discontinue.
Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1).Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
	Confirmed nephrotic syndrome	Permanently discontinue.

2.3 Dosage Modifications for Hepatic Impairment

Moderate and Severe Hepatic Impairment

In patients with moderate hepatic impairment [total bilirubin > 1.5 to 3 × upper limit of normal (ULN) and any alanine aminotransferase (ALT) value], consider alternatives to VOTRIENT. If VOTRIENT is used in patients with moderate hepatic impairment, reduce the VOTRIENT dose to 200 mg orally once daily.

VOTRIENT is not recommended in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any ALT value) [see Use in Specific Populations (8.7)].

2.4 Dosage Modifications for Drug Interactions

Strong CYP3A4 Inhibitors

Avoid concomitant use of strong CYP3A4 inhibitors by use of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers

Avoid concomitant use of strong CYP3A4 inducers by use of an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT is not recommended in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

Gastric Acid-Reducing Agents

Avoid concomitant use of gastric acid-reducing agents. If concomitant use of a gastric acid-reducing agent cannot be avoided, consider short-acting antacid in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate short-acting antacid and VOTRIENT dosing by several hours [see Drug Interactions (7.4), Clinical Pharmacology (12.3)].

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)].