FDA Label for Votrient

Warning: Hepatotoxicity

Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [see Warnings and Precautions (5.1)].

1       Indications And Usage

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

VOTRIENT is indicated for the treatment of patients 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.

2.1       Recommended Dosing

The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)]. The dose of VOTRIENT should not exceed 800 mg.

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 less than 12 hours until the next dose.

2.2       Dose Modification Guidelines

In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability.

In STS, a decrease or increase should be in 200-mg steps based on individual tolerability.

Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider 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. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

3       Dosage Forms And Strengths

200-mg tablets of VOTRIENT — modified capsule-shaped, gray, film-coated with GS JT debossed on one side. Each tablet contains 216.7 mg of pazopanib hydrochloride equivalent to 200 mg of pazopanib.

4       Contraindications

      None.

5.1       Hepatic Toxicity And Hepatic Impairment

In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (alanine transferase (ALT), aspartate aminotransferase (AST)) and bilirubin, was observed. 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 (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)].

In the randomized RCC trial, ALT greater than 3 X upper limit of normal (ULN) was reported in 18% and 3% of the groups receiving VOTRIENT and placebo, respectively. ALT greater than 10 X ULN was reported in 4% of patients who received VOTRIENT and in less than 1% of patients who received placebo. Concurrent elevation in ALT greater than 3 X ULN and bilirubin greater than 2 X ULN in the absence of significant alkaline phosphatase greater than 3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo.

In the randomized STS trial, ALT greater than 3 X ULN was reported in 18% and 5% of the groups receiving VOTRIENT and placebo, respectively. ALT greater than 8 X ULN was reported in 5% and 2% of the groups receiving VOTRIENT and placebo, respectively. Concurrent elevation in ALT greater than 3 X ULN and bilirubin  greater than 2 X ULN in the absence of significant alkaline phosphatase greater than 3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and less than 1% (1/123) on placebo.

Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure and 0.4% of patients (1/240) in the randomized STS trial died of hepatic failure.

• Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4.
  
• Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT returns to Grade 1 or baseline.
  
• Patients with isolated ALT elevations of greater than 8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations greater than 3 X ULN recur, then VOTRIENT should be permanently discontinued.
  
• If ALT elevations greater than 3 X ULN occur concurrently with bilirubin elevations greater than 2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. 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)]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT greater than 3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations.

Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

In patients with preexisting moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with preexisting severe hepatic impairment, defined as total bilirubin greater than 3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5.2       Qt Prolongation And Torsades De Pointes

In the RCC trials of VOTRIENT, QT prolongation (greater than or equal to 500 msec) was identified on routine electrocardiogram (ECG) monitoring in 2% (11/558) of patients. Torsades de pointes occurred in less than 1% (2/977) of patients who received VOTRIENT in the monotherapy trials.

In the randomized RCC and STS trials, 1% (3/290) of patients and 0.4% (1/240) of patients, respectively, who received VOTRIENT had postbaseline values between 500 to 549 msec. Postbaseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 268 patients who received placebo on the two trials had postbaseline QTc values greater than or equal to 500 msec.

VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed.

5.3       Cardiac Dysfunction

In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, myocardial dysfunction was defined as symptoms of cardiac dysfunction or greater than or equal to 15% absolute decline in LVEF compared with baseline or a decline in LVEF of greater than or equal to 10% compared with baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. Congestive heart failure occurred in 0.5% of patients on each arm. In the randomized STS trial, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared with 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient.

Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial 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. Blood pressure should be monitored and managed promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.11)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure.

5.4       Hemorrhagic Events

Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials; there were no reports of fatal hemorrhage in the STS trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT 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 (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in less than 1% (2/586) of patients treated with VOTRIENT. 

In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared with 8% (10/123) treated with placebo 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 in the STS population occurred in 1% (3/240) 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 and should not be used in those patients.

5.5       Arterial Thromboembolic Events

Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials and in no patients in the STS trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident, and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo in either trial. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients.

5.6       Venous Thromboembolic Events

In RCC and STS trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared with 2% with placebo. In the randomized RCC trial, the rate was 1% in both arms. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE.

5.7       Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been reported 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.

5.8       Gastrointestinal Perforation And Fistula

In the RCC and STS trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients and 1% (4/382) of patients receiving VOTRIENT, respectively. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials and in 0.3% (1/382) of these patients in the STS trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula.

5.9       Interstitial Lung Disease (Ild)/Pneumonitis

ILD/pneumonitis, which can be fatal, has been reported in association with VOTRIENT. In clinical trials, ILD/pneumonitis occurred in 0.1% of patients treated with VOTRIENT.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue VOTRIENT in patients developing ILD or pneumonitis.

5.10       Reversible Posterior Leukoencephalopathy Syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal.

RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS.

5.11       Hypertension

In clinical trials, hypertension (systolic blood pressure greater than or equal to 150 or diastolic blood pressure greater than or equal to 100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. 

Increased blood pressure should be treated promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite antihypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)].

5.12       Wound Healing

No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence.

5.13       Hypothyroidism

Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm of either trial had hypothyroidism. In RCC and STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) and 5% (20/382) of patients, respectively. Proactive monitoring of thyroid function tests is recommended. 

5.14       Proteinuria

In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared with none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. 

Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein greater than or equal to 3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)].

5.15       Infection

Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections.

5.16       Increased Toxicity With Other Cancer Therapy

VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

5.17       Increased Toxicity In Developing Organs

The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)].

5.18       Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, VOTRIENT can cause fetal harm when administered to a pregnant woman. Administration of VOTRIENT to pregnant rats and rabbits during the period of organogenesis resulted in maternal toxicity, teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose of 800 mg (based on AUC).

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VOTRIENT and for at least 2 weeks following the final dose [see Clinical Pharmacology (12.1) and Use in Specific Populations (8.1, 8.3)].

6.1       Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Potentially serious adverse reactions with VOTRIENT included:

• Hepatotoxicity [see Warnings and Precautions (5.1)]
  
• QT prolongation and torsades de pointes [see Warnings and Precautions (5.2)]
  
• Cardiac dysfunction [see Warnings and Precautions (5.3)]
  
• Hemorrhagic events [see Warnings and Precautions (5.4)]
  
• Arterial and venous thromboembolic events [see Warnings and Precautions (5.5 and 5.6)]
  
• Thrombotic microangiopathy [see Warnings and Precautions (5.7)]
  
• Gastrointestinal perforation and fistula [see Warnings and Precautions (5.8)]
  
• Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.9)]
  
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)]
  
• Hypertension [see Warnings and Precautions (5.11)]
  
• Infection [see Warnings and Precautions (5.15)]
  
• Increased toxicity with other cancer therapies [see Warnings and Precautions (5.16)]

Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range: 0.1 to 27.6), the most commonly observed adverse reactions (greater than or equal to 20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting.

The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1)]. The median duration of treatment was 7.4 months (range: 0 to 23) for patients who received VOTRIENT and 3.8 months (range: 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in greater than or equal to 10% of patients who received VOTRIENT.

Table 1. Adverse Reactions Occurring in greater than or equal to 10% of Patients with RCC Who Received VOTRIENT 

a     National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
	VOTRIENT			Placebo
	(N=290)			(N=145)
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Adverse Reactions	%	%	%	%	%	%
Diarrhea	52	3	<1	9	<1	0
Hypertension	40	4	0	10	<1	0
Hair color changes	38	<1	0	3	0	0
Nausea	26	<1	0	9	0	0
Anorexia	22	2	0	10	<1	0
Vomiting	21	2	<1	8	2	0
Fatigue	19	2	0	8	1	1
Asthenia	14	3	0	8	0	0
Abdominal pain	11	2	0	1	0	0
Headache	10	0	0	5	0	0

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in less than 10% (any grade) were alopecia (8% versus less than 1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus less than 1%), dyspepsia (5% versus less than 1%), dysphonia (4% versus less than 1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus less than 1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below:

Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in greater than 10% of patients who received VOTRIENT and more commonly (greater than or equal to 5%) in patients who received VOTRIENT versus placebo.

Table 2. Selected Laboratory Abnormalities Occurring in greater than 10% of Patients with RCC Who Received VOTRIENT and More Commonly (greater than or equal to 5%) in Patients Who Received VOTRIENT versus Placebo

a     National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
	VOTRIENT			Placebo
	(N = 290)			(N = 145)
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Parameters	%	%	%	%	%	%
Hematologic
Leukopenia	37	0	0	6	0	0
Neutropenia	34	1	<1	6	0	0
Thrombocytopenia	32	<1	<1	5	0	<1
Lymphocytopenia	31	4	<1	24	1	0
Chemistry
ALT increased	53	10	2	22	1	0
AST increased	53	7	<1	19	<1	0
Glucose increased	41	<1	0	33	1	0
Total bilirubin increased	36	3	<1	10	1	<1
Phosphorus decreased	34	4	0	11	0	0
Sodium decreased	31	4	1	24	4	0
Magnesium decreased	26	<1	1	14	0	0
Glucose decreased	17	0	<1	3	0	0

Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range: 0 to 53). The most commonly observed adverse reactions (greater than or equal to 20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation.

The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2)]. The median duration of treatment was 4.5 months (range: 0 to 24) for patients who received VOTRIENT and 1.9 months (range: 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 3 presents the most common adverse reactions occurring in greater than or equal to 10% of patients who received VOTRIENT.

Table 3. Adverse Reactions Occurring in ≥10% of Patients with STS Who Received VOTRIENT

a     National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b     27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.
	VOTRIENT			Placebo
	(N = 240)			(N = 123)
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Adverse Reactions	%	%	%	%	%	%
Fatigue	65	13	1	48	4	1
Diarrhea	59	5	0	15	1	0
Nausea	56	3	0	22	2	0
Weight decreased	48	4	0	15	0	0
Hypertension	42	7	0	6	0	0
Appetite decreased	40	6	0	19	0	0
Hair color changes	39	0	0	2	0	0
Vomiting	33	3	0	11	1	0
Tumor pain	29	8	0	21	7	2
Dysgeusia	28	0	0	3	0	0
Headache	23	1	0	8	0	0
Musculoskeletal pain	23	2	0	20	2	0
Myalgia	23	2	0	9	0	0
Gastrointestinal pain	23	3	0	9	4	0
Dyspnea	20	5	<1	17	5	1
Exfoliative rash	18	<1	0	9	0	0
Cough	17	<1	0	12	<1	0
Peripheral edema	14	2	0	9	2	0
Mucositis	12	2	0	2	0	0
Alopecia	12	0	0	1	0	0
Dizziness	11	1	0	4	0	0
Skin disorderb	11	2	0	1	0	0
Skin hypopigmentation	11	0	0	0	0	0
Stomatitis	11	<1	0	3	0	0
Chest pain	10	2	0	6	0	0

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in greater than or equal to 5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus less than 1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

Table 4 presents the most common laboratory abnormalities occurring in greater than 10% of patients who received VOTRIENT and more commonly (greater than or equal to 5%) in patients who received VOTRIENT versus placebo.

Table 4. Selected Laboratory Abnormalities Occurring in greater than 10% of Patients with STS Who Received VOTRIENT and More Commonly (≥5%) in Patients Who Received VOTRIENT versus Placebo

a     National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
	VOTRIENT			Placebo
	(N = 240)			(N = 123)
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Parameters	%	%	%	%	%	%
Hematologic
Leukopenia	44	1	0	15	0	0
Lymphocytopenia	43	10	0	36	9	2
Thrombocytopenia	36	3	1	6	0	0
Neutropenia	33	4	0	7	0	0
Chemistry
AST increased	51	5	3	22	2	0
ALT increased	46	8	2	18	2	1
Glucose increased	45	<1	0	35	2	0
Albumin decreased	34	1	0	21	0	0
Alkaline phosphatase increased	32	3	0	23	1	0
Sodium decreased	31	4	0	20	3	0
Total bilirubin increased	29	1	0	7	2	0
Potassium increased	16	1	0	11	0	0

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in both the RCC and STS clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in less than 1% (4/586) of patients.

Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm.

Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (less than 60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared with less than 1% (1/145) of patients treated with placebo. In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (less than 60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared with less than 1% (1/123) of patients treated with placebo.

Adverse Reactions in East Asian Patients: In an analysis of pooled clinical trials (N=1938) with VOTRIENT, Grade 3 and Grade 4 adverse reactions were observed more frequently in patients of East Asian descent than in patients of non-East Asian descent for neutropenia (12% versus 2%), thrombocytopenia (6% versus less than 1%) and palmar-plantar erythrodysethesia syndrome (6% versus 2%).

6.2       Postmarketing Experience

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

Eye Disorders: Retinal detachment/tear.

Gastrointestinal Disorders: Pancreatitis.

Blood and lymphatic system disorders: Polycythemia.

7.1       Drugs That Inhibit Or Induce Cytochrome P450 3A4 Enzymes

In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.

CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3)]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib.

CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)].

7.2       Drugs That Inhibit Transporters

In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect P-gp and BCRP.

Concomitant treatment with strong inhibitors of P-gp or BCRP should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit P-gp or BCRP should be considered.

7.3       Effects Of Pazopanib On Cyp Substrates

Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3)].

Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3)].

7.4       Effect Of Concomitant Use Of Votrient And Simvastatin

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy trials with VOTRIENT, ALT greater than 3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

7.5       Drugs That Raise Gastric Ph

In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and C_max). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2-receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3)].

8.1       Pregnancy

Risk Summary

Based on animal reproduction studies and its mechanism of action, VOTRIENT can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose of 800 mg (based on AUC) [see Data]. Advise pregnant women or women of childbearing potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In a female fertility and early embryonic development study, female rats were administered oral pazopanib at least 15 days prior to mating and for 6 days after mating, which resulted in increased pre-implantation loss and early resorptions at dosages greater than or equal to 30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8-fold the AUC at the MRHD of 800 mg/day). Postimplantation loss, embryolethality, and decreased fetal body weights were noted in females administered doses greater than or equal to 10 mg/kg/day (approximately 0.3-fold the AUC at the MRHD of 800 mg/day).

In embryo-fetal developmental toxicity studies in rats and rabbits, oral pazopanib was administered to pregnant animals during organogenesis. In rats, dose levels of greater than or equal to 3 mg/kg/day (approximately 0.1-fold the AUC at the MRHD of 800 mg/day) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch), incomplete or absent ossification, increases in postimplantation loss, embryolethality and reduced fetal body weight. In rabbits, maternal toxicity, increased postimplantation loss and abortion were observed at doses greater than or equal to 30 mg/kg/day (approximately 0.007 - fold the AUC at the MRHD of 800 mg/day). In addition, severe maternal body weight loss and 100% litter loss were observed at doses greater than or equal to 100 mg/kg/day (0.02-fold the AUC at the MRHD of 800 mg/day), while fetal weight was reduced at doses greater than or equal to 3 mg/kg/day (AUC not calculated).

8.2       Lactation

Risk Summary

There is no information regarding the presence of pazopanib or its metabolites in human milk, or their effects on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breast-fed infants from VOTRIENT, advise a lactating woman not to breastfeed during treatment with VOTRIENT and for 2 weeks after the final dose.

8.3       Females And Males Of Reproductive Potential

Pregnancy Testing

Based on animal reproduction studies and its mechanism of action, VOTRIENT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Verify pregnancy status of females of reproductive potential prior to starting treatment with VOTRIENT.

Contraception

Females

VOTRIENT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of VOTRIENT.

Males

To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with VOTRIENT and for at least 2 weeks after the last dose.

Infertility

Based on findings from animal studies, VOTRIENT may impair fertility in females and males of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)].

8.4       Pediatric Use

The safety and effectiveness of VOTRIENT in pediatric patients have not been established.

In rats, weaning occurs at Day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from Day 9 through Day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver, and heart at approximately 0.1fold the AUC in adults at the maximum recommended human dose (MRHD) of 800 mg/day of VOTRIENT. At approximately 0.4 fold the AUC in adults at the MRHD of 800 mg/day, pazopanib administration resulted in mortality.

In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses greater than or equal to 3 mg/kg/day (approximately 0.07 fold the AUC at the MRHD of 800 mg/day). Doses of 300 mg/kg/day (approximately 0.8 fold the AUC at the MRHD of 800 mg/day) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken, and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses greater than or equal to 30 mg/kg/day (approximately 0.35 fold the AUC at the MRHD of 800 mg/day) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning Day 21 postpartum (postweaning). In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses greater than or equal to 30 mg/kg (approximately 0.1 to 0.2 fold the AUC at the MRHD of 800 mg/day). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 fold the AUC at the MRHD of 800 mg/day, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.17)].

8.5       Geriatric Use

In pooled clinical trials with VOTRIENT, 30% (618/2,080) of patients were aged greater than or equal to 65 years. Patients aged greater than or equal to 65 years had an increase in ALT elevations of greater than 3 X ULN compared to patients aged less than 65 years (23% versus 18%) [see Warnings and Precautions (5.1)]. In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged greater than or equal to 65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. In the STS trials, 24% (93/382) of patients were aged greater than or equal to 65 years. Patients aged greater than or equal to 65 years had increased Grade 3 or 4 fatigue (19% versus 12% for less than 65), hypertension (10% versus 6%), decreased appetite (11% versus 2%), and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6       Hepatic Impairment

In clinical trials for VOTRIENT, patients with total bilirubin less than or equal to 1.5 X ULN and AST and ALT less than or equal to 2 X ULN were included [see Warnings and Precautions (5.1)].

An analysis of data from a pharmacokinetic trial of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment (either total bilirubin within normal limit [WNL] with ALT greater than ULN or bilirubin greater than 1 X to 1.5 X ULN regardless of the ALT value). The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin greater than 1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state C_max and AUC_(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin greater than 3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3)].

8.7       Renal Impairment

Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) were included in clinical trials for VOTRIENT.

There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since less than 4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30- to 150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10       Overdosage

Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively.

Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. 

Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

11       Description

VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C₂₁H₂₃N₇O₂S•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure:

The following chemical structure for VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C21H23N7O2S•HCl and a molecular weight of 473.99. - votrient 02

Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

Tablets of VOTRIENT are for oral administration. Each 200-mg tablet of VOTRIENT contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base.

The inactive ingredients of VOTRIENT are: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide. 

12.1       Mechanism Of Action

Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.

12.2       Pharmacodynamics

Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations.

The QT prolongation potential of pazopanib was assessed in a randomized, blinded, parallel trial (N=96) using moxifloxacin as a positive control. Pazopanib 800 mg was dosed under fasting conditions on Days 2 to 8 and 1,600 mg was dosed on Day 9 after a meal in order to increase exposure to pazopanib and its metabolites. No large changes (i.e., greater than 20 msec) in QTc interval following the treatment of pazopanib were detected in this QT trial. The trial was not able to exclude small changes (less than 10 msec) in QTc interval, because assay sensitivity below this threshold (less than 10 msec) was not established in this trial [see Warnings and Precautions (5.2)].

12.3       Pharmacokinetics

Absorption: Pazopanib is absorbed orally with median time to achieve peak concentrations of 2 to 4 hours after the dose. Daily dosing at 800 mg results in geometric mean AUC and C_max of 1,037 mcg•h/mL and 58.1 mcg/mL (equivalent to 132 μM), respectively. There was no consistent increase in AUC or C_max at pazopanib doses above 800 mg. 

Administration of a single pazopanib 400-mg crushed tablet increased AUC_(0-72) by 46% and C_max by approximately 2-fold and decreased T_max by approximately 2 hours compared with administration of the whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption are increased after administration of the crushed tablet relative to administration of the whole tablet. Therefore, due to this potential for increased exposure, tablets of VOTRIENT should not be crushed.

Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and C_max. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal [see Dosage and Administration (2.1)].

Distribution: Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 mcg/mL. In vitro studies suggest that pazopanib is a substrate for P-gp and BCRP.

Metabolism: In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.

Elimination: Pazopanib has a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via feces with renal elimination accounting for less than 4% of the administered dose.

Hepatic Impairment: Mild hepatic impairment was defined as either total bilirubin WNL with ALT greater than ULN or bilirubin greater than 1 X to 1.5 X ULN regardless of the ALT value. The median steady-state pazopanib C_max and AUC_(0-24) after a once-daily dose of 800 mg/day in patients (N=12) with mild impairment were 34 mcg/mL (range: 11 to 104) and 774 mcg•h/mL (range: 215 to 2,034), respectively. These were in a similar range as the median steady-state pazopanib C_max and AUC_(0-24) in patients (N=18) with no hepatic impairment (52 mcg/mL, range: 17 to 86 and 888 mcg•h/mL, range: 346 to 1,482, respectively) [see Dosage and Administration (2.2)].

Moderate hepatic impairment was defined as total bilirubin greater than 1.5 X to 3 X ULN regardless of the ALT value. The maximum tolerated pazopanib dose in patients with moderate impairment was 200 mg once daily. The median (N = 11) steady-state C_max with that regimen was 22 mcg/mL (range: 4.2 to 33), and the median AUC_(0-24) was 257 mcg•h/mL (range: 66 to 488). These values were approximately 43% and 29% of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function (N = 18) [see Dosage and Administration (2.2)]. 

Severe hepatic impairment was defined as total bilirubin greater than 3 X ULN regardless of the ALT value. Median exposures in patients with severe hepatic impairment receiving 200 mg once daily (N = 14) were unexpectedly lower than those observed in patients with moderate hepatic impairment receiving 200 mg once daily. The median steady-state C_max was 9.4 mcg/mL (range: 2.4 to 24), and the median AUC_(0-24) was 131 mcg•h/mL (range: 47 to 473). These values were approximately 18% and 15% of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function. Despite the observed concentrations, the dose of 200 mg was not well tolerated in patients with severe hepatic impairment. Use of VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

Drug Interactions: Coadministration of multiple doses of oral pazopanib 400 mg with multiple doses of oral ketoconazole 400 mg (strong CYP3A4/P-gp inhibitor) resulted in a 1.7-fold increase in the AUC_(0-24) and a 1.5-fold increase in the C_max of pazopanib compared with pazopanib administered alone. Concurrent administration of a single dose of pazopanib eye drops with ketoconazole in healthy volunteers resulted in a 2-fold and 1.5-fold increase in mean AUC(0-t) and C_max values, respectively [see Dosage and Administration (2.2), Drug Interactions (7.1)].

Administration of 1,500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, P-gp, and BCRP, with 800 mg pazopanib resulted in an approximately 50% to 60% increase in mean pazopanib AUC(0-24) and C_max compared with administration of 800 mg pazopanib alone.

In vitro studies with human liver microsomes showed that pazopanib inhibited the activities of CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human pregnane X receptor (PXR) assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30% in the mean AUC and C_max of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe substrate). Coadministration of pazopanib 800 mg once daily and paclitaxel 80 mg/m² (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and C_max, respectively [see Drug Interactions (7.3)].

Pazopanib exhibits pH-dependent solubility. In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a PPI, decreased the exposure of pazopanib by approximately 40% (AUC and C_max).

In vitro studies also showed that pazopanib inhibits UGT1A1 and organic anion-transporting polypeptide (OATP1B1) with IC₅₀s of 1.2 and 0.79 μM, respectively. Pazopanib may increase concentrations of drugs eliminated by UGT1A1 and OATP1B1.

12.5       Pharmacogenomics

Pazopanib can increase serum total bilirubin levels [see Warnings and Precautions (5.1)]. In vitro studies showed that pazopanib inhibits UGT1A1, which glucuronidates bilirubin for elimination. A pooled pharmacogenetic analysis of 236 Caucasian patients evaluated the TA-repeat polymorphism of UGT1A1 and its potential association with hyperbilirubinemia during pazopanib treatment. In this analysis, the (TA)7/(TA)7 genotype (UGT1A1*28/*28) (underlying genetic susceptibility to Gilbert’s syndrome) was associated with a statistically significant increase in the incidence of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.

In a pooled pharmacogenetic analysis of data from 31 clinical studies of pazopanib administered as either monotherapy or in combination with other agents, ALT greater than 3 X ULN (NCI CTC Grade 2) occurred in 32% (42/133) of HLA-B*57:01 allele carriers and in 19% (397/2101) of non-carriers and ALT greater than 5 X ULN (NCI CTC Grade 3) occurred in 19% (25/133) of HLA-B*57:01 allele carriers and in 10% (213/2101) of non-carriers. In this dataset, 6% (133/2234) of the patients carried the HLA-B*57:01 allele. Liver function should be monitored in all subjects receiving pazopanib, regardless of genotype [see Warnings and Precautions (5.1)].

13.1       Carcinogenesis, Mutagenesis, Impairment Of Fertility

The carcinogenic potential of pazopanib was evaluated in CD-1 mice, and Sprague-Dawley rats. Administration of pazopanib to mice for 2 years did not result in increased incidence of neoplasms at doses up to 100 mg/kg/day (approximately 1.4 -fold the AUC at the maximum recommended human dose (MRHD) of 800 mg/day). Administration of pazopanib to rats for 2 years resulted in findings of duodenal adenocarcinoma in males at 30 mg/kg/day (approximately 0.3 -fold the AUC at the MRHD of 800 mg/day) and in females at greater than or equal to 10 mg/kg/day (approximately 0.3 -fold the AUC at the MRHD of 800 mg/day). The human relevance of these neoplastic findings is unclear.  

Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. 

In an oral female fertility and early embryonic development study, female rats were administered pazopanib at least 15 days prior to mating, and for 6 days after mating. Pazopanib did affect fertility in female rats. Reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages greater than or equal to 30 mg/kg/day (approximately 0.4 -fold the AUC at the MRHD of 800 mg/day). Decreased corpora lutea and increased cysts were noted in mice given greater than or equal to 100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given greater than or equal to 300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 -fold the AUC at the MRHD of 800 mg/day). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 -fold the AUC at the MRHD of 800 mg/day).

Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses greater than or equal to 3 mg/kg/day, epididymal sperm concentrations at doses greater than or equal to 30 mg/kg/day, and sperm motility at greater than or equal to 100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of greater than or equal to 30 mg/kg/day (approximately 0.35 -fold the AUC at the MRHD of 800 mg/day); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

14.1       Renal Cell Carcinoma

The safety and efficacy of VOTRIENT in RCC were evaluated in a randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial. Patients (N = 435) with locally advanced and/or metastatic RCC who had received either no prior therapy or one prior cytokine-based systemic therapy were randomized (2:1) to receive VOTRIENT 800 mg once daily or placebo once daily. The primary objective of the trial was to evaluate and compare the 2 treatment arms for progression-free survival (PFS); the secondary endpoints included overall survival (OS), overall response rate (RR), and duration of response.

Of the total of 435 patients enrolled in this trial, 233 patients had no prior systemic therapy (treatment-naïve subgroup) and 202 patients received one prior IL-2 or INFα-based therapy (cytokine-pretreated subgroup). The baseline demographic and disease characteristics were balanced between the arms receiving VOTRIENT and placebo. The majority of patients were male (71%) with a median age of 59 years. Eighty-six percent of patients were Caucasian, 14% were Asian, and less than 1% were other. Forty-two percent were ECOG performance status 0 and 58% were ECOG performance status 1. All patients had clear cell histology (90%) or predominantly clear cell histology (10%). Approximately 50% of all patients had 3 or more organs involved with metastatic disease. The most common metastatic sites at baseline were lung (74%), lymph nodes (56%), bone (27%), and liver (25%).

A similar proportion of patients in each arm were treatment-naïve and cytokine-pretreated (see Table 5). In the cytokine-pretreated subgroup, the majority (75%) had received interferon-based treatment. Similar proportions of patients in each arm had prior nephrectomy (89% and 88% for VOTRIENT and placebo, respectively).

The analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire trial population. Efficacy results are presented in Table 5 and Figure 1.

Figure 1. Kaplan-Meier Curve for Progression-free Survival in RCC by Independent Assessment for the Overall Population (Treatment-naïve and Cytokine Pre-treated Populations) - votrient 03

At the protocol-specified final analysis of OS, the median OS was 22.9 months for patients randomized to VOTRIENT and 20.5 months for the placebo arm [HR = 0.91 (95% CI: 0.71, 1.16)]. The median OS for the placebo arm includes 79 patients (54%) who discontinued placebo treatment because of disease progression and crossed over to treatment with VOTRIENT. In the placebo arm, 95 (66%) patients received at least one systemic anticancer treatment after progression compared with 88 (30%) patients randomized to VOTRIENT.

14.2       Soft Tissue Sarcoma

The safety and efficacy of VOTRIENT in patients with STS were evaluated in a randomized, double-blind, placebo-controlled, multicenter trial. Patients (N = 369) with metastatic STS who had received prior chemotherapy, including anthracycline treatment, or were unsuited for such therapy, were randomized (2:1) to receive VOTRIENT 800 mg once daily or placebo. Patients with gastrointestinal stromal tumors (GIST) or adipocytic sarcoma were excluded from the trial. Randomization was stratified by the factors of WHO performance status (WHO PS) 0 or 1 at baseline and the number of lines of prior systemic therapy for advanced disease (0 or 1 versus 2+). Progression-free survival (PFS) was assessed by independent radiological review. Other efficacy endpoints included overall survival (OS), overall response rate, and duration of response.

The majority of patients were female (59%) with a median age of 55 years. Seventy-two percent of patients were Caucasian, 22% were Asian, and 6% were other. Forty-three percent of patients had leiomyosarcoma, 10% had synovial sarcoma, and 47% had other soft tissue sarcomas. Fifty-six percent of patients had received 2 or more lines of prior systemic therapy and 44% had received 0 or 1 lines of prior systemic therapy. The median duration of treatment was 4.5 months for patients on the pazopanib arm and 1.9 months for patients on the placebo arm.

Efficacy results are presented in Table 6 and Figure 2.

Figure 2. Kaplan-Meier Curve for Progression-free Survival in STS by Independent Assessment for the Overall Population - votrient 04

At the protocol-specified final analysis of OS, the median OS was 12.6 months for patients randomized to VOTRIENT and 10.7 months for the placebo arm [HR = 0.87 (95% CI: 0.67, 1.12)].

16      How Supplied/Storage And Handling

The 200-mg tablets of VOTRIENT are modified capsule-shaped, gray, film-coated with GS JT debossed on one side and are available in:

Bottles of 120 tablets: NDC 0078-0670-66

Store at room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17       Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide). The Medication Guide is contained in a separate leaflet that accompanies the product. 

However, inform patients of the following:

• Hepatic Toxicity and Hepatic Impairment: Inform patients that periodic laboratory testing will be performed. Advise patients to report signs and symptoms of liver dysfunction to their healthcare provider right away [see Warnings and Precautions (5.1)].
  
• QT Prolongation and Torsades de Pointes: Inform patients that ECG monitoring may be performed. Advise patients to inform their physicians of concomitant medications [see Warnings and Precautions (5.2)].
  
• Interstitial Lung Disease (ILD)/Pneumonitis: Advise patients to report pulmonary signs or symptoms indicative of ILD or pneumonitis [see Warnings and Precautions (5.9)]. 
  
• Cardiac Dysfunction: Advise patients to report hypertension or signs and symptoms of congestive heart failure [see Warnings and Precautions (5.3)].
  
• Hemorrhagic Events: Advise patients to report unusual bleeding [see Warnings and Precautions (5.4)].
  
• Arterial Thrombotic Events: Advise patients to report signs or symptoms of an arterial thrombosis [see Warnings and Precautions (5.5)].
  
• Pneumothorax and Venous Thromboembolic Events: Advise patients to report new onset of dyspnea, chest pain, or localized limb edema [see Warnings and Precautions (5.6), Adverse Reactions (6.1)].
  
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances) [see Warnings and Precautions (5.10)].
  
• Hypertension: Advise patients to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting [see Warnings and Precautions (5.11)].
  
• Gastrointestinal Perforation or Fistula: Advise patients to report signs and symptoms of a GI perforation or fistula [see Warnings and Precautions (5.8)].
  
• Wound healing: Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery [see Warnings and Precautions (5.12)].
  
• Hypothyroidism and Proteinuria: Inform patients that thyroid function testing and urinalysis will be performed during treatment [see Warnings and Precautions (5.13, 5.14)].
  
•  Infection: Advise patients to promptly report any signs or symptoms of infection [see Warnings and Precautions (5.15)].
  
• Embryo-Fetal Toxicity: Advise female patients to inform their healthcare provider of a known or suspected pregnancy during treatment with VOTRIENT. Inform female patients of the risk to a fetus and the potential loss of the pregnancy [see Warnings and Precautions (5.18) and Use in Specific Populations (8.1)].
  
• Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of VOTRIENT. Advise male patients with female partners of reproductive potential to use condoms during treatment with VOTRIENT and for at least 2 weeks after the last dose [see Warnings and Precautions (5.18) and Use in Specific Populations (8.3)].
  
• Gastrointestinal Adverse Reactions: Advise patients on how to manage nausea, vomiting, and diarrhea and to notify their healthcare provider if moderate to severe vomiting or diarrhea occurs or if there is a decrease in oral intake [see Adverse Reactions (6.1)].
  
• Drug Interactions: Advise patients to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements [see Drug Interactions (7)].
  
• Depigmentation: Advise patients that depigmentation of the hair or skin may occur during treatment with VOTRIENT [see Adverse Reactions (6.1)].
  
• Dosage and Administration: Advise patients to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal) [see Dosage and Administration (2.1)].

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

© Novartis

T2017-66
May 2017