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...+
VOTRIENT® (pazopanib) tablets is indicated for the treatment of adults with advanced renal cell carcinoma (RCC).
Important Safety Information for VOTRIENT® (pazopanib) tablets
Hepatic Toxicity: Severe and fatal hepatotoxicity has occurred. Patients older than 65 years are at an increased risk. Increases in serum transaminase levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome. In patients with preexisting moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.
QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (eg, calcium, magnesium, potassium) within the normal range should be performed. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating VOTRIENT and during treatment.
Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF), has occurred. 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 a randomized RCC trial of VOTRIENT compared with sunitinib, myocardial dysfunction occurred in 13% of the 362 patients on VOTRIENT who had baseline and postbaseline LVEF measurements. CHF occurred in 0.5% of patients. Monitor blood pressure (BP), and manage as appropriate. Monitor for clinical signs or symptoms of CHF. 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.
Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% of 586 patients in the RCC trials, and cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. In the randomized RCC trial, 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 (GI), and genitourinary hemorrhage. One percent of patients treated with VOTRIENT died from hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant GI hemorrhage in the past 6 months. Withhold VOTRIENT and resume at a reduced dose, or permanently discontinue, based on severity of hemorrhagic events.
Arterial Thromboembolic Events: In the RCC trials, fatal arterial thromboembolic events occurred in 0.3% of 586 patients. In the randomized RCC trial, 2% of 290 patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% had a cerebrovascular accident, and 1% had an event of transient ischemic attack. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the past 6 months. Permanently discontinue VOTRIENT in case of an arterial thromboembolic event.
Venous Thromboembolic Events (VTEs): VTEs, including venous thrombosis and fatal pulmonary embolus (PE), have occurred. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT. Monitor for signs and symptoms of VTE and PE. Withhold VOTRIENT and then resume at the same dose, or permanently discontinue, based on severity of VTE.
Thrombotic Microangiopathy (TMA): 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.
GI Perforation and Fistula: Across clinical trials, GI perforation or fistula was reported in 0.9% of 586 patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients. Monitor for signs and symptoms of GI perforation or fistula. Withhold VOTRIENT in case of grade 2 or grade 3 GI fistula, and resume based on medical judgment. Permanently discontinue VOTRIENT in case of GI perforation or grade 4 GI fistula.
Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis, which can be fatal, has been reported in 0.1% of patients in the clinical trials treated with VOTRIENT. Monitor patients for ILD/pneumonitis, and discontinue VOTRIENT if symptoms of ILD or pneumonitis develop.
Posterior Reversible Encephalopathy Syndrome (PRES): PRES has been reported in patients who received VOTRIENT and may be fatal. PRES is a neurologic disorder, which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension (HTN) may be present. Confirm diagnosis of PRES by magnetic resonance imaging.
Hypertension: HTN, including hypertensive crisis, has occurred in clinical trials. HTN occurs early in the course of treatment (approximately 40% of cases occurred by Day 9, and 90% of cases occurred in the first 18 weeks). Do not initiate VOTRIENT in patients with uncontrolled HTN. Optimize BP prior to initiating VOTRIENT. Monitor BP as clinically indicated, and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce VOTRIENT, or permanently discontinue, based on severity of HTN. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of HTN.
Risk of Impaired Wound Healing: Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, VOTRIENT has the potential to adversely affect wound healing. Withhold VOTRIENT at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing occurs. The safety of resuming VOTRIENT after wound healing complications have resolved has not been established.
Hypothyroidism: Hypothyroidism was reported in 7% of 290 patients treated with VOTRIENT in the randomized RCC trial. Monitor thyroid tests at baseline, during treatment, and as clinically indicated. Manage hypothyroidism as appropriate.
Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction (AR) in 9% of 290 patients receiving VOTRIENT, leading to treatment discontinuation in 2 patients. Perform baseline and periodic urinalysis during treatment with follow-up measurement of 24-hour urine protein as clinically indicated. Withhold VOTRIENT, then resume at a reduced dose, or permanently discontinue, based on severity of proteinuria. Permanently discontinue in patients with nephrotic syndrome.
Tumor Lysis Syndrome (TLS): Cases of TLS, including fatal cases, have been reported in patients with RCC treated with VOTRIENT. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis, and treat as clinically indicated.
Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms, and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT.
Increased Toxicity With Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, GI hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.
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. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early postnatal development, and resulted in toxicity to the lungs, liver, heart, and kidney, and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.
Embryo-Fetal Toxicity: VOTRIENT can cause fetal harm when administered to a pregnant woman based on animal reproduction studies and its mechanism of action. 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.
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. Advise males (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.
Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their health care 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% of 181 patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.
Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax.
Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% of 280 patients treated with VOTRIENT and in 11% of 144 patients on the placebo arm.
Drug Interactions: Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice.
Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.
Concomitant treatment with strong inhibitors of P-glycoprotein (PgP) or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib.
CYP Substrates: 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 ARs.
Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. Insufficient data exist to assess the risk of concomitant administration of alternative statins and VOTRIENT.
Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate antacid and pazopanib dosing by several hours.
Adverse Reactions in the Randomized RCC Trial: A dose interruption was required for 42% of patients on VOTRIENT. The VOTRIENT dose was reduced for 36% of patients.
The most common ARs (≥20%) for VOTRIENT vs placebo were diarrhea (52% vs 9%), HTN (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).
Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT vs placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%).
In a pooled analysis of VOTRIENT clinical trials, East Asian patients had a higher frequency of neutropenia, thrombocytopenia, and palmar-plantar erythrodysesthesia syndrome than non-East Asian patients. (See Adverse Reactions, Section 6.1, in full Prescribing Information.)
Please see full Prescribing Information, including Boxed WARNING, and Medication Guide.