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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 to 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, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, and hypertensive crisis [see WARNINGS AND PRECAUTIONS].

The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies 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 ( ≥ 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 study [see Clinical Studies]. 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 (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in > 10% of patients who received VOTRIENT.

Table 1: Adverse Reactions Occurring in ≥ 10% of Patients who Received VOTRIENT

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

Table 2 presents the most common laboratory abnormalities occurring in > 10% of patients who received VOTRIENT and more commonly ( ≥ 5%) in patients who received VOTRIENT versus placebo.

Table 2: Selected Laboratory Abnormalities Occurring in > 10% of Patients who Received VOTRIENT and More Commonly ( ≥ 5%) in Patients who Received VOTRIENT Versus Placebo

Hepatic Toxicity

In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT > 3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT > 10 X ULN was reported in 4% of patients who received VOTRIENT and in < 1% of patients who received placebo. Concurrent elevation in ALT > 3 X ULN and bilirubin > 2 X ULN in the absence of significant alkaline phosphatase > 3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS.]

Hypertension

In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients ( < 1%) on placebo. The majority of cases of hypertension were manageable with anti-hypertensive agents or dose reductions with 2/290 patients ( < 1%) permanently discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT has been associated with hypertensive crisis in patients with various cancer types including RCC. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See WARNINGS AND PRECAUTIONS.]

QT Prolongation and Torsades de Pointes

In a controlled clinical study with VOTRIENT, QT prolongation ( ≥ 500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 ( < 1%) patients treated with VOTRIENT in the RCC studies. [See WARNINGS AND PRECAUTIONS.]

Arterial Thrombotic Events

In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 ( < 1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See WARNINGS AND PRECAUTIONS.]

Hemorrhagic Events

In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) 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 (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See WARNINGS AND PRECAUTIONS.] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 ( < 1%) patients treated with VOTRIENT.

Hypothyroidism

In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-baseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See WARNINGS AND PRECAUTIONS.]

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 healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Proteinuria

In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. [See WARNINGS AND PRECAUTIONS.]

Lipase Elevations

In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients ( < 1%).

Cardiac Dysfunction

Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients ( < 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) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see DOSAGE AND ADMINISTRATION]. 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. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see DOSAGE AND ADMINISTRATION].

Effects of Pazopanib on CYP Substrates

Results from drug-drug interaction studies 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].

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.]

Effect of Concomitant use of VOTRIENT and Simvastatin

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT > 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]. Alternatively, consider discontinuing simvastatin [see WARNINGS AND PRECAUTIONS]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

Last reviewed on RxList: 4/4/2012
This monograph has been modified to include the generic and brand name in many instances.