SIDE EFFECTS

The data described below reflect exposure to SUTENT in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST [see Clinical Studies], an active-controlled trial (n=375) for the treatment of RCC [see Clinical Studies] or a placebo-controlled trial (n=83) for the treatment of pNET [see Clinical Studies]. The GIST and RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pNET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods.

The most common adverse reactions (≥20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding. The potentially serious adverse reactions of hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function are discussed in WARNINGS AND PRECAUTIONS. Other adverse reactions occurring in GIST, RCC and pNET studies are described below.

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.

Adverse Reactions in GIST Study A

Median duration of blinded study treatment was two cycles for patients on SUTENT (mean 3.0, range 1-9) and one cycle (mean 1.8, range 1-6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on SUTENT and none on placebo. Dose interruptions occurred in 59 patients (29%) on SUTENT and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the SUTENT and placebo groups, respectively.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on SUTENT versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 1: Adverse Reactions Reported in Study A in at Least 10% of GIST Patients who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo*

In the double-blind treatment phase of GIST Study A, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on SUTENT versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on SUTENT versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on SUTENT versus 2 (2%) on placebo.

Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities.

Table 2: Laboratory Abnormalities Reported in Study A in at Least 10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase*

After an interim analysis, the study was unblinded, and patients on the placebo arm were given the opportunity to receive open-label SUTENT treatment [see Clinical Studies]. For 241 patients randomized to the SUTENT arm, including 139 who received SUTENT in both the double-blind and open-label treatment phases, the median duration of SUTENT treatment was 6 cycles (mean 8.5, range 1 - 44). For the 255 patients who ultimately received open-label SUTENT treatment, median duration of study treatment was 6 cycles (mean 7.8, range 1 - 37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatmentrelated adverse reactions experienced by patients receiving SUTENT in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

Adverse Reactions in the Treatment-Naïve RCC Study

The as-treated patient population for the treatment-naive RCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to IFN-α. The median duration of treatment was 11.1 months (range: 0.4 - 46.1) for SUTENT treatment and 4.1 months (range: 0.1 - 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on SUTENT and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on SUTENT and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for SUTENT and 24% for IFN-α. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on SUTENT versus IFN-α, respectively.

Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT versus IFN-α.

Table 3: Adverse Reactions Reported in at Least 10% of Patients with RCC Who Received SUTENT or IFN-α*

Treatment-emergent Grade 3/4 laboratory abnormalities are presented in Table 4.

Table 4: Laboratory Abnormalities Reported in at Least 10% of Treatment-Naïve RCC Patients Who Received SUTENT or IFN-α

Adverse Reactions in the Phase 3 pNET Study

The median number of days on treatment was 139 days (range 13-532 days) for patients on SUTENT and 113 days (range 1-614 days) for patients on placebo. Nineteen patients (23%) on SUTENT and 4 patients (5%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on SUTENT and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on SUTENT and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for SUTENT and 17% for placebo.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on SUTENT versus placebo, respectively. Table 5 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT and reported more commonly in patients receiving SUTENT than in patients receiving placebo.

Table 5: Adverse Reactions Reported in the Phase 3 pNET Study in at Least 10% of Patients who Received SUTENT and More Commonly Than in Patients Given Placebo*

Table 6 provides common (≥10%) treatment-emergent laboratory abnormalities.

Table 6: Laboratory Abnormalities Reported in the Phase 3 pNET Study in at Least 10% of Patients Who Received SUTENT

Venous Thromboembolic Events

Seven patients (3%) on SUTENT and none on placebo in the double-blind treatment phase of GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT.

Thirteen (3%) patients receiving SUTENT for treatment-naïve RCC had venous thromboembolic events reported. Seven (2%) of these patients had pulmonary embolism, one was Grade 2 and six were Grade 4, and six (2%) patients had DVT, including three Grade 3. One patient was permanently withdrawn from SUTENT due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naïve RCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4. One patient (1%) receiving SUTENT for pNET had a venous thromboembolic event reported compared to 5 patients (6%) receiving placebo. The SUTENT patient had Grade 2 thrombosis. Two placebo patients had DVT, one was Grade 3, two placebo patients had pulmonary embolism, one was Grade 3 and one was Grade 4, and one placebo patient had Grade 3 jugular thrombosis.

Reversible Posterior Leukoencephalopathy Syndrome There have been rare (<1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None of these subjects had a fatal outcome to the event. Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Pancreatic and Hepatic Function

If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued. Pancreatitis was observed in 5 (1%) patients receiving SUTENT for treatment-naïve RCC compared to 1 (<1%) patient receiving IFN-α. Pancreatitis was observed in 1 (1%) patient receiving SUTENT for pNET and 1 (1%) patient receiving placebo. Hepatotoxicity was observed in patients receiving SUTENT [See BOXED WARNING and WARNINGS AND PRECAUTIONS].

Post-marketing Experience

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

Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have been reported.

Cases of myopathy and/or rhabdomyolysis with or without acute renal failure, in some cases with fatal outcome, have been reported. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

Thrombotic microangiopathy has been reported in patients on SUTENT. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Cases of fatal hemorrhage associated with thrombocytopenia have been reported.

Pulmonary embolism, in some cases with fatal outcome, has been reported.

Cases of renal impairment and/or failure, in some cases with fatal outcome, have been reported.

Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue SUTENT in patients with nephrotic syndrome.

Hypersensitivity reactions, including angioedema, have been reported.

Cases of fistula formation, sometimes associated with tumor necrosis and/or regression, in some cases with fatal outcome, have been reported.

Cases of arterial thromboembolic events, sometimes fatal, have been reported in patients treated with SUTENT. The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction.

Cases of ONJ have been reported in patients treated with SUTENT [see WARNINGS AND PRECAUTIONS].

Cases of TLS, some fatal, have been reported in patients treated with SUTENT [see WARNINGS AND PRECAUTIONS].

Cases of pulmonary hemorrhage, some fatal, have been reported in patients treated with SUTENT [see WARNINGS AND PRECAUTIONS].

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