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Sutent

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Sutent

Side Effects
Interactions

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*

Adverse Reaction, n (%) GIST
SUTENT
(n=202)
Placebo
(n=102)
All Grades Grade 3/4 All Grades Grade 3/4
Any 114 (56) 52 (51)
Gastrointestinal
  Diarrhea 81 (40) 9 (4) 27 (27) 0 (0)
  Mucositis/stomatitis 58 (29) 2 (1) 18 (18) 2 (2)
  Constipation 41 (20) 0 (0) 14 (14) 2 (2)
Cardiac
  Hypertension 31 (15) 9 (4) 11 (11) 0 (0)
Dermatology
  Skin discoloration 61 (30) 0 (0) 23 (23) 0 (0)
  Rash 28(14) 2 (1) 9 (9) 0 (0)
  Hand-foot syndrome 28 (14) 9 (4) 10 (10) 3 (3)
Neurology
  Altered taste 42 (21) 0 (0) 12 (12) 0 (0)
Musculoskeletal
  Myalgia/limb pain 28(14) 1 (1) 9 (9) 1 (1)
Metabolism/Nutrition
  Anorexiaa 67 (33) 1 (1) 30 (29) 5 (5)
  Asthenia 45 (22) 10 (5) 11 (11) 3 (3)
*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
a Includes decreased appetite

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*

Laboratory Parameter, n (%) GIST
SUTENT
(n=202)
Placebo
(n=102)
All Grades* Grade 3/4*a All Grades* Grade 3/4*b
Any 68 (34) 22 (22)
Gastrointestinal
  AST / ALT 78 (39) 3 (2) 23 (23) 1 (1)
  Lipase 50 (25) 20 (10) 17 (17) 7 (7)
  Alkaline phosphatase 48 (24) 7 (4) 21 (21) 4 (4)
  Amylase 35 (17) 10 (5) 12 (12) 3 (3)
  Total bilirubin 32 (16) 2 (1) 8 (8) 0 (0)
  Indirect bilirubin 20 (10) 0 (0) 4 (4) 0 (0)
Cardiac
  Decreased LVEF 22 (11) 2 (1) 3 (3) 0 (0)
Renal/Metabolic
  Creatinine 25(12) 1 (1) 7 (7) 0 (0)
  Potassium decreased 24 (12) 1 (1) 4 (4) 0 (0)
  Sodium increased 20 (10) 0 (0) 4 (4) 1 (1)
Hematology
  Neutrophils 107 (53) 20 (10) 4 (4) 0 (0)
  Lymphocytes 76 (38) 0 (0) 16 (16) 0 (0)
  Platelets 76 (38) 10 (5) 4 (4) 0 (0)
  Hemoglobin 52 (26) 6 (3) 22 (22) 2 (2)
LVEF=Left ventricular ejection fraction
*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
a Grade 4 laboratory abnormalities in patients on SUTENT included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%).
b Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).

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 treatment-related 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-Na´ve 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*

Adverse Reaction, n (%) Treatment-Naive RCC
SUTENT
(n=375)
IFN-α
(n=360)
All Grades Grade 3/4a All Grades Grade 3/4b
Any 372 (99) 290 (77) 355 (99) 197 (55)
Constitutional
  Fatigue 233 (62) 55 (15) 202 (56) 54 (15)
  Asthenia 96 (26) 42 (11) 81 (22) 21 (6)
  Fever 84 (22) 3 (1) 134 (37) 1 ( < 1)
  Weight decreased 60 (l6) 1 ( < 1) 60 (17) 3 (1)
  Chills 53 (14) 3 (1) 111 (31) 0 (0)
  Chest Pain 50 (13) 7 (2) 24 (7) 3 (1)
  Influenza like illness 18 (5) 0 (0) 54 (15) 1 ( < 1)
Gastrointestinal
  Diarrhea 246 (66) 37 (10) 76 (21) 1 ( < 1)
  Nausea 216 (58) 21 (6) 147 (41) 6 (2)
  Mucositis/stomatitis 178 (47) 13 (3) 19 (5) 2 ( < 1)
  Vomiting 148 (39) 19 (5) 62 (17) 4 (1)
  Dyspepsia 128 (34) 8 (2) 16 (4) 0 (0)
  Abdominal painc 113 (30) 20 (5) 42 (12) 5 (1)
  Constipation 85 (23) 4 (1) 49 (14) 1 ( < 1)
  Dry mouth 50 (13) 0 (0) 27 (7) 1 ( < 1)
  GERD/reflux esophagitis 47 (12) 1 ( < 1) 3 (1) 0(0)
  Flatulence 52 (14) 0 (0) 8 (2) 0 (0)
  Oral pain 54 (14) 2 ( < 1) 2 (1) 0 (0)
  Glossodynia 40 (11) 0 (0) 2 (1) 0 (0)
  Hemorrhoids 38 (10) 0 (0) 6 (2) 0 (0)
Cardiac
  Hypertension 127 (34) 50 (13) 13 (4) 1 ( < 1)
  Edema, peripheral 91 (24) 7 (2) 17 (5) 2 (1)
  Ejection fraction decreased 61 (16) 10 (3) 19 (5) 6 (2)
Dermatology
  Rash 109 (29) 6 (2) 39 (11) 1 ( < 1)
  Hand-foot syndrome 108 (29) 32 (8) 3 (1) 0 (0)
  Skin discoloration/ yellow skin 94 (25) 1 ( < 1) 0 (0) 0 (0)
  Dry skin 85 (23) 1 ( < 1) 26 (7) 0 (0)
  Hair color changes 75 (20) 0 (0) 1 ( < 1) 0 (0)
  Alopecia 51 (14) 0 (0) 34 (9) 0 (0)
  Erythema 46 (12) 2 ( < 1) 5 (1) 0 (0)
  Pruritus 44 (12) 1 ( < 1) 24 (7) 1 ( < 1)
Neurology
  Altered tasted 178 (47) 1 ( < 1) 54 (15) 0 (0)
  Headache 86 (23) 4 (1) 69 (19) 0 (0)
  Dizziness 43 (11) 2 ( < 1) 50 (14) 2 (1)
Musculoskeletal
  Back pain 105 (28) 19 (5) 52 (14) 7 (2)
  Arthralgia 111 (30) 10 (3) 69 (19) 4 (1)
  Pain in extremity/ limb discomfort 150 (40) 19 (5) 107 (30) 7 (2)
Endocrine
  Hypothyroidism 61 (16) 6 (2) 3 (1) 0 (0)
Respiratory
  Cough 100 (27) 3 (1) 51(14) 1 ( < 1)
  Dyspnea 99 (26) 24 (6) 71 (20) 15 (4)
  Nasopharyngitis 54 (14) 0 (0) 8 (2) 0 (0)
  Oropharyngeal Pain 51(14) 2 ( < 1) 9 (2) 0 (0)
  Upper respiratory tract infection 43 (11) 2 ( < 1) 9 (2) 0 (0)
Metabolism/Nutrition
  Anorexiae 182 (48) 11 (3) 153 (42) 7 (2)
Hemorrhage/Bleeding
  Bleeding, all sites 140 (37) 16 (4)f 35 (10) 3 (1)
Psychiatric
  Insomnia 57 (15) 3 ( < 1) 37 (10) 0 (0)
  Depressiong 40 (11) 0 (0) 51(14) 5 (1)
*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
a Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia ( < 1%), dyspnea ( < 1%), asthenia ( < 1%), fatigue ( < 1%), limb pain ( < 1%) and rash ( < 1%).
b Grade 4 ARs in patients on IFN-α included dyspnea (1%), fatigue (1%), abdominal pain ( < 1%) and depression ( < 1%).
c Includes flank pain
d Includes ageusia, hypogeusia and dysgeusia
e Includes decreased appetite
f Includes one patient with Grade 5 gastric hemorrhage
g Includes depressed mood

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

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

Laboratory Parameter, n (%) Treatment-Naive RCC
SUTENT
(n=375)
IFN-α
(n=360)
All Grades* Grade 3/4*a All Grades* Grade 3/4*b
Gastrointestinal
  AST 211 (56) 6 (2) 136 (38) 8 (2)
  ALT 192 (51) 10 (3) 144 (40) 9 (2)
  Lipase 211 (56) 69 (18) 165(46) 29 (8)
  Alkaline phosphatase 171 (46) 7 (2) 132 (37) 6 (2)
  Amylase 130 (35) 22 (6) 114 (32) 12 (3)
  Total bilirubin 75 (20) 3 (1) 8 (2) 0 (0)
  Indirect bilirubin 49(13) 4 (1) 3 (1) 0 (0)
Renal/Metabolic
  Creatinine 262 (70) 2 (<1) 183 (51) 1 (<1)
  Creatine kinase 183 (49) 9 (2) 40 (11) 4 (1)
  Uric acid 173 (46) 54 (14) 119 (33) 29 (8)
  Calcium decreased 156 (42) 4 (1) 145 (40) 4 (1)
  Phosphorus 116 (31) 22 (6) 87 (24) 23 (6)
  Albumin 106 (28) 4 (1) 72 (20) 0 (0)
  Glucose increased 86 (23) 21 (6) 55 (15) 22 (6)
  Sodium decreased 75 (20) 31 (8) 55 (15) 13 (4)
  Glucose decreased 65 (17) 0 (0) 43 (12) 1 (<1)
  Potassium increased 61 (16) 13 (3) 61 (17) 15 (4)
  Calcium increased 50 (13) 2 (<1) 35 (10) 5 (1)
  Potassium decreased 49 (13) 3 (1) 7 (2) 1 (<1)
  Sodium increased 48 (13) 0 (0) 38 (10) 0 (0)
Hematology
  Neutrophils 289 (77) 65 (17) 178(49) 31 (9)
  Hemoglobin 298 (79) 29 (8) 250 (69) 18 (5)
  Platelets 255 (68) 35 (9) 85 (24) 2 (1)
  Lymphocytes 256 (68) 66 (18) 245 (68) 93 (26)
  Leukocytes 293 (78) 29 (8) 202 (56) 8 (2)
*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
a Grade 4 laboratory abnormalities in patients on SUTENT included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT ( < 1%), creatine kinase ( < 1%), creatinine ( < 1%), glucose increased ( < 1%), calcium decreased ( < 1%), phosphorous ( < 1%), potassium increased ( < 1%), and sodium decreased ( < 1%).
b Grade 4 laboratory abnormalities in patients on IFN-α included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase ( < 1%), calcium increased ( < 1%), glucose decreased ( < 1%), potassium increased ( < 1%), and hemoglobin ( < 1%).

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*

Adverse Reaction, n (%) pNET
SUTENT
(n=83)
Placebo
(n=82)
All Grades Grade 3/4a All Grades Grade 3/4
Any 82 (99) 45 (54) 78 (95) 41 (50)
Constitutional
  Asthenia 28 (34) 4 (5) 22 (27) 3 (4)
  Fatigue 27(33) 4 (5) 22 (27) 7 (9)
  Weight decreased 13 (16) 1(1) 9 (11) 0 (0)
Gastrointestinal
  Diarrhea 49 (59) 4 (5) 32 (39) 2 (2)
  Stomatitis/oral 40 (48) 5 (6) 15 (18) 0 (0)
  Syndromesb Nausea 37 (45) 1 (1) 24 (29) 1 (1)
  Abdominal painc 32 (39) 4 (5) 28 (34) 8 (10)
  Vomiting 28 (34) 0 (0) 25 (31) 2 (2)
  Dyspepsia 12 (15) 0 (0) 5 (6) 0 (0)
Cardiac
  Hypertension 22 (27) 8 (10) 4 (5) 1 (1)
Dermatology
  Hair color changes 24 (29) 1 (1) 1 (1) 0 (0)
  Hand-foot syndrome 19(23) 5 (6) 2 (2) 0 (0)
  Rash 15 (18) 0 (0) 4 (5) 0 (0)
  Dry skin 12 (15) 0 (0) 9 (11) 0 (0)
Neurology
  Dysgeusia 17 (21) 0 (0) 4 (5) 0 (0)
  Headache 15 (18) 0 (0) 11 (13) 1 (1)
Musculoskeletal
  Arthralgia 12 (15) 0 (0) 5 (6) 0 (0)
Psychiatric
  Insomnia 15 (18) 0 (0) 10 (12) 0 (0)
Hemorrhage/Bleeding
  Bleeding eventsd 18(22) 0 (0) 8 (10) 3 (4)
  Epistaxis 17 (21) 1 (1) 4 (5) 0 (0)
*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
a Grade 4 ARs in patients on SUTENT included fatigue (1%).
b Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth.
c Includes abdominal discomfort, abdominal pain, and abdominal pain upper.
d Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.

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

Laboratory Parameter, n (%) pNET
SUTENT Placebo
N All Grades* Grade 3/4*a N All Grades* Grade 3/4*b
Gastrointestinal
  AST increased 82 59 (72) 4 (5) 80 56 (70) 2 (3)
  ALT increased 82 50 (61) 3 (4) 80 44 (55) 2 (3)
  Alkaline phosphatase increased  82 52 (63) 8 (10) 80 56 (70) 9 (11)
  Total bilirubin increased 82 30 (37) 1 (1) 80 22 (28) 3 (4)
  Amylase increased 74 15 (20) 3 (4) 74 7 (10) 1 (1)
  Lipase increased 75 13 (17) 4 (5) 72 8 (11) 3 (4)
Renal/Metabolic
  Glucose increased 82 58 (71) 10 (12) 80 62 (78) 14 (18)
  Albumin decreased 81 33 (41) 1 (1) 79 29 (37) 1 (1)
  Phosphorus decreased 81 29 (36) 6 (7) 77 17 (22) 4 (5)
  Calcium decreased 82 28 (34) 0 (0) 80 15 (19) 0 (0)
  Sodium decreased 82 24 (29) 2 (2) 80 27 (34) 2 (3)
  Creatinine increased 82 22 (27) 4 (5) 80 22 (28) 4 (5)
  Glucose decreased 82 18 (22) 2 (2) 80 12 (15) 3 (4)
  Potassium decreased 82 17 (21) 3 (4) 80 11(14) 0 (0)
  Magnesium decreased 52 10 (19) 0 (0) 39 4 (10) 0 (0)
  Potassium increased 82 15 (18) 1 (1) 80 9 (11) 1 (1)
Hematology
  Neutrophils decreased 82 58 (71) 13 (16) 80 13 (16) 0 (0)
  Hemoglobin decreased 82 53 (65) 0 (0) 80 44 (55) 1 (1)
  Platelets decreased 82 49 (60) 4 (5) 80 12 (15) 0 (0)
  Lymphocytes decreased 82 46 (56) 6 (7) 80 28 (35) 3 (4)
*Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
a Grade 4 laboratory abnormalities in patients on SUTENT included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%) and total bilirubin (1%).
b Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%) and lipase (1%).

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-na´ve 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-na´ve 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 reports ( < 1%), some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). 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-na´ve 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.

Blood and lymphatic system disorders: thrombotic microangiopathy; hemorrhage associated with thrombocytopenia*. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Gastrointestinal disorders: esophagitis

Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis.

Immune system disorders: hypersensitivity reactions, including angioedema.

Infections and infestations: serious infection (with or without neutropenia)*; necrotizing fasciitis, including of the perineum*. The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections,sepsis/septic shock.

Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression*; myopathy and/or rhabdomyolysis with or without acute renal failure*. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

Renal and urinary disorders: renal impairment and/or failure*; proteinuria; rare cases of nephritic syndrome. 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.

Respiratory disorders: pulmonary embolism*.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive dechallenges; erythema multiforme and Stevens-Johnson syndrome.

Vascular disorders: arterial thromboembolic events*. The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction.

*including some fatalities

Read the Sutent (sunitinib malate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

CYP3A4 Inhibitors

Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors [see DOSAGE AND ADMINISTRATION].

CYP3A4 Inducers

CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort) may decrease sunitinib concentrations. St. John’s Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John’s Wort concomitantly. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers [see DOSAGE AND ADMINISTRATION].

In Vitro Studies of CYP Inhibition and Induction

In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

Read the Sutent Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 10/7/2013
This monograph has been modified to include the generic and brand name in many instances.

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