sunitinib malate
Dosage Form: capsule
FULL PRESCRIBING INFORMATION
Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported. [See Warnings and Precautions (5.1)]
Indications and Usage for Sutent
Gastrointestinal Stromal Tumor (GIST)
Sutent is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.
Advanced Renal Cell Carcinoma (RCC)
Sutent is indicated for the treatment of advanced renal cell carcinoma.
Advanced Pancreatic Neuroendocrine Tumors (pNET)
Sutent is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.
Sutent Dosage and Administration
Recommended Dose for GIST and RCC
The recommended dose of Sutent for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). Sutent may be taken with or without food.
Recommended Dose for pNET
The recommended dose of Sutent for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. Sutent may be taken with or without food.
Dose Modification
Dose interruption and/or dose modification in 12.5 mg increments or decrements is recommended based on individual safety and tolerability. The maximum dose administered in the Phase 3 pNET study was 50 mg daily.
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. A dose reduction for Sutent to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily should be considered if Sutent must be co-administered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
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. A dose increase for Sutent to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily should be considered if Sutent must be co-administered with a CYP3A4 inducer. If dose is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Dosage Forms and Strengths
12.5 mg capsules
Hard gelatin capsule with orange cap and orange body, printed with white ink "Pfizer" on the cap and "STN 12.5 mg" on the body.
25 mg capsules
Hard gelatin capsule with caramel cap and orange body, printed with white ink "Pfizer" on the cap and "STN 25 mg" on the body.
50 mg capsules
Hard gelatin capsule with caramel top and caramel body, printed with white ink "Pfizer" on the cap and "STN 50 mg" on the body.
Contraindications
None
Warnings and Precautions
Hepatotoxicity
Sutent has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. Sutent should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart Sutent if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.
Safety in patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN has not been established.
Pregnancy
Sutent can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of Sutent should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of Sutent in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Sutent.
Left Ventricular Dysfunction
In the presence of clinical manifestations of congestive heart failure (CHF), discontinuation of Sutent is recommended. The dose of Sutent should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.
Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience. For GIST and RCC, more patients treated with Sutent experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or interferon-α (IFN-α). In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on Sutent and 3/102 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). Nine of 22 GIST patients on Sutent with LVEF changes recovered without intervention. Five patients had documented LVEF recovery following intervention (dose reduction: one patient; addition of antihypertensive or diuretic medications: four patients). Six patients went off study without documented recovery. Additionally, three patients on Sutent had Grade 3 reductions in left ventricular systolic function to LVEF <40%; two of these patients died without receiving further study drug. No GIST patients on placebo had Grade 3 decreased LVEF. In the double-blind treatment phase of GIST Study A, 1 patient on Sutent and 1 patient on placebo died of diagnosed heart failure; 2 patients on Sutent and 2 patients on placebo died of treatment-emergent cardiac arrest.
In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on Sutent and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on Sutent (7%) and seven on IFN-α (2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction was reported in four patients (1%) and CHF in two patients (<1%) who received Sutent.
In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on Sutent and no patients on placebo.
Patients who presented with cardiac events within 12 months prior to Sutent administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from Sutent clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving Sutent. Baseline and periodic evaluations of LVEF should also be considered while these patients are receiving Sutent. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.
QT Interval Prolongation and Torsade de Pointes
Sutent has been shown to prolong the QT interval in a dose dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed in <0.1% of Sutent-exposed patients.
Sutent should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using Sutent, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of Sutent should be considered [see Dosage and Administration (2.2)].
Hypertension
Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of Sutent is recommended until hypertension is controlled.
Of patients receiving Sutent for treatment-naïve RCC, 127/375 patients (34%) receiving Sutent compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naïve RCC patients (13%) on Sutent compared to 1/360 patients (<1%) on IFN-α. While all-grade hypertension was similar in GIST patients on Sutent compared to placebo, Grade 3 hypertension was reported in 9/202 GIST patients on Sutent (4%), and none of the GIST patients on placebo. Of patients receiving Sutent in the Phase 3 pNET study, 22/83 patients (27%) on Sutent and 4/82 patients (5%) on placebo experienced hypertension. Grade 3 hypertension was reported in 8/83 pNET patients (10%) on Sutent, and 1/82 patient (1%) on placebo. No Grade 4 hypertension was reported. Sutent dosing was reduced or temporarily delayed for hypertension in 21/375 patients (6%) on the treatment-naive RCC study and 7/83 pNET patients (8%). Four treatment-naïve RCC patients, including one with malignant hypertension, one patient with pNET, and no GIST patients discontinued treatment due to hypertension. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on Sutent (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on Sutent, in 3/360 patients (1%) on IFN-α, and in 8/80 pNET patients (10%) on Sutent and 2/76 pNET patients (3%) on placebo.
Hemorrhagic Events
Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving Sutent in a clinical trial for treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-α. Bleeding events occurred in 37/202 patients (18%) receiving Sutent in the double-blind treatment phase of GIST Study A, compared to 17/102 patients (17%) receiving placebo. Epistaxis was the most common hemorrhagic adverse event reported. Bleeding events, excluding epistaxis, occurred in 18/83 patients (22%) receiving Sutent in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving placebo. Epistaxis was reported in 17/83 patients (20%) receiving Sutent for pNET and 4 patients (5%) receiving placebo. Less common bleeding events in GIST, RCC and pNET patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In the double-blind treatment phase of GIST Study A, 14/202 patients (7%) receiving Sutent and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, one patient in GIST Study A taking placebo had a fatal gastrointestinal bleeding event during Cycle 2. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naïve patient. In the pNET study, 1/83 patients (1%) receiving Sutent had Grade 3 epistaxis, and no patients had other Grade 3 or 4 bleeding events. In pNET patients receiving placebo, 3/82 patients (4%) had Grade 3 or 4 bleeding events.
Tumor-related hemorrhage has been observed in patients treated with Sutent. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Fatal pulmonary hemorrhage occurred in 2 patients receiving Sutent on a clinical trial of patients with metastatic non-small cell lung cancer (NSCLC). Both patients had squamous cell histology. Sutent is not approved for use in patients with NSCLC. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving Sutent on Study A. Tumor hemorrhages were observed as early as Cycle 1 and as late as Cycle 6. One of these five patients received no further drug following tumor hemorrhage. None of the other four patients discontinued treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo arm were observed to undergo intratumoral hemorrhage. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations.
Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with Sutent.
Thyroid Dysfunction
Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of Sutent treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on Sutent treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.
Treatment-emergent acquired hypothyroidism was noted in eight GIST patients (4%) on Sutent versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on Sutent in the treatment-naïve RCC study and in three patients (1%) in the IFN-α arm. Hypothyroidism was reported as an adverse reaction in 6/83 patients (7%) on Sutent in the Phase 3 pNET study and in 1/82 patients (1%) in the placebo arm.
Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.
Wound Healing
Cases of impaired wound healing have been reported during Sutent therapy. Temporary interruption of Sutent therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume Sutent therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.
Adrenal Function
Physicians prescribing Sutent are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection.
Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT/MRI obtained in 336 patients after exposure to one or more cycles of Sutent demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of Sutent. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with Sutent. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12–16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency.
Laboratory Tests
CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with Sutent.
Adverse Reactions
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 (14.1)], an active-controlled trial (n=375) for the treatment of RCC [see Clinical Studies (14.2)] or a placebo-controlled trial (n=83) for the treatment of pNET [see Clinical Studies (14.3)]. 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 (5). 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.
| 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 | ||||
| Anorexia† | 67 (33) | 1 (1) | 30 (29) | 5 (5) |
| Asthenia | 45 (22) | 10 (5) | 11 (11) | 3 (3) |
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.
| Laboratory Parameter, n (%) | GIST | |||
|---|---|---|---|---|
| Sutent (n=202) | Placebo (n=102) | |||
| All Grades* | Grade 3/4*† | All Grades* | Grade 3/4*‡ | |
| LVEF=Left ventricular ejection fraction | ||||
| ||||
| 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) |
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 (14.1)]. 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-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.
| Adverse Reaction, n (%) | Treatment-Naïve RCC | |||
|---|---|---|---|---|
| Sutent (n=375) | IFN-α (n=360) | |||
| All Grades | Grade 3/4† | All Grades | Grade 3/4‡ | |
| ||||
| 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 (16) | 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 pain§ | 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 taste¶ | 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 | ||
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