CAPRELSA

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval [see Warnings and Precautions (5.1) ] . WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH See full prescribing information for complete boxed warning. CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval ( 5.1 ).

5 WARNINGS AND PRECAUTIONS Prolonged QT interval, torsades de pointes, and sudden death: Monitor electrocardiograms and levels of serum potassium, calcium, magnesium and TSH. Reduce CAPRELSA dose as appropriate. ( 2.1 , 5.1 ) Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, some fatal. Discontinue CAPRELSA for severe skin reactions. ( 2.1 , 5.2 ) Interstitial lung disease (ILD), including fatalities: investigate unexplained non-specific respiratory signs and symptoms. Discontinue CAPRELSA for confirmed ILD. ( 2.1 , 5.3 ) Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypertension, and reversible posterior leukoencephalopathy syndrome: Discontinue or interrupt CAPRELSA. ( 2.1 , 5.4 , 5.5 , 5.6 , 5.7 , 5.9 , 5.10 ) Impaired wound healing: Withhold for at least 1 month prior to elective surgery. Do not administer CAPRELSA for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment with CAPRELSA after resolution of wound healing complications has not been established. ( 5.14 ) Embryo-fetal toxicity: Can cause fetal harm. Advise women of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.15 , 8.1 ) Osteonecrosis, including osteonecrosis of the jaw: Withhold CAPRELSA for 1 month prior to scheduled dental surgery and permanently discontinue if osteonecrosis occurs ( 5.16 , 6.2 ). 5.1 QT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2) ] . Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than 450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate renal impairment and monitor QT interval frequently. Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline, 2 to 4 weeks and 8 to 12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to prolong the QT interval [see Warnings and Precautions (5.11) and Drug Interactions (7.4) ] . If such drugs are given to patients already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more frequently. Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration (2.1) ] . 5.2 Severe Skin Reactions Severe and sometimes fatal skin reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, have occurred in patients treated with CAPRELSA. Permanently discontinue CAPRELSA for severe skin reactions and refer the patient for urgent medical evaluation. Systemic therapies such as corticosteroids may be required. Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation. 5.3 Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms. Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed. 5.4 Ischemic Cerebrovascular Events Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event. 5.5 Hemorrhage Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage. 5.6 Heart Failure Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA. 5.7 Diarrhea Diarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early detection of QT prolongation resulting from dehydration [see Warnings and Precautions (5.1) ] . Interrupt CAPRELSA for severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration (2.1) ] . 5.8 Hypothyroidism In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly. 5.9 Hypertension Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA [see Dosage and Administration (2.1) ] . 5.10 Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS. 5.11 Drug Interactions Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) [see Drug Interactions (7.4) and Clinical Pharmacology (12.2) ] . 5.12 Renal Failure Renal failure occurred in patients treated with CAPRELSA [see Adverse Reactions (6.1) ]. Withhold, reduce the dose or permanently discontinue based on severity [see Dosage and Administration (2.1) ] . Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate renal impairment and monitor the QT interval closely [see Dosage and Administration (2.1) ] . Vandetanib is not recommended for use in patients with severe renal impairment (clearance below 30 mL/min). There is no information available for patients with end-stage renal disease requiring dialysis [see Boxed Warning , Dosage and Administration (2.1) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 5.13 Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration (2.1) ] . 5.14 Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Impaired wound healing has occurred in patients treated with CAPRELSA. Withhold CAPRELSA for at least 1 month prior to elective surgery. Do not administer CAPRELSA for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment with CAPRELSA after resolution of wound healing complications has not been established. 5.15 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, CAPRELSA can cause fetal harm when administered to a pregnant woman. In rats, vandetanib was embryotoxic, fetotoxic, and induced fetal malformations at exposures equivalent to or lower than those expected at the 300 mg clinical dose and had adverse effects on female fertility, embryofetal development, and postnatal development of pups. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CAPRELSA and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with CAPRELSA and for 4 months after the last dose [see Use in Specific Populations (8.1) , (8.3) ] . 5.16 Osteonecrosis Osteonecrosis, including osteonecrosis of the jaw (ONJ), has occurred during treatment with CAPRELSA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to and periodically during treatment with CAPRELSA. Advise patients regarding good oral hygiene practices. Avoid invasive dental procedures while on CAPRELSA treatment, particularly in patients at higher risk. Withhold CAPRELSA for at least one month prior to scheduled dental surgery or invasive dental procedures. Permanently discontinue CAPRELSA if ONJ develops. [see Adverse Reactions (6.2) ] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: QT Prolongation and Torsades de Pointes [see Boxed Warning , Warnings and Precautions (5.1) ] Severe Skin Reactions [see Warnings and Precautions (5.2) ] Interstitial Lung Disease [see Warnings and Precautions (5.3) ] Ischemic Cerebrovascular Events [see Warnings and Precautions (5.4) ] Hemorrhage [see Warnings and Precautions (5.5) ] Heart Failure [see Warnings and Precautions (5.6) ] Diarrhea [see Warnings and Precautions (5.7) ] Hypothyroidism [see Warnings and Precautions (5.8) ] Hypertension [see Warnings and Precautions (5.9) ] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10) ] Renal Failure [see Warnings and Precautions (5.12) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.15) ] Osteonecrosis [see Warnings and Precautions (5.16) ] The most common adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5 % have been diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infections, decreased appetite and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, Contact Sanofi Genzyme at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58% male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection, decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109 (47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of 231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia (1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation (0.9%), and hypertension (0.9%). Table 1: Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in CAPRELSA-Treated Patients During Randomized Treatment (Between-Arm Difference of ≥5% [All Grades] CTCAE version 3 was used to grade adverse events. ) System Organ Class CAPRELSA 300 mg Placebo Preferred Term N=231 N=99 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Diarrhea/Colitis 57 11 27 2 Nausea 33 1 16 0 Abdominal Pain Includes abdominal pain, abdominal pain upper, lower abdominal pain, and abdominal discomfort. 21 3 11 0 Vomiting 15 1 7 0 Dyspepsia 11 0 4 0 Dry Mouth 9 0 3 0 Skin and Cutaneous Disorders Rash Includes rash, rash (erythematous, generalized, macular, maculopapular, papular, pruritic, and exfoliative), dermatitis, dermatitis bullous, generalized erythema, and eczema. 53 5 12 0 Dermatitis Acneiform/Acne 35 1 7 0 Dry Skin 15 0 5 0 Photosensitivity Reaction 13 2 0 0 Pruritus 11 1 4 0 Nail abnormalities Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection. 9 0 0 0 Alopecia 8 N/A 0 N/A Vascular Disorders Hypertension/Hypertensive Crisis/Accelerated Hypertension 33 9 5 1 Nervous System Disorders Headache 26 1 9 0 Dysgeusia 8 0 3 0 General Disorders Fatigue Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group. 24 6 23 1 Infections Upper Respiratory Tract Infections Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and tracheitis. 23 0 16 0 Metabolic and Nutritional Disorders Decreased Appetite 21 4 12 0 Hypocalcemia 11 2 3 0 Investigations ECG QT Prolonged 69% had QT prolongation >450 ms and 7% had QT prolongation >500 ms by ECG using Fridericia correction. 14 8 1 1 Eye Disorders Corneal Abnormalities Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits, and acquired corneal dystrophy. 13 0 1 0 Blurred Vision 9 0 1 0 Renal Disorders Proteinuria 10 0 2 0 Psychiatric Disorders Depression 10 2 3 0 Endocrine Disorders Hypothyroidism 6 0 0 0 Musculoskeletal Disorders Muscle Spasms 6 0 1 0 Other Clinically Relevant Adverse Effects In patients with medullary thyroid cancer treated with CAPRELSA or placebo (NCT00410761), clinically important uncommon adverse drug reactions included pancreatitis (0.4% vs 0%), intestinal perforation (0.4% vs 0%), and heart failure (0.9% vs 0%). Blurred vision was commonly reported (9% vs 1%) in this trial. Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination, including slit lamp examination, in patients who report visual changes. Grade 1 to 2 bleeding events were also more common in patients receiving CAPRELSA compared to placebo (14% vs 7%). Table 2: Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at a Higher Incidence in CAPRELSA-Treated Patients (Between-Arm Difference of ≥5% [All Grades] CTCAE version 3 was used to grade laboratory abnormalities. ) Laboratory Abnormalities CAPRELSA 300 mg N=231 Placebo N=99 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistries Hypocalcemia 57 6 25 3 ALT Increased 51 2 19 0 Hypoglycemia 24 0 7 1 Creatinine Increased 16 0 1 0 Hypomagnesemia 7 <1 2 0 Hematologic Neutropenia 10 <1 5 2 Thrombocytopenia 9 0 3 0 No patient with a Grade 3 to 4 ALT elevation had a concomitant increase in bilirubin in the MTC study. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of CAPRELSA. 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. Vascular disorders : Arterial (including aortic) aneurysms, dissections, and rupture Musculoskeletal and connective tissue disorders : Osteonecrosis General disorders: Impaired wound healing

<table width="95%"><caption>Table 1: Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in CAPRELSA-Treated Patients During Randomized Treatment (Between-Arm Difference of &#x2265;5% [All Grades]<footnote>CTCAE version 3 was used to grade adverse events.</footnote>)</caption><col align="left" valign="middle" width="40%"/><col align="center" valign="middle" width="15%"/><col align="center" valign="middle" width="15%"/><col align="center" valign="middle" width="15%"/><col align="center" valign="middle" width="15%"/><thead><tr><th styleCode="Rrule Lrule">System Organ Class</th><th styleCode="Rrule" colspan="2">CAPRELSA 300 mg</th><th styleCode="Rrule" colspan="2">Placebo</th></tr><tr styleCode="Botrule"><th styleCode="Rrule Lrule"> Preferred Term</th><th styleCode="Rrule" colspan="2">N=231</th><th styleCode="Rrule" colspan="2">N=99</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea/Colitis</td><td styleCode="Rrule">57</td><td styleCode="Rrule">11</td><td styleCode="Rrule">27</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">33</td><td styleCode="Rrule">1</td><td styleCode="Rrule">16</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal Pain<footnote>Includes abdominal pain, abdominal pain upper, lower abdominal pain, and abdominal discomfort.</footnote></td><td styleCode="Rrule">21</td><td styleCode="Rrule">3</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">15</td><td styleCode="Rrule">1</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspepsia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry Mouth</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Skin and Cutaneous Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash<footnote>Includes rash, rash (erythematous, generalized, macular, maculopapular, papular, pruritic, and exfoliative), dermatitis, dermatitis bullous, generalized erythema, and eczema.</footnote></td><td styleCode="Rrule">53</td><td styleCode="Rrule">5</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dermatitis Acneiform/Acne</td><td styleCode="Rrule">35</td><td styleCode="Rrule">1</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry Skin</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Photosensitivity Reaction</td><td styleCode="Rrule">13</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pruritus</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nail abnormalities<footnote>Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection.</footnote></td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alopecia</td><td styleCode="Rrule">8</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">0</td><td styleCode="Rrule">N/A</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Vascular Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertension/Hypertensive Crisis/Accelerated Hypertension</td><td styleCode="Rrule">33</td><td styleCode="Rrule">9</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">26</td><td styleCode="Rrule">1</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysgeusia</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group.</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">6</td><td styleCode="Rrule">23</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper Respiratory Tract Infections<footnote>Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and tracheitis.</footnote></td><td styleCode="Rrule">23</td><td styleCode="Rrule">0</td><td styleCode="Rrule">16</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased Appetite</td><td styleCode="Rrule">21</td><td styleCode="Rrule">4</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypocalcemia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> ECG QT Prolonged<footnote>69% had QT prolongation &gt;450 ms and 7% had QT prolongation &gt;500 ms by ECG using Fridericia correction.</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">8</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Eye Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Corneal Abnormalities<footnote>Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits, and acquired corneal dystrophy.</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Blurred Vision</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Renal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Proteinuria</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Depression</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Endocrine Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypothyroidism</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Musculoskeletal Disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Muscle Spasms</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="95%"><caption>Table 2: Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at a Higher Incidence in CAPRELSA-Treated Patients (Between-Arm Difference of &#x2265;5% [All Grades]<footnote>CTCAE version 3 was used to grade laboratory abnormalities.</footnote>)</caption><col align="left" valign="top" width="40%"/><col align="center" valign="top" width="12%"/><col align="center" valign="top" width="18%"/><col align="center" valign="top" width="12%"/><col align="center" valign="top" width="18%"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" align="left">Laboratory Abnormalities</th><th styleCode="Rrule" colspan="2">CAPRELSA 300 mg N=231</th><th styleCode="Rrule" colspan="2">Placebo N=99</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule" valign="middle">Grade 3 or 4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule" valign="middle">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Chemistries</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypocalcemia</td><td styleCode="Rrule">57</td><td styleCode="Rrule">6</td><td styleCode="Rrule">25</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> ALT Increased</td><td styleCode="Rrule">51</td><td styleCode="Rrule">2</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoglycemia</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Creatinine Increased</td><td styleCode="Rrule">16</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypomagnesemia</td><td styleCode="Rrule">7</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Hematologic</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">5</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule"> Thrombocytopenia</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr></tbody></table>