FDA label eaa0ba8d-65e2-427c-ba1c-faeb6ff25c1a

BOXED WARNING SECTION WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving vandetanib. Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Hypocalcemia, hypokalemia and/or hypomagnesemia must be corrected prior to vandetanib administration and should be periodically monitored. Drugs known to prolong the QT interval should be avoided. If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended. Given the half-life of 19 days, ECGs should be obtained to monitor the QT at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessment should be conducted as described above. Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately. Only prescribers and pharmacies certified through the vandetanib REMS education program are able to prescribe and dispense vandetanib [see Warnings and Precautions (5.15) ]. WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH See full prescribing information for complete boxed warning. Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving vandetanib. Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Hypocalcemia, hypokalemia and/or hypomagnesemia must be corrected prior to vandetanib administration and should be periodically monitored. Drugs known to prolong the QT interval should be avoided. If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended. Given the half-life of 19 days, ECGs should be obtained to monitor the QT at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessment should be conducted as described above. Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately. Only prescribers and pharmacies certified through the vandetanib REMS education program are able to prescribe and dispense vandetanib (5.15) .

5. WARNINGS AND PRECAUTIONS Prolonged QT Interval, Torsades de pointes, and sudden death have been reported. Monitor electrocardiograms and levels of serum potassium, calcium, magnesium and TSH at baseline, 2-4 weeks and 8-12 weeks after starting treatment with vandetanib, and every 3 months thereafter and following dose adjustments. Dose reduce as appropriate ( 2.1 , 5.1 ). Stevens-Johnson syndrome resulting in death has been observed. Severe skin reactions may prompt permanent discontinuation of vandetanib ( 2.1 , 5.2 ). Interstitial lung disease, resulting in death has been reported. Interrupt vandetanib and investigate unexplained dyspnea, cough, and fever. Appropriate measures should be taken for ILD ( 2.1 , 5.3 ). Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypothyroidism, hypertension, and reversible posterior leukoencephalopathy syndrome, have been observed ( 2.1, 5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 ). Vandetanib can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid pregnancy while receiving vandetanib and for four months following treatment ( 5.14 , 8.1 ). Because of the risks of QT prolongation, Torsades de pointes and sudden death, vandetanib is available only through a restricted distribution program called the Vandetanib REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense vandetanib. To learn about the specific REMS requirements and to enroll in the Vandetanib REMS Program call 1-800-236–9933 or visit www.vandetanibrems.com ( 5.15 ). 5.1 QT Prolongation and Torsades de Pointes Vandetanib can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.4) ]. Torsades de pointes, ventricular tachycardia and sudden deaths have been reported in patients administered vandetanib. Vandetanib treatment should not be started in patients whose QTcF interval is greater than 450 ms. Vandetanib should not be given to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely. An ECG and levels of serum potassium, calcium, magnesium and TSH should be obtained at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Electrolytes and ECGs may require more frequent monitoring in case of diarrhea. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessments should be conducted as described above. Serum potassium levels should be maintained at 4 mEq/L or higher (within normal range) and serum magnesium and serum calcium should be kept within normal range to reduce the risk of electrocardiogram QT prolongation. Avoid using vandetanib with drugs known to prolong the electrocardiogram QT interval [see Warnings and Precautions ( 5.11 ) and Drug Interactions (7.3) ]. If such drugs are given to patients already receiving vandetanib and no alternative therapy exists, ECG monitoring of the QT interval should be performed more frequently. Patients who develop a QTcF greater than 500 ms should stop taking vandetanib until QTcF returns to less than 450 ms. Dosing of vandetanib can be resumed at a reduced dose [see Dosage and Administration (2.1) ]. 5.2 Skin Reactions and Stevens-Johnson Syndrome Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have been reported with vandetanib. Treatment of severe skin reactions has included systemic corticosteroids and permanent discontinuation of vandetanib. Mild to moderate skin reactions may manifest as rash, acne, dry skin, dermatitis, pruritis and other skin reactions (including photosensitivity reactions and palmar-plantar erythrodysesthesia syndrome). Mild to moderate skin reactions have been treated with topical and systemic corticosteroids, oral antihistamines, and topical and systemic antibiotics. If CTCAE grade 3 or greater skin reactions occur, vandetanib treatment should be stopped until improved. Upon improvement, consideration should be given to continuing treatment at a reduced dose or permanent discontinuation of vandetanib. [see Dosage and Administration (2.1) ] Photosensitivity reactions are increased with vandetanib. Patients should be advised to wear sunscreen and protective clothing when exposed to the sun. Due to the long half-life of vandetanib, protective clothing and sunscreen should continue for 4 months after discontinuation of treatment. 5.3 Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis has been observed with vandetanib and deaths have been reported. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of ILD and have few or no symptoms may continue vandetanib therapy with close monitoring at the discretion of the treating physician. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids and antibiotics may be indicated. For cases where symptoms of ILD are severe, discontinue vandetanib therapy and the use of corticosteroids and antibiotics may be indicated until clinical symptoms resolve. Even upon resolution of severe ILD, permanent discontinuation of vandetanib should be considered. 5.4 Ischemic Cerebrovascular Events Ischemic cerebrovascular events have been observed with vandetanib and some cases have been fatal. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events were observed more frequently with vandetanib compared to placebo (1.3% compared to 0%) and no deaths were reported. The safety of resumption of vandetanib therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue vandetanib in patients who experience a severe ischemic cerebrovascular event. 5.5 Hemorrhage Serious hemorrhagic events, which in some cases were fatal, have been observed with vandetanib. There were no fatal bleeding events in the randomized MTC study. Three patients died of fatal bleeding events while on vandetanib therapy in clinical studies. Do not administer vandetanib to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue vandetanib in patients with severe hemorrhage. 5.6 Heart Failure Heart failure has been observed with vandetanib and some cases have been fatal. Discontinuation of vandetanib may be necessary in patients with heart failure. Heart failure may not be reversible upon stopping vandetanib. Monitor for signs and symptoms of heart failure. 5.7 Diarrhea Diarrhea was observed in patients who received vandetanib. Routine anti-diarrheal agents are recommended. Diarrhea may cause electrolyte imbalances. Since QT prolongation is seen with vandetanib, serum electrolytes and ECGs should be carefully monitored in patients with diarrhea. [see Warnings and Precautions (5.1) ] If severe diarrhea develops, vandetanib treatment should be stopped until diarrhea improves. Upon improvement, treatment with vandetanib should be resumed at a reduced dose [see Dosage and Administration (2.1) ]. 5.8 Hypothyroidism In the randomized MTC study where 90% of the patients enrolled had prior thyroidectomy, increases in the dose of the thyroid replacement therapy were required in 49% of the patients randomized to vandetanib compared to 17% of the patients randomized to placebo. Thyroid-stimulating hormone (TSH) should be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment with vandetanib and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, thyroid hormone levels should be examined and thyroid replacement therapy should be adjusted accordingly. 5.9 Hypertension Hypertension, including hypertensive crisis, has been observed with vandetanib. All patients should be monitored for hypertension and it should be controlled as appropriate. Dose reduction or interruption may be necessary. If high blood pressure cannot be controlled, vandetanib should not be restarted [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 been observed with vandetanib. This syndrome should be considered 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 vandetanib, including one pediatric patient, also had hypertension. Discontinuation of vandetanib treatment in patients with RPLS should be considered. 5.11 Drug Interactions The administration of vandetanib with agents that are strong CYP3A4 inducers should be avoided [see Dosage and Administration (2.3) and Drug Interactions (7.1) ]. The administration of vandetanib 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 cloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided [see Drug Interactions (7.3) ]. 5.12 Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely. There is no information available for patients with end-stage renal disease requiring dialysis. [see Boxed Warning , Dosage and Administration (2.4) and Use in Specific Populations (8.6) ] 5.13 Hepatic Impairment Vandetanib 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 (2.5) ] 5.14 Use in Pregnancy Vandetanib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using vandetanib. In nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. As expected from its pharmacological actions, vandetanib has shown significant effects on all stages of female reproduction in rats. 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 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with vandetanib. Women should be advised that they must use effective contraception to prevent pregnancy during treatment and for at least four months following the last dose of vandetanib [see Use in Specific Populations (8.1) ]. 5.15 Vandetanib REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, vandetanib is available only through a restricted distribution program called Vandetanib REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense vandetanib. An overview of the requirements for prescribers and pharmacies is included below. • To be certified, prescribers must review the educational materials, agree to comply with the REMS requirements and enroll in the program. To be certified, pharmacies that dispense vandetanib must enroll in the program, train their pharmacy staff to verify that each prescription is written by a certified prescriber before dispensing to a patient, and agree to comply with the REMS requirements. To learn about the specific REMS requirements and to enroll in the Vandetanib REMS Program call 1-800-236-9933 or visit www.vandetanibrems.com.

6. ADVERSE REACTIONS The most commonly reported adverse drug reactions (>20%) have been diarrhea, rash, acne, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. The most common laboratory abnormalities (>20%) were decreased calcium, increased ALT, and decreased glucose [see Dosage and Administration (2.1) and Warnings and Precautions ( 5.2 , 5.3 and 5.9 )]. 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. The most common adverse drug reactions (>20%) seen with vandetanib have been diarrhea, rash, acne, nausea, hypertension, headache, fatigue, decreased appetite and abdominal pain. The most common laboratory abnormalities (>20%) were decreased calcium, increased ALT, and decreased glucose ( 2.1 . 5.2 , 5.7 , 5.9 , 6.1 ). To report SUSPECTED ADVERSE REACTIONS, Contact AstraZeneca 1–800–236–9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1. Clinical Studies Experience Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with vandetanib 300 mg (n=231) or Placebo (n= 99). Patients with investigator-determined progression or patients who continued treatment after the data cut-off could receive open label vandetanib. The following adverse reactions have been reported. [see Clinical Studies (14) ] Table 1 - Adverse Reactions in > 10% of Patients on Vandetanib During Randomized Treatment Preferred Term Vandetanib 300 mg N=231 Placebo N=99 All Grades Grade 3–4 All Grades Grade 3–4 Diarrhea/Colitis 132 (57%) 26 (11%) 27 (27%) 2 (2%) Rash Includes rash, rash erythematous, generalized, macular, maculo-papular, papular, pruritic, exfoliative, dermatitis, dermatitis bullous, generalized erythema and eczema. 123 (53%) 11 (5%) 12 (12%) 0 Dermatitis Acneiform/Acne 81 (35%) 2 (1%) 7 (7%) 0 Nausea 77 (33%) 2 (1%) 16 (16%) 0 Hypertension/Hypertensive Crisis/Accelerated Hypertension 76 (33%) 20 (9%) 5 (5%) 1 (1%) Headache 59 (26%) 2 (1%) 9 (9%) 0 Fatigue 55 (24%) 13 (6%) 23 (23%) 1 (1%) Decreased Appetite 49 (21%) 10 (4%) 12 (12%) 0 Abdominal Pain Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort 48 (21%) 6 (3%) 11 (11%) 0 Dry Skin 35 (15%) 0 5 (5%) 0 Vomiting 34 (15%) 2 (1%) 7 (7%) 0 Asthensia 34 (15%) 6 (3%) 11 (11%) 1 (1%) ECG QT Prolonged 69% had QT prolongation >450ms and 7% had QT prolongation >500ms by ECG using Fridericia correction. 33 (14%) 18 (8%) 1 (1%) 1 (1%) Photosensitivity Reaction 31 (13%) 4 (2%) 0 0 Insomnia 30 (13%) 0 10 (10%) 0 Nasopharyngitis 26 (11%) 0 10 (10%) 0 Dyspepsia 25 (11%) 0 4 (4%) 0 Hypocalcemia 25 (11%) 4 (2%) 3 (3%) 0 Cough 25 (11%) 0 10 (10%) 0 Pruritus 25 (11%) 3 (1%) 4 (4%) 0 Weight Decreased 24 (10%) 2 (1%) 9 (9%) 0 Proteinuria 23 (10%) 0 2 (2%) 0 Depression 22 (10%) 4 (2%) 3 (3%) 0 Adverse reactions resulting in death in patients receiving vandetanib (N=5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. Adverse reactions resulting in death in patients receiving placebo were gastrointestinal hemorrhage (1%) and gastroenteritis (1%). In addition there was one sudden death and one death from cardiopulmonary arrest, in patients receiving vandetanib after data cut-off. Causes of discontinuation in vandetanib-treated patients in >1 patient included asthenia, fatigue, rash, arthralgia, diarrhea, hypertension, prolonged QT interval, increase in creatinine and pyrexia. Serious adverse events in vandetanib-treated patients in >2% of patients included diarrhea, pneumonia, and hypertension. Clinically important uncommon adverse drug reactions in patients who received vandetanib versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). In the integrated summary of safety database, the most common cause of death in patients who received vandetanib was pneumonia. The incidence of Grade 1-2 bleeding events was 14% in patients receiving vandetanib compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study. The incidence was similar in the 300 mg monotherapy safety program with a 13% incidence. Blurred vision was more common in patients who received vandetanib versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. It is unknown if this will improve after discontinuation. Ophthalmologic examination, including slit lamp, is recommended in patients who report visual changes. If a patient has blurred vision, do not drive or operate machinery. Table 2 provides the frequency and severity of laboratory abnormalities reported for patients with medullary thyroid cancer receiving randomized treatment with vandetanib or placebo. Table 2 - Laboratory Abnormalities in Patients with MTC Laboratory Parameter Vandetanib 300 mg Placebo N=99 All Grades Grade 3–4 All Grades Grade 3–4 Chemistries Calcium Decreased 132 (57%) 13 (6%) 25 (25%) 3 (3%) ALT Increased 118 (51%) 4 (2%) 19 (19%) 0 Glucose Decreased 55 (24%) 0 7 (7%) 1 (1%) Creatinine Increased 38 (16%) 0 1 (1%) 0 Bilirubin Increased 29 (13%) 0 17 (17%) 0 Magnesium Decreased 17 (17%) 1 (<1%) 2 (2%) 0 Calcium Increased 16 (7%) 2 (1%) 9 (9%) 1 (1%) Potassium Decreased 15 (6%) 1 (<1%) 3 (3%) 0 Potassium Increased 13 (6%) 1 (<1%) 4 (4%) 2 (2%) Glucose Increased 12 (5%) 4 (2%) 7 (7%) 0 Magnesium Increased 6 (3%) 0 4 (4%) 0 Hematologic WBC Decreased 45 (19%) 0 25 (25%) 0 Hemoglobin Decreased 31 (13%) 1 (<1%) 19 (19%) 2 (2%) Neutrophils Decreased 21 (10%) 1 (<1%) 5 (5%) 2 (2%) Platelets Decreased 18 (9%) 0 3 (3%) 0 Alanine aminotransferase elevations occurred in 51% of patients on vandetanib in the randomized medullary thyroid cancer (MTC) study. Grade 3-4 ALT elevations were seen in 2% of patients and no patients had a concomitant increase in bilirubin. Elevations in ALT have resulted in temporary discontinuation of vandetanib. However, 16 of 22 patients with a grade 2 elevation in ALT continued 300 mg vandetanib. Seven patients who continued vandetanib had a normal ALT within 6 months. In the protocol, ALT was monitored every 3 months and more frequently as indicated.

<table width="100%"> <col width="26%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <thead> <tr> <th align="left" styleCode="Botrule " valign="top"> <content styleCode="bold">Preferred Term</content> </th> <th align="center" colspan="2" styleCode="Botrule " valign="middle"> <content styleCode="bold">Vandetanib 300 mg N=231</content> </th> <th align="center" colspan="2" styleCode="Botrule " valign="top"> <content styleCode="bold">Placebo N=99</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"> <paragraph>All Grades</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>Grade 3&#x2013;4</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>All Grades</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>Grade 3&#x2013;4</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Diarrhea/Colitis</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>132 (57%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>26 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>27 (27%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Rash<footnote ID="_RefFN1302708713-1">Includes rash, rash erythematous, generalized, macular, maculo-papular, papular, pruritic, exfoliative, dermatitis, dermatitis bullous, generalized erythema and eczema.</footnote> </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>123 (53%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>11 (5%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>12 (12%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Dermatitis Acneiform/Acne</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>81 (35%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>7 (7%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>77 (33%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>16 (16%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Hypertension/Hypertensive Crisis/Accelerated Hypertension</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>76 (33%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>20 (9%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>5 (5%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>59 (26%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>9 (9%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Fatigue</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>55 (24%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>13 (6%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>23 (23%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Decreased Appetite</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>49 (21%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>10 (4%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>12 (12%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Abdominal Pain<footnote ID="_RefFN1302708788-1">Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort</footnote> </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>48 (21%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>6 (3%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>11 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Dry Skin</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>35 (15%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>5 (5%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>34 (15%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>7 (7%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Asthensia</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>34 (15%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>6 (3%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>11 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>ECG QT Prolonged<footnote ID="_RefFN1302708878-1">69% had QT prolongation &gt;450ms and 7% had QT prolongation &gt;500ms by ECG using Fridericia correction.</footnote> </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>33 (14%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>18 (8%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Photosensitivity Reaction</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>31 (13%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (2%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Insomnia</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>30 (13%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>10 (10%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Nasopharyngitis</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>26 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>10 (10%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Dyspepsia</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>25 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (4%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Hypocalcemia</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>25 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (2%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>3 (3%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Cough</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>25 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>10 (10%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Pruritus</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>25 (11%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>3 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (4%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Weight Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>24 (10%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>9 (9%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Proteinuria</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>23 (10%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Depression</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>22 (10%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (2%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>3 (3%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID0EGYAE" width="100%"> <caption>Table 2 - Laboratory Abnormalities in Patients with MTC</caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr> <th align="left" styleCode="Botrule " valign="top"> <content styleCode="bold">Laboratory Parameter</content> </th> <th align="center" colspan="2" styleCode="Botrule " valign="top"> <content styleCode="bold">Vandetanib 300 mg</content> </th> <th align="center" colspan="2" styleCode="Botrule " valign="top"> <content styleCode="bold">Placebo N=99</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Botrule " valign="top"/> <td styleCode="Botrule " valign="top"> <paragraph>All Grades</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>Grade 3&#x2013;4</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>All Grades</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>Grade 3&#x2013;4</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph> <content styleCode="bold">Chemistries</content> </paragraph> </td> <td colspan="4" styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Calcium Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>132 (57%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>13 (6%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>25 (25%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>3 (3%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>ALT Increased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>118 (51%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (2%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>19 (19%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Glucose Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>55 (24%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>7 (7%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Creatinine Increased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>38 (16%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Bilirubin Increased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>29 (13%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>17 (17%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Magnesium Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>17 (17%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (&lt;1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Calcium Increased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>16 (7%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>9 (9%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (1%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Potassium Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>15 (6%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (&lt;1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>3 (3%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Potassium Increased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>13 (6%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (&lt;1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (4%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Glucose Increased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>12 (5%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (2%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>7 (7%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Magnesium Increased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>6 (3%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>4 (4%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph> <content styleCode="bold">Hematologic</content> </paragraph> </td> <td colspan="4" styleCode="Botrule " valign="top"/> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>WBC Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>45 (19%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>25 (25%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Hemoglobin Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>31 (13%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (&lt;1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>19 (19%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Neutrophils Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>21 (10%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (&lt;1%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>5 (5%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>Platelets Decreased</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>18 (9%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>3 (3%)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>