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BOXED WARNING SECTION WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving CAPRELSA. CAPRELSA should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Hypocalcemia, hypokalemia and/or hypomagnesemia must be corrected prior to CAPRELSA 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 CAPRELSA 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 restricted distribution program are able to prescribe and dispense CAPRELSA [see Warnings and Precautions (5.15)]. 1. INDICATIONS AND USAGE 1.1. Medullary Thyroid Cancer (MTC) CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use of CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease should be carefully considered because of the treatment related risks of CAPRELSA. 2. DOSAGE AND ADMINISTRATION The recommended daily dose is 300 mg of CAPRELSA taken orally. CAPRELSA treatment should be continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs.
CAPRELSA may be taken with or without food. If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose. For Patients who have Difficulty Swallowing Solids CAPRELSA tablets should not be crushed. If CAPRELSA tablets cannot be taken whole, the tablets can be dispersed in a glass containing 2 ounces of non-carbonated water and stirred for approximately 10 minutes until the tablet is dispersed (will not completely dissolve). No other liquids should be used. The dispersion should be swallowed immediately. To ensure the full dose is received, any residues in the glass should be mixed again with an additional 4 ounces of non-carbonated water and swallowed. The dispersion can also be administered through nasogastric or gastrostomy tubes. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly. Avoid exposure to crushed tablets. 2.1 Dosage Adjustment In the event of corrected QT interval, Fridericia (QTcF) greater than 500 ms, interrupt dosing until QTcF returns to less than 450 ms, then resume at a reduced dose.
For CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or greater toxicity, interrupt dosing until toxicity resolves or improves to CTCAE grade 1, and then resume at a reduced dose. Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions (5.1-5.7, 5.9)]. The 300-mg daily dose can be reduced to 200 mg (two 100-mg tablets) and then to 100 mg for CTCAE grade 3 or greater toxicities. 2.2 Elderly No adjustment in starting dose is required for patients over 65 years of age. There are limited data for patients over the age of 75. [see Dosage and Administration (2.4)] 2.3 Concomitant Strong CYP3A4 Inducers Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also avoid taking St. John’s Wort. [see Warnings and Precautions (5.11)and Drug Interactions (7.1)] 2.4 Patients With Renal Impairment The starting dose should be reduced to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment. [see Warnings and Precautions (5.12)and Use in Specific Populations (8.6)] 2.5 Patients with Hepatic Impairment Single dose pharmacokinetic data from volunteers with hepatic impairment receiving 800 mg suggest that there were no differences in pharmacokinetics compared to patients with normal hepatic function. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is not recommended for use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, as safety and efficacy have not been established. 3. DOSAGE FORMS & STRENGTHS CAPRELSA 100-mg tablets are white, round, biconvex, film-coated, and intagliated with ‘Z 100‘ on one side and plain on the reverse side. CAPRELSA 300-mg tablets are white, oval, biconvex, film-coated, and intagliated with ‘Z 300’ on one side and plain on the reverse side. 4. CONTRAINDICATIONS Do not use in patients with congenital long QT syndrome [see Boxed Warning]. 5. WARNINGS AND PRECAUTIONS 5.1 QT Prolongation and Torsades de Pointes CAPRELSA 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 CAPRELSA. CAPRELSA treatment should not be started in patients whose QTcF interval is greater than 450 ms. CAPRELSA should not be given 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. CAPRELSA 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 CAPRELSA 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 CAPRELSA 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 CAPRELSA 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 CAPRELSA until QTcF returns to less than 450 ms. Dosing of CAPRELSA 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 CAPRELSA. Treatment of severe skin reactions has included systemic corticosteroids and permanent discontinuation of CAPRELSA. 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, CAPRELSA treatment should be stopped until improved. Upon improvement, consideration should be given to continuing treatment at a reduced dose or permanent discontinuation of CAPRELSA. [see Dosage and Administration (2.1)] Photosensitivity reactions are increased with CAPRELSA. Patients should be advised to wear sunscreen and protective clothing when exposed to the sun. Due to the long half-life of CAPRELSA, 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 CAPRELSA 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 CAPRELSA 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 CAPRELSA therapy and the use of corticosteroids and antibiotics may be indicated until clinical symptoms resolve. Even upon resolution of severe ILD, permanent discontinuation of CAPRELSA should be considered. 5.4 Ischemic Cerebrovascular Events Ischemic cerebrovascular events have been observed with CAPRELSA and some cases have been fatal. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events were observed more frequently with CAPRELSA compared to placebo (1.3% compared to 0%) and no deaths were reported. 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, which in some cases were fatal, have been observed with CAPRELSA. There were no fatal bleeding events in the randomized MTC study. Three patients died of fatal bleeding events while on CAPRELSA therapy in clinical studies. Do not administer CAPRELSA to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage. 5.6 Heart Failure Heart failure has been observed with CAPRELSA and some cases have been fatal. Discontinuation of CAPRELSA may be necessary in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA. Monitor for signs and symptoms of heart failure. 5.7 Diarrhea Diarrhea was observed in patients who received CAPRELSA. Routine anti-diarrheal agents are recommended. Diarrhea may cause electrolyte imbalances. Since QT prolongation is seen with CAPRELSA, serum electrolytes and ECGs should be carefully monitored in patients with diarrhea. [see Warnings and Precautions (5.1)] If severe diarrhea develops, CAPRELSA treatment should be stopped until diarrhea improves. Upon improvement, treatment with CAPRELSA 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 CAPRELSA 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 CAPRELSA 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 CAPRELSA. 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, CAPRELSA 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 CAPRELSA. 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 CAPRELSA, including one pediatric patient, also had hypertension. Discontinuation of CAPRELSA treatment in patients with RPLS should be considered. 5.11 Drug Interactions The administration of CAPRELSA with agents that are strong CYP3A4 inducers should be avoided [see Dosage and Administration (2.3)and Drug Interactions (7.1)]. The 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 cloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided [see Drug Interactions (7.3)]. 5.12 Renal Impairment CAPRELSA 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 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 (2.5)] 5.14 Use in Pregnancy CAPRELSA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using CAPRELSA. 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 CAPRELSA. 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 CAPRELSA [see Use in Specific Populations (8.1)]. 5.15 CAPRELSA REMS (Risk eva luation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the restricted distribution program called CAPRELSA REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense CAPRELSA. An overview of the requirements for prescribers and pharmacies is included below.
To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.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, 5.3and 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. 6.1. Clinical Studies Experience Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 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 CAPRELSA. The following adverse reactions have been reported. [see Clinical Studies (14)] Table 1 - Adverse Reactions in >10% of Patients on CAPRELSA During Randomized Treatment
Adverse reactions resulting in death in patients receiving CAPRELSA (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 CAPRELSA after data cut-off. Causes of discontinuation in CAPRELSA-treated patients in >1 patient included asthenia, fatigue rash, arthralgia, diarrhea, hypertension, prolonged QT interval, increase in creatinine and pyrexia. Serious adverse events in CAPRELSA-treated patients in >2% of patients included diarrhea, pneumonia, and hypertension. Clinically important uncommon adverse drug reactions in patients who received CAPRELSA 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 CAPRELSA was pneumonia. The incidence of Grade 1-2 bleeding events was 14% in patients receiving CAPRELSA 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 CAPRELSA 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 CAPRELSA or placebo.
Alanine aminotransferase elevations occurred in 51% of patients on CAPRELSA 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 CAPRELSA. However, 16 of 22 patients with a grade 2 elevation in ALT continued 300 mg CAPRELSA. Seven patients who continued CAPRELSA had a normal ALT within 6 months. In the protocol, ALT was monitored every 3 months and more frequently as indicated. 7. DRUG INTERACTIONS 7.1 CYP3A4 Inducers Drugs that are CYP3A4 inducers can alter CAPRELSA plasma concentrations. The concomitant use of known strong CYP3A4 inducers should be avoided while receiving CAPRELSA therapy. St. John’s Wort may decrease CAPRELSA exposure unpredictably and should be avoided [see Dosage and Administration (2.3) and Warnings and Precautions (5.11)]. 7.2 CYP3A4 Inhibitors In healthy subjects, no clinically significant interaction was shown between CAPRELSA and the potent CYP3A4 inhibitor, itraconazole. 7.3 Drugs that Prolong the QT Interval The administration of CAPRELSA with agents that may prolong the QT interval should be avoided [see Warnings and Precautions (5.11)]. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Pregnancy Category D [see Warnings and Precautions (5.14)] CAPRELSA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of CAPRELSA in pregnant women. CAPRELSA is embryotoxic, fetotoxic, and teratogenic to rats, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. When vandetanib was administered to female rats prior to mating and through the first week of pregnancy, there were increases in pre-implantation loss and post-implantation loss resulting in a significant reduction in the number of live embryos. This dose administered to rats during organogenesis, caused an increase in post-implantation loss including embryofetal death. Vandetanib caused total litter loss when administered at a dose of 25 mg/kg/day during organogenesis until expected parturition. When administered during organogenesis, vandetanib doses of 1, 10 and 25 mg/kg/day (approximately 0.03, 0.4, and 1.0 times respectively, the Cmax in patients with cancer at the recommended human dose) caused malformations of the heart vessels and delayed ossification of the skull, vertebrae and sternum, indicating delayed fetal development. A no effect level for these malformations was not identified in this study. In a rat pre- and post-natal development study, at doses producing maternal toxicity (1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib, decreased pup survival, and/or reduced post-natal pup growth. Reduced post-natal pup growth was associated with a delay in physical development. 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 pregnancy while taking CAPRELSA and for at least four months following the last dose of CAPRELSA. 8.3. Nursing Mothers In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CAPRELSA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4. Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established. 8.5. Geriatric Use In total, 18% of medullary thyroid cancer patients treated with CAPRELSA were age 65 years or older, and 3% were 75 years and older. No overall differences in safety and efficacy were observed between elderly and younger patients. No adjustment in starting dose is required for patients over 65 years of age. There are limited data for patients over the age of 75 years. 8.6 Renal Impairment The pharmacokinetics of CAPRELSA were eva luated after a single dose of 800 mg in subjects with mild (n = 6), moderate (n = 8), and severe (n = 6) renal impairment and normal (n = 10) renal function. Subjects with mild renal impairment had comparable mean AUC and clearance values to those with normal renal function. In subjects with moderate and severe renal impairment, the average AUC of CAPRELSA increased by 39% and 41%, respectively, compared to patients with normal renal function. The starting dose should be reduced to 200 mg in patients with moderate and severe renal impairment [see Dosage and Administration (2.4)and Warnings and Precautions (5.12)]. 8.7 Hepatic Impairment The pharmacokinetics of CAPRELSA were eva luated after a single dose of 800 mg in subjects with mild (n = 8), moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment had comparable mean AUC and clearance values to those with normal hepatic function. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). 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 (2.5) and Warnings and Precautions (5.13)]. 10. OVERDOSAGE There is no specific treatment in the event of overdose with CAPRELSA and possible symptoms of overdose have not been established. Because of the 19-day half-life, adverse reactions may not resolve quickly. In phase 1 clinical trials, a limited number of patients were treated with daily doses of up to 600 mg and healthy volunteers with daily doses up to 1200 mg. An increase in the frequency and severity of some adverse reactions, like rash, diarrhea and hypertension, was observed at multiple doses at and above 300 mg in healthy volunteer studies and in patients. In addition the possibility of QTc prolongation and Torsades de pointes should be considered. Adverse reactions associated with overdose are to be treated symptomatically; in particular, severe diarrhea must be managed appropriately. In the event of an overdose, further doses of CAPRELSA must be interrupted, and appropriate measures taken to assure that an adverse event has not occurred, i.e., ECG within 24 hours to determine QTc prolongation [see Dosage and Administration (2.1)]. 11. DESCRIPTION CAPRELSA tablets for daily oral administration are available in two dosage strengths, 100 mg and 300 mg, containing 100 mg and 300 mg of vandetanib, respectively. The tablet cores contain the following inactive ingredients: Tablet core: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet film-coat contains the following inactive ingredients: hypromellose 2910, macrogol 300, and titanium dioxide E171. Vandetanib is chemically described as N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy]quinazolin-4-amine. The structural and molecular formulas are:  C22H24BrFN4O2 Vandetanib has a molecular weight of 475.36. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F ). 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action Vandetanib is a kinase inhibitor. In vitro studies have shown that vandetanib inhibits the activity of tyrosine kinases including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases. Vandetanib inhibits endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival in vitro. In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells. In vivo vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer. In vitro studies have shown that vandetanib also inhibits the activity of other tyrosine kinases, including rearranged during transfection (RET) and VEGF receptor-3 (Flt-4) . There is no evidence of a relationship between RET mutations and efficacy with vandetanib. 12.3. Pharmacokinetics A population pharmacokinetic analysis of CAPRELSA was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of CAPRELSA at the 300 mg dose in MTC patients are characterized by a mean clearance of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life of 19 days. Absorption Following oral administration of CAPRELSA, absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. CAPRELSA accumulates approximately 8-fold on multiple dosing with steady state achieved from approximately 3 months. Exposure to vandetanib is unaffected by food. Distribution Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 93.7% (range 92.2 to 95.7%). Metabolism Following oral dosing of 14C-vandetanib, unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by CYP3A4 and vandetanib-N-oxide by flavin–containing monooxygenase enzymes FMO1 and FMO3. N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7-17.1% and 1.4-2.2%, respectively, of those of vandetanib. Excretion Within a 21-day collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in feces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life. Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2 marker substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of approximately 2.1 μg/mL. This is higher than vandetanib plasma concentrations (approximately 0.81 μg/mL) observed after multiple dosing at 300 mg. Inhibition of renal excretion of creatinine by vandetanib provides an explanation for increases in plasma creatinine seen in human subjects receiving vandetanib. Special Populations Effects of Age and Gender In a population pharmacokinetic eva luation in cancer patients, no relationship was apparent between oral clearance and patient age or gender. Ethnicity Based on a cross-study comparison in a limited number of patients, Japanese (N=3) and Chinese (N=7) patients had on average exposures that were higher than Caucasian (N=7) patients receiving the same dose. Pediatric The pharmacokinetics of CAPRELSA have not been eva luated in pediatric patients. 12.4 QT Prolongation In 231 medullary thyroid cancer patients randomized to receive CAPRELSA 300 mg once daily in the phase 3 clinical trial, CAPRELSA was associated with sustained plasma concentration-dependent QT prolongation. Based on the exposure-response relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 35 (33-36) ms for the 300-mg dose. The ΔQTcF remained above 30 ms for the duration of the trial (up to 2 years). In addition, 36% of patients experienced greater than 60 ms increase in ΔQTcF and 4.3% of patients had QTcF greater than 500 ms. Cases of Torsades de pointes and sudden death have been reported [see Boxed Warning and Warnings and Precautions (5.1, 5.11)]. 13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with vandetanib. Vandetanib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo rat micronucleus assay. Based on nonclinical findings, male and female fertility may be impaired by treatment with vandetanib. In a fertility study in male rats, vandetanib had no effect on copulation or fertility rate when undosed females were mated with males administered 1, 5, or 20 mg/kg/day of vandetanib (approximately 0.03, 0.22, or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). There was a slight decrease in the number of live embryos at 20 mg/kg/day and an increase in preimplantation loss at >5 mg/kg/day. In a female fertility study, there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy incidence and an increase in implantation loss. In a repeat-dose toxicity study in rats, there was a decrease in the number of corpora lutea in the ovaries of rats administered 75 mg/kg/day vandetanib (approximately 1.8 times the AUC in patients with cancer at the recommended human dose) for 1 month. 13.2. Animal Pharmacology and/or Toxicology In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that CAPRELSA slows but does not prevent wound healing. The appropriate interval between discontinuation of CAPRELSA and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined. Nodular masses were observed in a 6-month toxicology study in rats during treatment with ≥5 mg/kg/day vandetanib (approximately 0.22 or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). Masses were palpable during clinical assessments as early as week 13, were observed in multiple organs, and were associated with hemorrhagic or inflammatory findings. 14. CLINICAL STUDIES A double-blind, placebo-controlled study randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to CAPRELSA 300 mg (n=231) versus Placebo (n=100). The primary objective was demonstration of improvement in progression-free survival (PFS) with CAPRELSA compared to placebo. Other endpoints included eva luation of overall survival and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator’s assessment, patients were discontinued from blinded study treatment and given the option to receive open-label CAPRELSA. Nineteen percent (44/231) of the patients initially randomized to CAPRELSA opted to receive open-label CAPRELSA after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label CAPRELSA after disease progression. The result of the PFS analysis, based on the central review RECIST assessment, showed a statistically significant improvement in PFS for patients randomized to CAPRELSA (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24-0.53; p<0.0001). Analyses in the subgroups of patients who were symptomatic or had progressed within 6 months prior to their enrollment showed similar PFS results (HR = 0.31 95% CI: 0.19, 0.53 for symptomatic patients; HR = 0.41 95% CI: 0.25, 0.66 for patients who had progressed within 6 months prior to enrollment). At the time of the primary analysis of PFS, 15% of the patients had died and there was no significant difference in overall survival between the two treatment groups. The overall objective response rate (ORR) for patients randomized to CAPRELSA was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses.
Figure 1- Progression Free Survival
100 mg Tablets Available in bottles containing 30 tablets (NDC 0310–7820–30). 300 mg Tablets Available in bottles containing 30 tablets (NDC 0310–7840–30). 16.1. Storage and Handling CAPRELSA tablets should be stored at 25°C (77°F); excursions permitted to 15oC – 30oC (59oF – 86oF) [See USP controlled room temperature]. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 CAPRELSA tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets.
Vandetanib用于治疗遗传性甲状腺髓样癌伴有局部和远处侵润患者 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
