Caprelsa Information
Caprelsa (Vandetanib) Boxed Warning Section
Caprelsa (Vandetanib) can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving Caprelsa (Vandetanib) . Caprelsa (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 Caprelsa (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 Caprelsa (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 restricted distribution program are able to prescribe and dispense Caprelsa (Vandetanib)
Caprelsa (Vandetanib) . Dosage And Administration
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.
Caprelsa (Vandetanib) . Dosage Forms & Strengths
Caprelsa (Vandetanib) 100-mg tablets are white, round, biconvex, film-coated, and intagliated with ‘Z 100‘ on one side and plain on the reverse side.
Caprelsa (Vandetanib) 300-mg tablets are white, oval, biconvex, film-coated, and intagliated with ‘Z 300’ on one side and plain on the reverse side.
Caprelsa (Vandetanib) . Contraindications
Do not use in patients with congenital long QT syndrome .
Caprelsa (Vandetanib) . Warnings And Precautions
Caprelsa (Vandetanib) can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using Caprelsa (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. Because of the risk of QT prolongation, Torsades de pointes, and sudden death, Caprelsa (Vandetanib) is available only through the restricted distribution program called Caprelsa (Vandetanib) REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense Caprelsa (Vandetanib) .
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 (Vandetanib) REMS Program, call 1-800-236-9933 or visit www.Caprelsa (Vandetanib) rems.com.
Caprelsa (Vandetanib) . 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 .
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.
Caprelsa (Vandetanib) . Use In Specific Populations
Caprelsa (Vandetanib) can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Caprelsa (Vandetanib) in pregnant women. Caprelsa (Vandetanib) 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 (Vandetanib) and for at least four months following the last dose of Caprelsa (Vandetanib) .
The pharmacokinetics of Caprelsa (Vandetanib) were evaluated 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 (Vandetanib) 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 .
The pharmacokinetics of Caprelsa (Vandetanib) were evaluated 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 (Vandetanib) is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. .
Caprelsa (Vandetanib) . Overdosage
There is no specific treatment in the event of overdose with Caprelsa (Vandetanib) 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 (Vandetanib) 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 .
Caprelsa (Vandetanib) . Description
Caprelsa (Vandetanib) 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:
CHBrFNO
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 ).
Caprelsa (Vandetanib) . Clinical Pharmacology
Vandetanib is a kinase inhibitor. 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 models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival . 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
In vitro
There is no evidence of a relationship between RET mutations and efficacy with vandetanib.
A population pharmacokinetic analysis of Caprelsa (Vandetanib) was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of Caprelsa (Vandetanib) 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 (Vandetanib) , absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Caprelsa (Vandetanib) 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 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 C-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 C-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 C-creatinine by HEK-OCT2 cells, with a mean IC 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 evaluation 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 (Vandetanib) have not been evaluated in pediatric patients.
Caprelsa (Vandetanib) . Nonclinical Toxicology
Carcinogenicity studies have not been conducted with vandetanib.
Vandetanib was not mutagenic in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the cytogenetic assay using human lymphocytes or in the 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.
In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that Caprelsa (Vandetanib) slows but does not prevent wound healing. The appropriate interval between discontinuation of Caprelsa (Vandetanib) 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.
Caprelsa (Vandetanib) . Clinical Studies
A double-blind, placebo-controlled study randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to Caprelsa (Vandetanib) 300 mg (n=231) versus Placebo (n=100).
The primary objective was demonstration of improvement in progression-free survival (PFS) with Caprelsa (Vandetanib) compared to placebo. Other endpoints included evaluation 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 (Vandetanib) . Nineteen percent (44/231) of the patients initially randomized to Caprelsa (Vandetanib) opted to receive open-label Caprelsa (Vandetanib) after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label Caprelsa (Vandetanib) 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 (Vandetanib) (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24-0.53; p
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 (Vandetanib) was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses.
Caprelsa (Vandetanib) . Patient Counseling Information
Patients of childbearing potential must be told to use effective contraception during therapy and for at least four months following their last dose of Caprelsa (Vandetanib) .
Breast-feeding mothers are advised to discontinue nursing while receiving Caprelsa (Vandetanib) therapy.
Caprelsa (Vandetanib) . Medication Guide
Read this Medication Guide before you start taking Caprelsa (Vandetanib) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.
Your healthcare provider should perform tests to check the levels of your blood potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) as well as the electrical activity of your heart with a test called an electrocardiogram (ECG). You should have these tests:
Your healthcare provider may stop your Caprelsa (Vandetanib) treatment for a while and restart you at a lower dose if you have QT prolongation.
Caprelsa (Vandetanib) is a prescription medicine used to treat medullary thyroid cancer that cannot be removed by surgery or that has spread to other parts of the body. It takes a long time to get rid of Caprelsa (Vandetanib) from your body and you may be at risk for side effects related to Caprelsa (Vandetanib) after you have stopped your treatment.
It is not known if Caprelsa (Vandetanib) is safe and effective in children.
Do not take Caprelsa (Vandetanib) if you have had QT prolongation.
Especially tell your healthcare provider if you take:
Ask your healthcare provider if you are not sure if your medicine is one listed above.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
Call your healthcare provider right away if you take too much Caprelsa (Vandetanib) .
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Caprelsa (Vandetanib) . For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Caprelsa (Vandetanib) for a condition for which it was not prescribed. Do not give Caprelsa (Vandetanib) to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes important information about Caprelsa (Vandetanib) . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Caprelsa (Vandetanib) that is written for health professionals.
For more information, go to www.Caprelsa (Vandetanib) .com or call 1-800-236-9933.
Active ingredient: vandetanib
Inactive ingredients:
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distirbuted by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Issued 06–2011
Caprelsa (Vandetanib) is a registered trademark of the AstraZeneca group of companies
©AstraZeneca 2011
