Included as part of the PRECAUTIONS section.

QT Prolongation and Torsades de Pointes

CAPRELSA can prolong the QT interval in a concentration-dependent manner [see CLINICAL PHARMACOLOGY]. 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 DRUG INTERACTIONS]. 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].

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, pruritus 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]

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.

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.

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.

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.

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.

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. 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].

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.

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].

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.

Drug Interactions

The administration of CAPRELSA with agents that are strong CYP3A4 inducers should be avoided [see DOSAGE AND ADMINISTRATION) and DRUG INTERACTIONS].

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 chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided [see DRUG INTERACTIONS].

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 and Use In Specific Populations]

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]

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].

CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program

Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through a 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 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 CAPRELSA 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 CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

QT INTERVAL

CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden death have been reported in patients administered CAPRELSA. Patients should be advised that their electrolytes and the electrical activity of their heartbeat (via an ECG) should be monitored regularly during treatment with CAPRELSA.

Rash

Patients taking CAPRELSA should be told they may be more susceptible to sunburn and to use appropriate sun protection (e.g., sunscreen and/or clothing) while taking CAPRELSA and for at least 4 months after drug discontinuation. Patients should consult their physician promptly if they develop a skin rash.

Interstitial Lung Disease

Patients should be told to contact their physician promptly if they develop sudden onset or worsening of breathlessness, persistent cough or fever.

Diarrhea

Patients should be informed that they may experience diarrhea while taking CAPRELSA. Patients should also be advised to use standard anti-diarrheal medications and to seek medical attention if their diarrhea becomes persistent or severe. Patients with diarrhea should contact their physician to have their electrolytes monitored.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Patients should be told to contact their physician promptly if they experience seizures, headaches, visual disturbances, confusion or difficulty thinking.

Pregnancy and Nursing

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.

Breast-feeding mothers are advised to discontinue nursing while receiving CAPRELSA therapy.

Drug Handling

CAPRELSA tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided.

Nonclinical Toxicology

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 CAPRELSA. 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS AND PRECAUTIONS].

CAPRELSA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of CAPRELSA in pregnant women. 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 both malformations of the heart vessels and skeletal variations including delayed ossification of the skull, vertebrae and sternum, indicating delayed fetal development. A no effect level for the 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.

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.

Pediatric Use

Safety and efficacy of CAPRELSA in pediatric patients have not been established.

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.

Renal Impairment

The pharmacokinetics of CAPRELSA 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 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 [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Hepatic Impairment

The pharmacokinetics of CAPRELSA 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 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 and WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 10/18/2012
This monograph has been modified to include the generic and brand name in many instances.