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Caprelsa

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Caprelsa

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 occurred in patients treated with CAPRELSA.

Do not start CAPRELSA treatment in patients whose QTcF interval is greater than 450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor QT interval frequently.

Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium levels within normal ranges to reduce the risk of QT prolongation.

Avoid using CAPRELSA with drugs known to prolong the QT interval [see DRUG INTERACTIONS]. If such drugs are given to patients already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more frequently.

Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see DOSAGE AND ADMINISTRATION].

Skin Reactions And Stevens-Johnson Syndrome

Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions [see DOSAGE AND ADMINISTRATION].

Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation.

Interstitial Lung Disease

Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms.

Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed.

Ischemic Cerebrovascular Events

Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event.

Hemorrhage

Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥ ½ teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage.

Heart Failure

Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA.

Diarrhea

Diarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see DOSAGE AND ADMINISTRATION].

Hypothyroidism

In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 -4 weeks and 8 -12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.

Hypertension

Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA [see DOSAGE AND ADMINISTRATION].

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS.

Drug Interactions

Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Renal Impairment

Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis [see BOXED WARNING, DOSAGE AND ADMINISTRATION, Use in Specific Populations and CLINICAL PHARMACOLOGY].

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].

Embryofetal Toxicity

Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. 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 and had adverse effects on female fertility, embryofetal development, and postnatal development of pups.

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 a fetus. Women of childbearing potential should avoid pregnancy. Advise women of childbearing potential that they must use effective contraception during CAPRELSA 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 the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense CAPRELSA.

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 Prolongation and Torsades de Pointes: Advise patients to contact their healthcare provider in the event of syncope, pre-syncopal symptoms, and cardiac palpitations. Advise patients that their healthcare provider will monitor their electrolytes and ECGs during treatment [see WARNINGS AND PRECAUTIONS].
  • Severe skin reactions and Stevens-Johnson Syndrome: Advise patients to contact their healthcare provider in the event of skin reactions or rash. [see WARNINGS AND PRECAUTIONS].
  • Interstitial Lung Disease (ILD): Advise patients to contact their health care provider in the event of sudden onset or worsening of breathlessness, persistent cough or fever. [see WARNINGS AND PRECAUTIONS].
  • Diarrhea: Advise patients to contact their healthcare provider in the event of diarrhea [see WARNINGS AND PRECAUTIONS ]
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Advise patients to contact their healthcare provider in the event of seizures, headaches, visual disturbances, confusion or difficulty thinking [see WARNINGS AND PRECAUTIONS]
  • Fetal Toxicity: Because CAPRELSA can cause fetal harm, advise patients of reproductive potential to use effective contraception during therapy and for at least four months following their last dose of CAPRELSA, and to immediately contact their health care provider if pregnancy is suspected or confirmed [see Pregnancy, Females and Males of Reproductive Potential].
  • Nursing Infants: Because of the potential for serious adverse reactions in nursing infants from CAPRELSA, advise breast feeding mothers to discontinue nursing while receiving therapy [see Nursing Mothers].
  • Photosensitivity: Advise patients to use appropriate sun protection due to the increased susceptibility to sunburn while taking CAPRELSA and for at least 4 months after drug discontinuation [see WARNINGS AND PRECAUTIONS].
  • Administration: Advise patients that CAPRELSA can be taken with or without food and not to crush CAPRELSA tablets [see Pharmacokinetics].

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 either 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 of male rats, vandetanib had no effect on copulation or fertility rate when untreated 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); however, in the same study there was a slight decrease in the number of live embryos in females mated with males treated at the 20 mg/kg/day dose level and an increase in preimplantation loss in females mated with males administered vandetanib at doses of ≥ 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 one month 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 exposure measured by AUC in patients with cancer at the recommended human dose).

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS AND PRECAUTIONS]

Risk Summary

Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to those expected at the recommended human dose of 300 mg/day. If CAPRELSA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal data

When vandetanib was administered to female rats prior to mating and through the first week of pregnancy at a dose of 25 mg/kg/day (approximately equal to the human exposure at the recommended dose based on Cmax), there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of live embryos.

During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in post-implantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times the human exposure at the recommended dose by Cmax) treatment with vandetanib resulted in increases in late embryofetal death and decreases in fetal birth weight. A no effect level for malformations was not identified in this study. Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times, the Cmax in patients with cancer at the recommended dose) resulted in dose dependent increases in both malformations of the heart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicating delayed fetal development.

In a rat pre-and post-natal development study, at doses producing mild 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.

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

The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently compared to younger patients.

Renal Impairment

Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥ 30 to < 50 mL/min) and severe (creatinine clearance < 30 mL/min) renal impairment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

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].

Females And Males Of Reproductive Potential

Contraception

Females of reproductive potential should avoid pregnancy.

Use effective contraception during treatment and up to 4 months after the last dose of CAPRELSA.

Infertility

There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate that vandetanib can impair male and female fertility [see Nonclinical Toxicology].

Last reviewed on RxList: 4/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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Additional Caprelsa Information

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