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.

2.1 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.

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 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.