DIQTA 1.0: Drug-Induced QT Prolongation Atlas

VANDETANIB

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIQT concern

Severity Score:5.0

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

BOXED WARNING
WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH
CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA [see WARNINGS AND PRECAUTIONS (5.1, 5.16)].
WARNINGS AND PRECAUTIONS
QT Prolongation and Torsades de Pointes
CAPRELSA can prolong the QT interval in a concentration-dependent manner [see CLINICAL PHARMACOLOGY (12.2)]. 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 WARNINGS AND PRECAUTIONS (5.11) and DRUG INTERACTIONS (7.4)]. 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 (2.1)].
[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 [see WARNINGS AND PRECAUTIONS (5.1)]. Interrupt CAPRELSA for severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see DOSAGE AND ADMINISTRATION (2.1)].
[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 (7.4) and CLINICAL PHARMACOLOGY (12.2)].
[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 (2.1), USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)].
[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.
DRUG INTERACTIONS
Drugs that Prolong the QT Interval
Avoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see WARNINGS AND PRECAUTIONS (5.11)].
CONTRAINDICATIONS
Do not use in patients with congenital long QT syndrome [see BOXED WARNING].
OVERDOSAGE
In the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adverse reactions may not resolve quickly.
DOSAGE AND ADMINISTRATION
Dosage Adjustment
Interrupt CAPRELSA for the following:
Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns to less than 450 ms.
CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1.
For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade 1 severity, if continued treatment is warranted.
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), (5.2), (5.3), (5.4), (5.5), (5.6), (5.7), and (5.9)].
ADVERSE REACTIONS
Clinical Trials Experience
Among CAPRELSA-treated patients, dose interruption occurred in 109 (47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of 231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia (1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation (0.9%), and hypertension (0.9%).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
In 231 patients with medullary thyroid cancer 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 occurred [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1), (5.11)].
PATIENT COUNSELING INFORMATION
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 (5.1)].
MEDICATION GUIDE
CAPRELSA can cause a change in the electrical activity of your heart called QT prolongation, which can cause irregular heartbeats and that may lead to death. You should not take CAPRELSA if you have had a condition called long QT syndrome since birth.
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:
Before starting CAPRELSA
Regularly during CAPRELSA treatment:
2 to 4 weeks after starting CAPRELSA
8 to 12 weeks after starting CAPRELSA
every 3 months thereafter
if your healthcare provider changes your dose of CAPRELSA
if you start taking medicine that causes QT prolongation
as instructed by your healthcare provider
Your healthcare provider may stop your CAPRELSA treatment for a while and restart you at a lower dose if you have QT prolongation.
Call your healthcare provider right away if you feel faint, light-headed, or feel your heart beating irregularly while taking CAPRELSA. These may be symptoms related to QT prolongation.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24006

Other ADRs

3463

38378124

Odds Ratio = 39.702

Drug Property Information

ATC Code(s):

L01EX04 - vandetanib

L01EX -
L01E -
L01 - ANTINEOPLASTIC AGENTS
L - ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Active Ingredient:VANDETANIB

Active Ingredient UNII:YO460OQ37K

Drugbank ID:DB05294

PubChem Compound:3081361

CTD ID:C452423

PharmGKB:PA166118341

CAS Number:443913-73-3

Dosage Form(s):tablet, film coated

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
COC1=C(OCC2CCN(C)CC2)C=C2N=CN=C(NC3=C(F)C=C(Br)C=C3)C2=C1

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