DIQTA 1.0: Drug-Induced QT Prolongation Atlas

RANOLAZINE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Moderate-DIQT concern

Severity Score:2.0

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

WARNINGS AND PRECAUTIONS
QT Interval Prolongation
Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner.
Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death [see Clinical Studies (14.2)]. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.
[Renal Failure]
Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) while taking ranolazine. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue ranolazine and treat appropriately [see Use in Specific Populations (8.7)].
Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.
OVERDOSAGE
Hypotension, QT prolongation, bradycardia, myoclonic activity, severe tremor, unsteady gait/incoordination, dizziness, nausea, vomiting, dysphasia, and hallucinations have been seen in cases of oral overdose of ranolazine. In cases of extreme overdose of ranolazine fatal outcomes have been reported. In clinical studies, high intravenous exposure resulted in diplopia, paresthesia, confusion, and syncope.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of ranolazine’s antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain.
The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.
[Pharmacodynamics]
Electrocardiographic Effects
Dose and plasma concentration-related increases in the QTc interval [see Warnings and Precautions (5.1)], reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with ranolazine. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc. At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about 6 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see Contraindications (4)].
Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine.
PATIENT COUNSELING INFORMATION
QT Interval Prolongation
Inform patients that ranolazine extended-release tablets may produce changes in the electrocardiogram (QTc interval prolongation) [see Warnings and Precautions (5.1)].
Advise patients to inform their physician of any personal or family history of QTc prolongation, congenital long QT syndrome, or if they are receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone) [see Warnings and Precautions (5.1)].
USE IN SPECIFIC POPULATIONS
Use in Patients with Hepatic Impairment
Ranolazine is contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild (Child- Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment [see Clinical Pharmacology (12.2)].
[Use in Patients with Renal Impairment]
A pharmacokinetic study of ranolazine in subjects with severe renal impairment (CrCL < 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice a day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other 2 subjects improved upon drug discontinuation [see Warnings and Precautions (5.2)]. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue ranolazine if acute renal failure develops.
In a separate study, Cmax was increased between 40% and 50% in patients with mild, moderate, or severe renal impairment compared to patients with no renal impairment, suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24019

Other ADRs

21397

38360190

Odds Ratio = 5.449

Drug Property Information

ATC Code(s):

C01EB18 - ranolazine

C01EB1 -
C01EB - Other cardiac preparations
C01E - OTHER CARDIAC PREPARATIONS
C01 - CARDIAC THERAPY
C - CARDIOVASCULAR SYSTEM

Active Ingredient:RANOLAZINE

Active Ingredient UNII:A6IEZ5M406

Drugbank ID:DB00243

PubChem Compound:56959

CTD ID:D000069458

PharmGKB:PA164746007

CAS Number:95635-55-5

Dosage Form(s):tablet, extended release

Route(s) Of Administrator:oral

Daily Dose:

1500.0 mg/day C01EB18

Chemical Structure:

SMILE Code:
COC1=CC=CC=C1OCC(O)CN1CCN(CC(=O)NC2=C(C)C=CC=C2C)CC1

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