DIQTA 1.0: Drug-Induced QT Prolongation Atlas

PALIPERIDONE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIQT concern

Severity Score:4.0

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

WARNINGS AND PRECAUTIONS
QT Prolongation
Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.
In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n = 50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended 12 mg dose of paliperidone extended-release tablets (C max ss = 113 ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which C max ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study.
For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the paliperidone extended-release tablets 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving paliperidone extended-release tablets had a QTcLD exceeding 500 msec at any time in any of these three studies.
OVERDOSAGE
Human Experience
While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of paliperidone extended-release tablets was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.
Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.
[Management of Overdosage]
There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered.
In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly, the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.
ADVERSE REACTIONS
Overall Adverse Reaction Profile
The following adverse reactions are discussed in more detail in other sections of the labeling:
Increased mortality in elderly patients with dementia-related psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)]
Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS (5.2)]
Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS (5.3)]
QT prolongation [see WARNINGS AND PRECAUTIONS (5.4)]
Tardive dyskinesia [see WARNINGS AND PRECAUTIONS (5.5)]
Metabolic changes [see WARNINGS AND PRECAUTIONS (5.6)]
Hyperprolactinemia [see WARNINGS AND PRECAUTIONS (5.7)]
Potential for gastrointestinal obstruction [see WARNINGS AND PRECAUTIONS (5.8)]
Orthostatic hypotension and syncope [see WARNINGS AND PRECAUTIONS (5.9)]
Falls [see WARNINGS AND PRECAUTIONS (5.10)]
Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS (5.11)]
Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS (5.12)]
Seizures [see WARNINGS AND PRECAUTIONS (5.13)]
Dysphagia [see WARNINGS AND PRECAUTIONS (5.14)]
Priapism [see WARNINGS AND PRECAUTIONS (5.15)]
Thrombotic thrombocytopenic purpura (TTP) [see WARNINGS AND PRECAUTIONS (5.16)]
Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS (5.17)]
Antiemetic effect [see WARNINGS AND PRECAUTIONS (5.18)]
Patients with Concomitant Illness [see WARNINGS AND PRECAUTIONS (5.19)]

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24012

Other ADRs

62021

38319566

Odds Ratio = 2.059

Drug Property Information

ATC Code(s):

N05AX13 - paliperidone

N05AX - Other antipsychotics
N05A - ANTIPSYCHOTICS
N05 - PSYCHOLEPTICS
N - NERVOUS SYSTEM

Active Ingredient:PALIPERIDONE

Active Ingredient UNII:838F01T721

Drugbank ID:DB01267

PubChem Compound:115237

CTD ID:D000068882

PharmGKB:PA163518919

CAS Number:144598-75-4

Dosage Form(s):tablet, film coated, extended release

Route(s) Of Administrator:oral

Daily Dose:

6.0 mg/day N05AX13

Chemical Structure:

SMILE Code:
CC1=C(CCN2CCC(CC2)C2=NOC3=C2C=CC(F)=C3)C(=O)N2CCCC(O)C2=N1

Reference

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