From the Guidelines
Paliperidone can prolong the QT interval, requiring caution when prescribing this antipsychotic medication. Patients should undergo baseline ECG monitoring before starting paliperidone, with follow-up ECGs recommended after dose increases or when adding other QT-prolonging medications. The typical oral dose range for paliperidone is 3-12 mg daily, with a recommended starting dose of 6 mg once daily, while the long-acting injectable form (Invega Sustenna) ranges from 39-234 mg monthly. Dose reductions are necessary for patients with renal impairment. Avoid using paliperidone in patients with congenital long QT syndrome, significant cardiac arrhythmias, or QTc intervals exceeding 500 ms. Exercise caution when combining paliperidone with other QT-prolonging medications, electrolyte abnormalities (especially hypokalemia and hypomagnesemia), or in elderly patients. The QT prolongation occurs because paliperidone blocks potassium channels in cardiac cells, delaying ventricular repolarization, which can potentially lead to torsades de pointes, a life-threatening arrhythmia, though this serious complication is rare with therapeutic doses in patients without additional risk factors 1.
Key Considerations
- Baseline ECG monitoring is essential before starting paliperidone
- Follow-up ECGs are recommended after dose increases or when adding other QT-prolonging medications
- Dose reductions are necessary for patients with renal impairment
- Avoid using paliperidone in patients with congenital long QT syndrome, significant cardiac arrhythmias, or QTc intervals exceeding 500 ms
- Exercise caution when combining paliperidone with other QT-prolonging medications, electrolyte abnormalities, or in elderly patients
Mechanism of QT Prolongation
The QT prolongation occurs because paliperidone blocks potassium channels in cardiac cells, delaying ventricular repolarization, which can potentially lead to torsades de pointes, a life-threatening arrhythmia. This is supported by studies that have shown that paliperidone can prolong the QT interval in a dose-dependent manner 1.
Clinical Implications
The clinical implications of paliperidone-induced QT prolongation are significant, as it can increase the risk of torsades de pointes and other life-threatening arrhythmias. Therefore, it is essential to carefully monitor patients taking paliperidone, especially those with underlying cardiac conditions or taking other QT-prolonging medications 1.
From the FDA Drug Label
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. 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.
Paliperidone and QT Interval: 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.
- The 8 mg dose of paliperidone showed a mean increase of 12.3 msec in QTcLD.
- The maximum recommended dose of 12 mg had a lower peak plasma concentration than the 8 mg dose used in the QT study.
- Key considerations for the use of paliperidone include:
- Avoiding combination with other QTc-prolonging drugs
- Avoiding use in patients with congenital long QT syndrome or a history of cardiac arrhythmias
- Monitoring for torsade de pointes and sudden death in high-risk patients 2
From the Research
Paliperidone and QT Interval
- Paliperidone, a second-generation antipsychotic, has been reported to cause QT interval prolongation, which is associated with an increased risk of torsade de pointes (TdP) 3.
- The QT interval prolongation effect of paliperidone is thought to be due to its ability to block the HERG current at clinically relevant concentrations 3.
- A study found that paliperidone prolonged the QT interval by 15.7 ± 5.3 milliseconds at a dose of 1 mg/kg in guinea pigs 3.
- Another study found that the QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone 4.
- A randomized, double-blind, placebo-controlled study found that paliperidone extended release was noninferior to quetiapine in terms of its effect on QTc intervals 5.
Risk of Torsade de Pointes
- Torsade de pointes is a rare form of tachyarrhythmia that can potentially be fatal due to its tendency to degenerate into ventricular fibrillation 6.
- Prolonged QT interval is known to be a risk factor for torsade de pointes, but there is no defined duration of a QT interval that can lead to an increased risk of torsade de pointes 6.
- A study found that the overall risk of torsade de pointes and sudden death associated with antipsychotics, including paliperidone, is low 7.
Monitoring and Prevention
- Electrocardiogram (ECG) monitoring is useful when administering antipsychotic medications, including paliperidone, in the presence of co-existing risk factors 7.
- However, routine ECG monitoring is not mandatory in the absence of cardiac risk factors 7.
- Simple ECG monitoring and treatment for the respective cause may help save the lives of patients with known long QT syndrome or those on QT-prolonging drugs, including paliperidone 6.