First-generation antipsychotic, diphenylbutylpiperidine derivative
Brand names: Orap
Updated · Methodology
Second line
Pimozide is a second-line antipsychotic for Tourette syndrome in patients over 12 with severe motor or vocal tics when behavioural therapy and alpha-2 agonists (clonidine, guanfacine) failed. approved this indication in 1984. and AEMPS support use only after ECG screening with dose titrated by QTc. Long-term treatment requires weight and metabolic monitoring.
Sources
ICD-10: F95.2 · ICD-11: 8A05.00
Blocks postsynaptic dopamine D2 receptors in the striatum and mesolimbic system, plus 5-HT2A receptors and L-type calcium channels. Long half-life (about 55 hours) supports once-daily dosing. Metabolised by CYP3A4 and to a lesser extent CYP1A2; the main adverse risk is QT prolongation and dose-dependent sinus node suppression.
AEMPS summary of product characteristics (section 4.6): the safety of pimozide in pregnancy has not been established, so it should not be given to women of childbearing potential, particularly in the first trimester, unless the physician judges that the expected benefits outweigh the potential risk to the fetus. Animal data showed some embryotoxicity at doses similar to the maximum human dose, and fetal growth retardation and fetal toxicity at about 6 times that dose (mg/kg basis); no teratogenic effects were seen. Newborns exposed to antipsychotics, including pimozide, in the third trimester are at increased risk of extrapyramidal and withdrawal symptoms of varying severity: agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress or feeding disorders.
Pimozide passes into breast milk. Breastfeeding during treatment is not recommended.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Pimozide is broken down by CYP3A4, and grapefruit juice inhibits this enzyme. Excess pimozide lengthens the QT interval and can trigger torsade de pointes, a ventricular arrhythmia felt as palpitations or fainting that can cause sudden death. The Orap SmPC says to avoid grapefruit juice during treatment.
Source: AEMPS: Ficha técnica de Orap 1 mg comprimidos (pimozida) (2018)
21 pairs found. Sorted from critical to minor.
Mechanism
Amiodarone is a moderate CYP3A4 inhibitor and the strongest clinical QT prolonger. Double torsades risk. Orap Section 4 + additive QT effect.
Symptoms
QT prolongation (amiodarone itself extends 30–50 ms), syncope, torsades de pointes.
Management
Combination contraindicated. For atrial fibrillation in a pimozide patient, use a beta-blocker for rate control or catheter ablation.
Sources
Mechanism
CYP3A4 inhibition by atazanavir raises pimozide – torsades de pointes.
Symptoms
QT prolongation, syncope.
Management
Combination contraindicated.
Mechanism
Both drugs prolong the QT interval on the electrocardiogram (ECG). The pimozide label reports QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation at therapeutic doses. The azithromycin label reports QT prolongation and torsade de pointes. According to the US pimozide label, macrolide use in patients with a prolonged QT interval, such as pimozide can produce, has rarely been associated with ventricular arrhythmias. Two sudden deaths were reported when clarithromycin was added to pimozide. The pharmacokinetic contribution of azithromycin is small. Its label calls it a weak cytochrome P450 inhibitor and finds no clinically significant inhibition of the enzyme CYP3A4, one of the two main routes of pimozide breakdown. The label does not fully rule such inhibition out, though. Azithromycin stays in the body for a long time: its terminal half-life is about 68 hours, and low concentrations persist after the course ends (azithromycin label). The labels give no study of this pair.
Symptoms
QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). The danger is ventricular arrhythmia: torsade de pointes, ventricular tachycardia and ventricular fibrillation, up to cardiac arrest and sudden death (pimozide and azithromycin labels). An arrhythmia episode presents as palpitations, dizziness or fainting. The risk is higher in women and older people and with low potassium or magnesium, clinically relevant bradycardia, arrhythmias or severe heart failure (azithromycin and pimozide labels).
Management
The combination is contraindicated. The US pimozide label names azithromycin among the macrolide antibiotics that must not be given with pimozide (pimozide label, US Food and Drug Administration, ). The Spanish pimozide summary of product characteristics (SmPC) contraindicates pimozide with any drug known to prolong the QT interval and with macrolide antibiotics (pimozide SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). Azithromycin's own label puts it in the QT-prolonging group: it reports QT prolongation and torsade de pointes (azithromycin SmPC, AEMPS). The azithromycin labels are softer. The Spanish one asks for caution with such drugs and gives pimozide as an example, and the US one asks prescribers to weigh benefits and risks (azithromycin labels, AEMPS and FDA). The strictest document applies. If a patient taking pimozide needs an antibiotic, do not prescribe azithromycin. Clarithromycin and erythromycin are also contraindicated, and the US pimozide label also rules out sparfloxacin, gatifloxacin and moxifloxacin with pimozide (pimozide label, FDA). If a patient already takes both drugs, stop one of them. For any pimozide treatment, record an electrocardiogram (ECG) before the start and repeat it during treatment. Keep potassium and magnesium in the normal range, and stop pimozide if the QT or corrected QT (QTc) interval exceeds 500 ms (pimozide labels, AEMPS and FDA).
Sources
Mechanism
Both drugs prolong the QT interval, and both labels assume the effects add up. Both labels cite the same study: in subjects on citalopram 40 mg once daily for 11 days, a single 2 mg dose of pimozide increased QTc by a mean of about 10 ms compared with pimozide alone. The labels differ on pharmacokinetics. The pimozide label states that citalopram did not change pimozide AUC or Cmax; the Spanish citalopram label reports a rise that was not consistent through the study. The pimozide label calls the mechanism of this pharmacodynamic interaction unknown.
Symptoms
QT prolongation itself causes no symptoms and shows only on the ECG. The danger is ventricular arrhythmia, above all torsade de pointes. Both labels report such cases, and the pimozide label also reports ventricular tachycardia, ventricular fibrillation and sudden death, including at therapeutic doses. Arrhythmia presents as dizziness, palpitations or syncope (citalopram label, ). The citalopram label reports torsade de pointes mainly in women and in patients with hypokalaemia, a pre-existing long QT interval or heart disease.
Management
The combination is contraindicated in all four labels. The Spanish pimozide label names citalopram in its contraindications (pimozide label, AEMPS). The Spanish citalopram label bans concomitant use in a dedicated paragraph because the interaction appeared at a low pimozide dose (citalopram label). The US labels of both drugs repeat the ban (citalopram and pimozide labels, ). Do not give citalopram to a patient on pimozide who needs an antidepressant; if a patient already takes both, stop one of the drugs. The ban also covers other serotonin reuptake inhibitors, named as sertraline, paroxetine and escitalopram (pimozide label), and any drug that prolongs the QT interval (pimozide and citalopram labels). Choose the replacement outside those lists. For any pimozide treatment, take an ECG before the start and repeat it during treatment, correct potassium and magnesium, and stop pimozide if QT or QTc exceeds 500 ms (pimozide label).
Sources
Mechanism
Clarithromycin is a strong CYP3A4 inhibitor. Pimozide is 80% metabolised by CYP3A4; concentration rises 5–7 fold during co-administration. Orap Section 4 strict contraindication – risk of QT prolongation, torsades de pointes and sudden cardiac death.
Symptoms
Within 3–7 days: palpitations, dizziness, syncope. ECG QTc above 500 ms, ventricular ectopy; in severe cases torsades de pointes progressing to ventricular fibrillation.
Management
Combination contraindicated. For infection in a pimozide patient use azithromycin (no CYP3A4 inhibition) or another antibiotic class (amoxicillin for typical pneumonia). If clarithromycin is needed, hold pimozide for the course and resume 7 days after the last dose.
Sources
Mechanism
Cobicistat is a strong CYP3A4 inhibitor (potency similar to ritonavir). Tybost Section 4.3 strict contraindication with pimozide.
Symptoms
QT prolongation, syncope, torsades de pointes.
Management
Combination contraindicated. For HIV, switch to a regimen without cobicistat (dolutegravir + 2 NRTIs).
Mechanism
Erythromycin is a moderate-to-strong CYP3A4 inhibitor. Pimozide concentration rises 3–5 fold, with additive QT prolongation (erythromycin itself is a QT prolonger). Orap Section 4 contraindication.
Symptoms
QT prolongation, syncope, torsades de pointes within 3–10 days.
Management
Combination contraindicated. Alternative: azithromycin or another class. If erythromycin is needed, hold pimozide for the course.
Sources
Mechanism
Both drugs prolong the QT interval: escitalopram in a dose-dependent way (escitalopram label), pimozide up to ventricular arrhythmias at therapeutic doses (pimozide label). No study of this exact pair exists. The labels rely on data with racemic citalopram: a single 2 mg dose of pimozide given with citalopram 40 mg once daily increased QTc by a mean of about 10 ms (pimozide label, ). The US escitalopram label adds that racemic citalopram increases plasma concentrations of pimozide, a drug with a narrow therapeutic index. There is also a kinetic side: escitalopram inhibits CYP2D6 (escitalopram label), this enzyme partly metabolises pimozide, and the Spanish pimozide label contraindicates CYP2D6 inhibitors (pimozide label).
Symptoms
QT prolongation causes no symptoms and shows only on the ECG. The danger is ventricular arrhythmia, above all torsade de pointes. The escitalopram label reports such cases mainly in women and in patients with hypokalaemia, a pre-existing long QT interval or other heart disease. The pimozide label also reports ventricular tachycardia, ventricular fibrillation and sudden death. Arrhythmia presents as dizziness, palpitations or syncope.
Management
The combination is contraindicated. The Spanish pimozide label names escitalopram in its contraindications (pimozide label, AEMPS). The Spanish escitalopram label bans concomitant use with drugs that prolong the QT interval and names pimozide among the examples (escitalopram label). The US labels of both drugs repeat the ban (escitalopram and pimozide labels, ). Do not give escitalopram to a patient on pimozide; if a patient already takes both, stop one of the drugs. The pimozide ban extends to sertraline, paroxetine and citalopram (pimozide label) and to any drug that prolongs the QT interval (pimozide and escitalopram labels). Choose the replacement outside those lists. For any pimozide treatment, take an ECG before the start and repeat it during treatment, correct potassium and magnesium before the start, and stop pimozide if QT or QTc exceeds 500 ms (pimozide label). If signs of arrhythmia appear on escitalopram, stop it and take an ECG (escitalopram label).
Sources
Mechanism
Pimozide is cleared in the liver mainly by CYP3A4, and fluconazole inhibits this enzyme. Pimozide levels rise, and pimozide itself prolongs the QT interval, so the risk of a dangerous ventricular arrhythmia, torsades de pointes, goes up (both SmPCs). Fluconazole keeps inhibiting the enzyme for 4–5 days after it is stopped (fluconazole SmPC).
Symptoms
QT prolongation on the ECG and ventricular arrhythmias, including torsades de pointes: palpitations, skipped beats, dizziness, fainting. Ventricular tachycardia, ventricular fibrillation and sudden death have been reported with pimozide (pimozide SmPC).
Management
The combination is contraindicated in the Spanish SmPCs of fluconazole and pimozide and in the fluconazole label. Lowering the pimozide dose does not remove the risk, and no document allows it. For a fungal infection in a patient on pimozide, choose a drug that does not inhibit CYP3A4 or CYP2D6: the pimozide SmPC contraindicates inhibitors of both enzymes. If fluconazole has already been given, start pimozide no earlier than 4–5 days after fluconazole is stopped, when its effect on the enzyme has worn off (fluconazole SmPC). Do an ECG before starting pimozide and periodically during treatment. If QT prolongation or an arrhythmia appears, review the need for pimozide; pimozide is contraindicated with low potassium or magnesium (pimozide SmPC).
Sources
Mechanism
The liver breaks down pimozide mainly through the enzymes CYP3A4 and CYP2D6, and to a lesser extent CYP1A2 (pimozide label). Fluvoxamine inhibits all three: CYP1A2 strongly, CYP3A4 and CYP2D6 to a lesser degree (fluvoxamine label). The US fluvoxamine label considers it a likely potent CYP3A4 inhibitor because fluvoxamine 100 mg daily roughly doubled the plasma concentrations of alprazolam, a CYP3A4 substrate (fluvoxamine label, US Food and Drug Administration, ). The Spanish fluvoxamine label explains the contraindication by the narrow therapeutic index of pimozide and its known ability to prolong the QT interval. According to the US label, raised pimozide levels prolong QT and have been linked to torsade de pointes, sometimes fatal. The labels give no study of pimozide levels with fluvoxamine.
Symptoms
QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). The danger is ventricular arrhythmia: torsade de pointes, ventricular tachycardia and ventricular fibrillation, up to cardiac arrest and sudden death (pimozide and fluvoxamine labels). An episode presents as palpitations, dizziness or fainting. Excess pimozide also strengthens its usual effects, above all extrapyramidal ones: tremor, muscle rigidity and akathisia, an inability to sit still (pimozide label). The risk of arrhythmia is higher with low potassium or magnesium and with a slow heart rate (pimozide label).
Management
The combination is contraindicated. The Spanish fluvoxamine summary of product characteristics (SmPC) bans it in both the contraindications and the interactions sections (fluvoxamine SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The US label lists it under contraindications (fluvoxamine label, US Food and Drug Administration, ). The US pimozide label places fluvoxamine among the less potent inhibitors of the enzyme CYP3A4 that should also be avoided (pimozide label, FDA). The Spanish pimozide SmPC contraindicates pimozide with any inhibitor of CYP3A4 or CYP2D6 (pimozide SmPC, AEMPS). If a patient taking pimozide needs an antidepressant, do not prescribe fluvoxamine. If a patient already takes both drugs, stop one of them. Many other antidepressants are also ruled out with pimozide: sertraline, paroxetine, citalopram and escitalopram by name, fluoxetine as a CYP2D6 inhibitor and tricyclic antidepressants as drugs that prolong the QT interval (pimozide SmPC, AEMPS). Choose the replacement outside those lists. For any pimozide treatment, record an electrocardiogram (ECG) before the start and repeat it during treatment. Keep potassium and magnesium in the normal range, and stop pimozide if the QT or corrected QT (QTc) interval exceeds 500 ms (pimozide labels, AEMPS and FDA).
Sources
Mechanism
Both drugs prolong the QT interval. For haloperidol, there are reports of QTc prolongation, ventricular arrhythmias and sudden death, with higher risk at high doses, high plasma concentrations and parenteral, especially intravenous, use (haloperidol label). For pimozide, there are reports of QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation at therapeutic doses (pimozide label). Both labels assume the effects add up, and each lists the other drug among contraindicated QT-prolonging drugs. There is also a kinetic side: haloperidol inhibits CYP2D6 (haloperidol label), this enzyme partly metabolises pimozide, and the Spanish pimozide label contraindicates CYP2D6 inhibitors (pimozide label). The labels cite no study of pimozide concentrations on haloperidol. Both drugs block dopamine D2 receptors, so motor side effects, hyperprolactinaemia and the risk of neuroleptic malignant syndrome add up.
Symptoms
QT prolongation causes no symptoms and shows only on the ECG; arrhythmia presents as palpitations, dizziness or syncope, and both labels report sudden death (haloperidol and pimozide labels). Double dopamine blockade brings tremor, rigidity, hypersalivation, bradykinesia, akathisia and acute dystonia (haloperidol label). Neuroleptic malignant syndrome usually starts with high fever, followed by muscle rigidity, unstable blood pressure and pulse, and altered consciousness (both labels).
Management
The combination is contraindicated. The Spanish haloperidol label bans concomitant use with drugs that prolong the QT interval and names pimozide among the examples (haloperidol label, AEMPS). The Spanish pimozide label contraindicates any drug known to prolong QT as well as CYP2D6 inhibitors (pimozide label). The US pimozide label contraindicates other drugs that prolong the QT interval (pimozide label, ). The US haloperidol label is softer and only calls for particular caution with such drugs (haloperidol label, FDA), but the strictest document applies. Under the US label, pimozide in Tourette's disorder is meant for patients who cannot tolerate or do not respond to haloperidol (pimozide label, FDA): the two are replacements for each other, not partners. If a patient takes both, stop one of them. For each drug on its own: before starting haloperidol, take an ECG, correct potassium and magnesium and then monitor electrolytes; reduce the dose if QTc lengthens and stop haloperidol if QTc exceeds 500 ms (haloperidol label). On pimozide, take an ECG before the start and repeat it during treatment, and stop the drug if QT or QTc exceeds 500 ms (pimozide label).
Sources
Mechanism
Itraconazole is the strongest clinical CYP3A4 inhibitor. Pimozide concentration rises 10+ fold; torsades de pointes risk is maximal. Orap Section 4 strict contraindication.
Symptoms
QT prolongation by day 3, syncope, torsades de pointes.
Management
Combination contraindicated. Alternative antifungal: terbinafine for superficial infections. For systemic infections, hold pimozide one week before itraconazole and resume 2 weeks after.
Sources
Mechanism
Ketoconazole is a strong CYP3A4 inhibitor. Pimozide rises 8-fold, QT extends past 500 ms. Orap Section 4.
Symptoms
Progressive QT prolongation within 5 days, torsades de pointes risk.
Management
Combination contraindicated. Alternative: terbinafine or fluconazole for limited infections (fluconazole is a weaker CYP3A4 inhibitor but still requires ECG monitoring).
Sources
Mechanism
The liver breaks down pimozide mainly through the enzymes CYP3A4 and CYP2D6, and to a lesser extent CYP1A2 (pimozide label). Miconazole inhibits CYP3A4 and the enzyme CYP2C9. The oral gel label calls it a clinically potent inhibitor of CYP3A4 substrates: the gel is held in the mouth and then swallowed, and miconazole reaches the blood. The Spanish pimozide label lists miconazole among the azole antifungals that, according to in vitro data, may markedly raise pimozide levels. High pimozide levels can prolong the QT interval and cause life-threatening torsade de pointes (pimozide and miconazole oral gel labels). Cream and vaginal forms put far less miconazole into the blood. Less than 1% of a skin dose is absorbed. After a 1200 mg vaginal dose, peak plasma levels are more than 100 times lower than after oral or intravenous use (miconazole cream and vaginal ovule labels). The labels give no study of pimozide levels with miconazole.
Symptoms
QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). The danger is ventricular arrhythmia: torsade de pointes, ventricular tachycardia and ventricular fibrillation, up to cardiac arrest and sudden death (pimozide label). An episode presents as palpitations, dizziness or fainting. Excess pimozide also strengthens its usual effects, above all extrapyramidal ones: tremor, muscle rigidity and akathisia, an inability to sit still (pimozide label). The risk of arrhythmia is higher with low potassium or magnesium and with a slow heart rate (pimozide label).
Management
The combination is contraindicated. The miconazole oral gel summary of product characteristics (SmPC) lists pimozide among the drugs that prolong the QT interval and must not be combined with oral miconazole (miconazole oral gel SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The Spanish pimozide SmPC contraindicates azole antifungals and other inhibitors of the enzyme CYP3A4 and names miconazole among the azoles (pimozide SmPC, AEMPS). The US pimozide label contraindicates itraconazole and ketoconazole by name and says pimozide should not be given with azole antifungals in general (pimozide label, US Food and Drug Administration, ). The ban also applies when the gel is used for oral or oesophageal candidiasis. The gel is held in the mouth and then swallowed, and miconazole reaches the blood (miconazole oral gel SmPC). For a patient taking pimozide, choose an antifungal outside the azole group. The pimozide SmPC also names ketoconazole, itraconazole and fluconazole among the azoles (pimozide SmPC, AEMPS). If a patient already takes pimozide and oral miconazole, stop one of them. The cream and vaginal ovule labels do not mention pimozide. They state that little miconazole reaches the blood and that clinically relevant interactions are rare. They ask for caution with warfarin and other vitamin K antagonists, oral antidiabetic drugs and phenytoin (miconazole cream and vaginal ovule SmPCs, AEMPS). The Spanish pimozide SmPC does not separate azoles by dosage form, and the documents give no separate rule for topical forms in patients taking pimozide. For any pimozide treatment, record an electrocardiogram (ECG) before the start and repeat it during treatment. Keep potassium and magnesium in the normal range, and stop pimozide if the QT or corrected QT (QTc) interval exceeds 500 ms (pimozide labels, AEMPS and FDA).
Sources
Mechanism
Posaconazole is a strong CYP3A4 inhibitor. Pimozide rises, torsades risk. Orap Section 4 + Noxafil Section 4.3.
Symptoms
QT prolongation within 5 days.
Management
Combination contraindicated. Hold pimozide for the entire course.
Sources
Mechanism
Quinidine is a strong CYP2D6 inhibitor (secondary pimozide pathway) and itself a QT prolonger. Double torsades risk. Orap Section 4.
Symptoms
QT prolongation by day 3, syncope, torsades de pointes.
Management
Combination contraindicated. If antiarrhythmic is needed in a pimozide patient, discuss catheter ablation or rate control with a beta-blocker without QT effect.
Sources
Mechanism
Ritonavir is the strongest ARV CYP3A4 inhibitor. Pimozide concentration rises 15-fold. Orap Section 4 strict contraindication.
Symptoms
QT prolongation, syncope, torsades de pointes.
Management
Combination contraindicated. For HIV in a pimozide patient, switch ARV to a regimen without ritonavir or cobicistat (e.g., dolutegravir + 2 NRTIs).
Sources
Mechanism
Sertraline raises pimozide concentrations. With a single 2 mg dose of pimozide on top of sertraline 200 mg/day at steady state, pimozide AUC and Cmax rose by about 40% (pimozide label Orap, 4.5; Zoloft label, 12.3). The sertraline label quotes about 35% (4.5). The mechanism is unknown (sertraline label, 4.5). The pimozide label suggests that serotonin reuptake inhibitors may inhibit its CYP2D6 metabolism and names paroxetine and fluoxetine (Orap, 4.5). Pimozide has a narrow therapeutic index, and higher concentrations raise the risk of QTc prolongation and ventricular arrhythmias (Zoloft label, 7.1). Sertraline itself prolongs QTc in a concentration-dependent way (sertraline label, 4.4; Zoloft, 5.10), so the pharmacodynamic effect on repolarisation comes on top of the kinetic interaction. Pimozide doses above 2 mg have not been studied with sertraline (Zoloft, 12.3).
Symptoms
QTc prolongation on the ECG, T-wave changes and U waves (pimozide label), torsade de pointes, ventricular arrhythmias, sudden death. The patient experiences palpitations, dizziness or syncope. With pimozide 2 mg the study showed no ECG change, but there are no data for higher doses (Zoloft, 12.3). The risk is higher with hypokalaemia and hypomagnesaemia, bradycardia, heart disease and a family history of QT prolongation (sertraline label, 4.4). It is also higher in CYP2D6 poor metabolisers, 5–10% of the population, whose pimozide concentrations match those seen with strong inhibitors (Orap, 4.4).
Management
The combination is contraindicated from both sides. The AEMPS sertraline label (4.3) bars use with pimozide outright, and the AEMPS pimozide label (Orap, 4.3) bars pimozide with serotonin reuptake inhibitors and names sertraline. The labels say the same: sertraline is contraindicated in patients taking pimozide (Zoloft, section 4), and pimozide is contraindicated in patients on sertraline (Contraindications). If a patient is already on both, the combination is stopped and an ECG is recorded. Another drug of the same class is not an automatic replacement. The pimozide label also contraindicates paroxetine, citalopram and escitalopram (Orap, 4.3) and names fluoxetine as a CYP2D6 inhibitor (Orap, 4.5); the FDA label says to avoid fluvoxamine as a CYP3A4 inhibitor and reports bradycardia with fluoxetine. Pimozide needs an ECG before the start and periodically during treatment, and is stopped at QT or QTc above 500 ms (Orap, 4.4). Hypokalaemia and hypomagnesaemia are contraindications for it (Orap, 4.3); potassium is corrected before the start and kept normal (FDA label). Sertraline is used with caution in patients with risk factors for QTc prolongation (sertraline label, 4.4; Zoloft, 5.10).
Sources
Mechanism
Sotalol is a class III antiarrhythmic: it lengthens ventricular repolarisation and the QT interval, which is both its therapeutic action and its main risk. According to the label (Sotapor, 4.4), the rate of serious proarrhythmia rises with the dose: 0.5% at 81–160 mg/day, 1.8% at 161–320 mg/day, 4.5% at 321–480 mg/day. Pimozide prolongs QT on its own: its label describes QT prolongation, ventricular arrhythmias, torsade de pointes and sudden death even in patients without risk factors (Orap, 4.4). The effects add up, and the pimozide label expects an additive effect on QT with antiarrhythmic agents. The interaction is purely pharmacodynamic; the documents describe no kinetic component.
Symptoms
QT and QTc prolongation on the ECG, flattening or inversion of the T wave, appearance of a U wave (pimozide label), then torsade de pointes, sustained ventricular tachycardia or ventricular fibrillation, sudden death. The patient experiences palpitations, dizziness or syncope. The risk is higher with a pre-treatment QTc above 450 ms, heart rate below 60 beats per minute, hypokalaemia and hypomagnesaemia, in women, with reduced creatinine clearance, heart failure and a history of ventricular arrhythmias (sotalol labels).
Management
The combination is contraindicated from both sides. The AEMPS sotalol label (Sotapor, 4.3) bars sotalol with QT-prolonging drugs and names pimozide; the AEMPS pimozide label (Orap, 4.3 and 4.5) bars pimozide with such drugs and names sotalol. The pimozide label contraindicates use with any drug that prolongs the QT interval and names sotalol in Drug Interactions. The FDA sotalol label (Betapace, 5.1) says to avoid the combination. If a patient is on both, the torsade-inducing drug is withdrawn. If the combination cannot be avoided, QT is measured before starting and the ECG is monitored (sotalol label, 4.5). Sotalol is started in hospital with continuous ECG monitoring for at least 3 days, after a baseline ECG, normalised potassium and magnesium and a creatinine clearance to set the dosing interval; QTc is checked 2–4 hours after each dose increase (Betapace, 2.1). Sotalol is contraindicated at serum potassium below 4 mEq/L (Betapace, 4). Starting at 80 mg with gradual titration lowers the proarrhythmia risk; at QTc above 480 ms on treatment, benefit and risk are reassessed and dose reduction or withdrawal is seriously considered (Sotapor, 4.4). Pimozide needs an ECG before the start and periodically during treatment, and is stopped at QT or QTc above 500 ms (Orap, 4.4). The FDA label rules out further dose increases at QTc above 0.52 s in adults (0.47 s in children) or more than 25% above baseline. Potassium is corrected before pimozide and kept normal (FDA pimozide label); potassium-wasting diuretics are avoided with pimozide (Orap, 4.5).
Sources
Mechanism
Voriconazole is a strong CYP3A4 inhibitor and itself a QT prolonger. Double torsades risk. Orap Section 4.
Symptoms
QTc above 500 ms by day 2–3, syncope, torsades de pointes.
Management
Combination contraindicated. For invasive mycosis in a pimozide patient, hold pimozide during the voriconazole course and resume 7 days after.
Sources
Mechanism
Both antipsychotics prolong the QT interval. Ziprasidone does so dose-dependently, to a mild-to-moderate degree (ziprasidone label); in placebo-controlled trials QTc rose by about 10 ms at the highest recommended daily dose of 160 mg (ziprasidone label, ). For pimozide, there are reports of QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation at therapeutic doses (pimozide label). No study of the pair exists, and both labels assume the effects add up (ziprasidone and pimozide labels). No kinetic contribution is expected: ziprasidone has little inhibitory effect on cytochrome enzymes, including CYP3A4 and CYP2D6, which metabolise pimozide (ziprasidone label). Both drugs block dopamine D2 receptors, so motor side effects and the risk of neuroleptic malignant syndrome also add up.
Symptoms
QT prolongation causes no symptoms and shows only on the ECG. The ziprasidone label names palpitations, dizziness, syncope or seizures as possible signs of a malignant arrhythmia (ziprasidone label); the pimozide label also reports sudden death and cardiac arrest (pimozide label). Double dopamine blockade presents as tremor, rigidity, akathisia and acute dystonia, and neuroleptic malignant syndrome as high fever, muscle rigidity, unstable blood pressure and pulse, and altered consciousness (both labels).
Management
The combination is contraindicated. The Spanish ziprasidone label names pimozide in its contraindications (ziprasidone label, AEMPS). The US ziprasidone label lists pimozide among the drugs that should not be given with ziprasidone (ziprasidone label, ). The Spanish pimozide label contraindicates any drug known to prolong the QT interval and stresses that its list of examples is not exhaustive (pimozide label). The US pimozide label names ziprasidone outright (pimozide label, FDA). Do not prescribe the two drugs together. If a patient on one of them needs another antipsychotic, choose one that does not prolong the QT interval, because the ban in both labels covers that whole class (ziprasidone and pimozide labels). For each drug on its own: before starting ziprasidone, correct potassium and magnesium, and in patients with stable heart disease take an ECG (ziprasidone label); on pimozide, take an ECG before the start and repeat it during treatment (pimozide label). With palpitations, dizziness, syncope or seizures, take an ECG to look for arrhythmia (ziprasidone label), and stop the drug if QTc exceeds 500 ms (ziprasidone and pimozide labels).
Sources
Verbatim lines from the interaction sections, in the language of the label
«Está contraindicado el uso concomitante de pimozida con fármacos de los que se conoce su efecto de prolongar el intervalo QT (ver sección 4.3 Contraindicaciones), incluyendo ciertos antiarrítmicos…»AEMPS, section 4.5 · Open on CIMA
«Está contraindicado el uso concomitante de pimozida con fármacos de los que se conoce su efecto de prolongar el intervalo QT (ver sección 4.3 Contraindicaciones), incluyendo ciertos antiarrítmicos…»AEMPS, section 4.5 · Open on CIMA
«Está contraindicado el uso concomitante de pimozida con fármacos de los que se conoce su efecto de prolongar el intervalo QT (ver sección 4.3 Contraindicaciones), incluyendo ciertos antiarrítmicos…»AEMPS, section 4.5 · Open on CIMA
«Está contraindicado el uso concomitante de fármacos que inhiben el CYP3A4, tales como antifúngicos azólicos, antivirales inhibidores de la proteasa , antibióticos macrólidos y nefazodona (Ver sección…»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by pimozide. Specifically…»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus may likewise impair pimozide metabolism, pimozide is contraindicated in patients receiving the…»FDA, section 4 · Open on DailyMed
«DRUG INTERACTIONS: Because pimozide prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines…»FDA, section 7 · Open on DailyMed
«Está contraindicado el uso concomitante de pimozida con fármacos de los que se conoce su efecto de prolongar el intervalo QT (ver sección 4.3 Contraindicaciones), incluyendo ciertos antiarrítmicos…»AEMPS, section 4.5 · Open on CIMA
«Está contraindicado el uso concomitante de Orap/AEMPS, section 4.3 · Open on CIMA
«DRUG INTERACTIONS: Pimozide and Celexa: In a controlled study, a single dose of pimozide 2 mg coadministered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean…»FDA, section 7 · Open on DailyMed
«El metabolismo de pimozida es catalizado principalmente por el citocromo P4503A4 (CYP3A4) y CYP2D6 y con menor implicación por el CYP1A2. Datos in vitro indican que los inhibidores especialmente…»AEMPS, section 4.5 · Open on CIMA
«CONTRAINDICATIONS: Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by pimozide. Specifically…»FDA, section 4 · Open on DailyMed
«Está contraindicado el uso concomitante de pimozida con fármacos de los que se conoce su efecto de prolongar el intervalo QT (ver sección 4.3 Contraindicaciones), incluyendo ciertos antiarrítmicos…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Because pimozide prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Because pimozide prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines…»FDA, section 7 · Open on DailyMed
«El metabolismo de pimozida es catalizado principalmente por el citocromo P4503A4 (CYP3A4) y CYP2D6 y con menor implicación por el CYP1A2. Datos in vitro indican que los inhibidores especialmente…»AEMPS, section 4.5 · Open on CIMA
«CONTRAINDICATIONS: Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by pimozide. Specifically…»FDA, section 4 · Open on DailyMed
«Está contraindicado el uso concomitante de Orap/AEMPS, section 4.3 · Open on CIMA
«El metabolismo de pimozida es catalizado principalmente por el citocromo P4503A4 (CYP3A4) y CYP2D6 y con menor implicación por el CYP1A2. Datos in vitro indican que los inhibidores especialmente…»AEMPS, section 4.5 · Open on CIMA
«El metabolismo de pimozida es catalizado principalmente por el citocromo P4503A4 (CYP3A4) y CYP2D6 y con menor implicación por el CYP1A2. Datos in vitro indican que los inhibidores especialmente…»AEMPS, section 4.5 · Open on CIMA
«Está contraindicado el uso concomitante de Orap/AEMPS, section 4.3 · Open on CIMA
«El metabolismo de pimozida es catalizado principalmente por el citocromo P4503A4 (CYP3A4) y CYP2D6 y con menor implicación por el CYP1A2. Datos in vitro indican que los inhibidores especialmente…»AEMPS, section 4.5 · Open on CIMA
«CONTRAINDICATIONS: Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus may likewise impair pimozide metabolism, pimozide is contraindicated in patients receiving the…»FDA, section 4 · Open on DailyMed
«El metabolismo de pimozida es catalizado principalmente por el citocromo P4503A4 (CYP3A4) y CYP2D6 y con menor implicación por el CYP1A2. Datos in vitro indican que los inhibidores especialmente…»AEMPS, section 4.5 · Open on CIMA
«Medicamentos que inducen Torsades de pointes: Algunos antipsicóticos, como clorpromazina, tioridazina, flufenazina, pimozida, haloperidol, amisulprida y sertindol.»AEMPS, section 4.5 · Open on CIMA
«CONTRAINDICATIONS: Antipsychotics Lurasidone (with ritonavir), pimozide»FDA, section 4 · Open on DailyMed
«Prolongación del intervalo QT: No se han realizado estudios farmacocinéticos y farmacodinámicos con citalopram y otros medicamentos que prolonguen el intervalo QT. No se puede excluir que exista un…»AEMPS, section 4.5 · Open on CIMA
«CONTRAINDICATIONS: taking pimozide because of risk of QT prolongation [see Drug Interactions ( 7 )] .»FDA, section 4 · Open on DailyMed
«La administración concomitante de claritromicina y cualquiera de los siguientes principios activos está contraindicada: astemizol, cisaprida, domperidona, pimozida y terfenadina. Dicha asociación…»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Cisapride and pimozide (4.2)»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: Antipsychotics: lurasidone, pimozide»FDA, section 4 · Open on DailyMed
«lurasidona , pimozida, quetiapina, sertindol (ver sección 4.5)»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: • Alpha 1-adrenoreceptor antagonist: alfuzosin • Anti-gout: colchicine, in patients with renal and/FDA, section 4 · Open on DailyMed
«Prolongación del intervalo QT: No se han realizado estudios farmacocinéticos ni farmacodinámicos con escitalopram combinado con otros medicamentos que prolonguen el intervalo QT. No se puede excluir…»AEMPS, section 4.5 · Open on CIMA
«CONTRAINDICATIONS: taking pimozide [see Drug Interactions ( 7 )].»FDA, section 4 · Open on DailyMed
«Está contraindicada la administración de terfenadina a pacientes en tratamiento con dosis múltiples de 400 mg o superiores de fluconazol al día, en base a los resultados de un estudio de…»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Pimozide: Do not use. Risk of QT prolongation and drug interaction. ( 4.2 , 5.11 , 7.7 , 7.8 )»FDA, section 4 · Open on DailyMed
«Medicamentos con estrecho margen terapéutico: Debido al estrecho índice terapéutico de la pimozida y su conocida capacidad para prolongar el intervalo QT, está contraindicado el uso concomitante de…»AEMPS, section 4.5 · Open on CIMA
«Efectos cardiovasculares: Otros antipsicóticos (p. ej., derivados de la fenotiazina, sertindol, pimozida, ziprasidona).»AEMPS, section 4.5 · Open on CIMA
«Agentes reguladores de lípidos: Pimozida»AEMPS, section 4.3 · Open on CIMA
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Pimozide is evaluated for the following indications with varying evidence strength: Tourette syndrome (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Pimozide (≥ 1 in 100): Drowsiness, Dry mouth, Constipation, Tremor, Weight gain, Sedation. See the Safety section for uncommon and serious reactions.
AEMPS summary of product characteristics (section 4.6): the safety of pimozide in pregnancy has not been established, so it should not be given to women of childbearing potential, particularly in the first trimester, unless the physician judges that the expected benefits outweigh the potential risk to the fetus. Animal data showed some embryotoxicity at doses similar to the maximum human dose, and fetal growth retardation and fetal toxicity at about 6 times that dose (mg/kg basis); no teratogenic effects were seen. Newborns exposed to antipsychotics, including pimozide, in the third trimester are at increased risk of extrapyramidal and withdrawal symptoms of varying severity: agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress or feeding disorders.
Pimozide passes into breast milk. Breastfeeding during treatment is not recommended.
Pimozide is contraindicated in: Congenital long QT syndrome; Combination with QT-prolonging agents (amiodarone, sotalol, high-dose citalopram, moxifloxacin, ondansetron); Combination with strong CYP3A4 inhibitors (clarithromycin, erythromycin, itraconazole, ketoconazole, voriconazole, posaconazole, ritonavir, cobicistat); Severe depression with CNS depression; Parkinson disease. Full list in the Safety section.
Direct links to regulator labels. Open in a new tab.
Quetiapine, Risperidone, Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), Valeriana officinalis (root extract), Zolpidem, Chamomile (Matricaria chamomilla / recutita, flowers), Haloperidol, Melatonin