Quetiapine

Mechanism

Quetiapine is an atypical antipsychotic, and antipsychotics appear among the QT examples in both SSRI labels. Post-marketing reports describe QT prolongation at therapeutic doses, and the quetiapine SmPC calls for caution with any QT-prolonging drug. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the citalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Quetiapine is often added to an antidepressant in resistant depression, which is exactly why this pair deserves attention up front: the SSRI label files antipsychotics under contraindicated combinations. If the regimen is assembled anyway, an ECG with QTc is taken before the start and two weeks in, with potassium and magnesium kept normal.

Mechanism

Clarithromycin blocks CYP3A4 – the main quetiapine metabolic route. Quetiapine plasma levels rise 6-fold, with stronger sedation, orthostatic hypotension, and QT effect.

Symptoms

Marked sedation, drowsiness, orthostatic hypotension with syncope on standing. Tachycardia, QT prolongation. In older patients: fall and fracture risk.

Management

The AEMPS label for quetiapine lists the combination with CYP3A4 inhibitors, clarithromycin included, as contraindicated. The FDA label reduces the quetiapine dose sixfold with ECG monitoring instead. Alternative antibiotics: azithromycin or doxycycline, with little effect on CYP3A4. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole.

Mechanism

Quetiapine is an atypical antipsychotic, and antipsychotics appear among the QT examples in both SSRI labels. Post-marketing reports describe QT prolongation at therapeutic doses, and the quetiapine SmPC calls for caution with any QT-prolonging drug. The escitalopram SmPC contraindicates any QT-prolonging drug alongside it: the ban is written broadly, and the classes in brackets are examples.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the escitalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Quetiapine is often added to an antidepressant in resistant depression, which is exactly why this pair deserves attention up front: the SSRI label files antipsychotics under contraindicated combinations. If the regimen is assembled anyway, an ECG with QTc is taken before the start and two weeks in, with potassium and magnesium kept normal.

Mechanism

Ketoconazole is a potent CYP3A4 inhibitor – the main quetiapine metabolic route. Quetiapine plasma levels rise 6- to 7-fold. Marked sedation, orthostatic hypotension, QT prolongation emerge.

Symptoms

Deep sedation, orthostatic hypotension with syncope, tachycardia, QT prolongation on ECG. Older patients: fall risk.

Management

The AEMPS label for quetiapine lists the combination with ketoconazole as contraindicated: quetiapine exposure rises 5 to 8 times. The FDA label reduces the quetiapine dose sixfold with ECG monitoring instead. Alternative antifungals: terbinafine or echinocandins. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole.

Mechanism

Quetiapine is cleared via hepatic CYP3A4. Ritonavir is the strongest available CYP3A4 inhibitor. Quetiapine plasma levels rise 6- to 10-fold.

Symptoms

Marked sedation, orthostatic hypotension with syncope, tachycardia, QT prolongation on ECG. Hyperglycaemia and metabolic disturbance worsen. Older patients face higher fall and fracture risk.

Management

The combination is not prescribed. Alternative antipsychotics on ritonavir: paliperidone (minimal CYP3A4 metabolism) or aripiprazole with caution and a 50% dose cut.

Mechanism

Both drugs depress the central nervous system. The alprazolam SmPC warns that with antipsychotics the depressant effect can increase, up to respiratory depression, coma and death. Quetiapine acts mainly on the central nervous system, so its SmPC asks for caution when it is combined with other centrally acting drugs.

Symptoms

Drowsiness, sedation, slowed reactions, poor coordination. Quetiapine can cause a drop in blood pressure on standing with dizziness, mostly at the start of treatment and during dose titration, and together with sedation this raises the risk of falls, above all in older people (quetiapine and alprazolam SmPCs). Marked central nervous system depression can lead to slowed breathing and coma (alprazolam SmPC). Driving and operating machinery become riskier.

Management

The combination is not prohibited, but the alprazolam SmPC requires limiting the dose and duration of its use with antipsychotics, and quetiapine is one of them. The US Food and Drug Administration (FDA) alprazolam label requires the same with any central nervous system depressant, and the quetiapine SmPC asks for caution with other centrally acting drugs. Alprazolam is given for as short a time as possible, no longer than 2–4 weeks without reassessment; older or debilitated patients start at a lower dose, the dose is reduced in chronic respiratory insufficiency, and alprazolam is contraindicated in severe respiratory insufficiency and sleep apnoea syndrome (alprazolam SmPC). Warn the patient about drowsiness and dizziness on standing, especially at the start of quetiapine treatment and during dose titration (quetiapine SmPC).

Mechanism

Both drugs prolong the QT interval. For amiodarone this is part of its main action: PR and QT intervals lengthen by about 10% (amiodarone label, US Food and Drug Administration, FDA). After quetiapine reached the market, QT prolongation was reported at therapeutic doses and in overdose (quetiapine SmPC). Together they raise the risk of torsades de pointes. Quetiapine is also cleared mainly by CYP3A4 (quetiapine SmPC), which amiodarone inhibits (amiodarone SmPC), so quetiapine levels may rise.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

The combination is avoided: the quetiapine label approved by the US Food and Drug Administration (FDA) names amiodarone among QT-prolonging drugs whose combination with quetiapine should be avoided, and the FDA amiodarone label advises against combining it with QT-prolonging drugs. The Spanish amiodarone SmPC allows the combination only after a careful benefit-risk assessment for the individual patient and with QT monitoring (amiodarone SmPC). Low potassium increases QT prolongation on amiodarone, so a potassium deficit is corrected (amiodarone SmPC). Quetiapine needs particular caution in older patients and in congenital long QT syndrome, heart failure, cardiac hypertrophy, low potassium or low magnesium (quetiapine SmPC). Amiodarone interactions can persist for several months after it is stopped (amiodarone SmPC).

Mechanism

Both drugs prolong the QT interval. The amitriptyline SmPC lists QT-prolonging drugs, including some antipsychotics, among combinations that are not recommended because of the risk of ventricular arrhythmias (amitriptyline SmPC), and QT prolongation has been reported with quetiapine at therapeutic doses (quetiapine SmPC). A second mechanism is the combined anticholinergic effect: in quetiapine it comes from its metabolite norquetiapine (quetiapine SmPC), and amitriptyline has its own (amitriptyline label of the US Food and Drug Administration, FDA). Tricyclic antidepressants and neuroleptics inhibit each other's metabolism, which can lower the seizure threshold (amitriptyline SmPC). The quetiapine SmPC also warns about serotonin syndrome with tricyclic antidepressants.

Symptoms

Palpitations, dizziness, fainting; QT prolongation on the electrocardiogram (ECG) and, in severe cases, torsades de pointes. Dry mouth, constipation, urinary retention, blurred vision, fast heart rate; in older people, confusion, slowed thinking, delirium and falls. Drowsiness and dizziness on standing. Raised body temperature has been reported when amitriptyline is combined with anticholinergic or neuroleptic drugs, especially in hot weather.

Management

The amitriptyline SmPC lists QT-prolonging drugs among combinations that are not recommended (amitriptyline SmPC), and the US Food and Drug Administration (FDA) says quetiapine should be avoided with other drugs known to prolong the QT interval (quetiapine FDA label). Avoid the combination where possible. If it is still needed, take into account the situations in which the quetiapine SmPC asks for particular caution: older age, congenital long QT, heart failure, cardiac hypertrophy, low potassium or magnesium (quetiapine SmPC). In older patients, start amitriptyline at low doses and observe them closely (amitriptyline FDA label). Because of the combined anticholinergic effect, use quetiapine with caution in patients with urinary retention, enlarged prostate, bowel obstruction, raised intraocular pressure or narrow-angle glaucoma (quetiapine SmPC). The dose of either drug may need adjustment because each inhibits the metabolism of the other (amitriptyline SmPC).

Mechanism

Quetiapine lowers the seizure threshold, especially at doses above 300 mg/day. Bupropion is a potent proconvulsant. Additive seizure risk.

Symptoms

Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.

Management

Avoid the combination, especially with quetiapine above 300 mg. Alternative antipsychotics: olanzapine or aripiprazole (minimal seizure threshold effect). Alternative antidepressants: sertraline or escitalopram.

Mechanism

Carbamazepine strongly induces CYP3A4, the liver enzyme that is the main route of quetiapine breakdown. In a study in patients, quetiapine exposure (area under the concentration-time curve) on carbamazepine fell on average to 13% of the baseline value, and even lower in some patients (quetiapine SmPC). The effect also runs the other way: quetiapine can raise the active carbamazepine metabolite, carbamazepine-10,11-epoxide (carbamazepine SmPC).

Symptoms

Quetiapine loses its effect: hallucinations, delusions and agitation return, and in bipolar disorder the risk of a new manic or depressive episode rises. Excess carbamazepine epoxide causes dizziness, somnolence, ataxia and double vision. If carbamazepine is stopped but the raised quetiapine dose is kept, quetiapine levels rise: somnolence, dizziness, orthostatic hypotension.

Management

Quetiapine may be started in a patient on carbamazepine only if its benefit outweighs the risk of withdrawing the inducer; the inducer is changed gradually and, if needed, replaced with a non-inducer such as sodium valproate (quetiapine SmPC). If the combination is needed for longer than 7–14 days, the quetiapine dose is increased up to 5-fold of the original dose, titrated to clinical response and tolerability (US Food and Drug Administration (FDA) quetiapine label). The Spanish SmPC caps the daily quetiapine dose at 750 mg in schizophrenia and 800 mg in bipolar disorder (quetiapine SmPC). After carbamazepine is stopped, the quetiapine dose is brought back to the original level within 7–14 days (quetiapine FDA label). Because of the epoxide rise, the carbamazepine dose is adjusted or its blood levels are monitored (carbamazepine SmPC).

Mechanism

Both drugs prolong the QT interval. Dronedarone prolongs the corrected QT interval (QTc) by about 10 ms (dronedarone SmPC). After quetiapine reached the market, QT prolongation was reported at therapeutic doses and in overdose (quetiapine SmPC). Together they raise the risk of torsades de pointes. Dronedarone is also a moderate CYP3A4 inhibitor (dronedarone SmPC), and quetiapine is cleared mainly by this enzyme (quetiapine SmPC), so quetiapine levels may rise.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

The combination is avoided: the quetiapine label approved by the US Food and Drug Administration (FDA) advises against using it with class III antiarrhythmics, and dronedarone is one of them. The dronedarone SmPC contraindicates it with drugs that can induce torsades de pointes and lists them: phenothiazines, tricyclic antidepressants, some oral macrolides, class I and III antiarrhythmics; quetiapine is not on that list (dronedarone SmPC). If the combination is still needed, potassium and magnesium deficits are corrected before and during dronedarone treatment, the electrocardiogram (ECG) is checked regularly, and dronedarone is stopped if the corrected QT interval (QTc) reaches 500 ms or more (dronedarone SmPC). Quetiapine needs particular caution in older patients and in congenital long QT syndrome, heart failure, cardiac hypertrophy, low potassium or low magnesium (quetiapine SmPC).

Mechanism

Dual antipsychotic therapy – additive risk of extrapyramidal symptoms, sedation, QT prolongation, and metabolic side effects. Polypharmacy without therapeutic rationale in most cases.

Symptoms

Sedation, extrapyramidal symptoms (tremor, rigidity, akathisia), QT prolongation on ECG. Metabolic effects: weight gain, dyslipidaemia (from quetiapine).

Management

Avoid the combination. Choose one antipsychotic: quetiapine for schizophrenia with anxious-depressive component or bipolar disorder; haloperidol for acute psychotic agitation. If dual therapy is needed, restrict to short-term use during acute psychotic episodes.

Mechanism

Additive CNS and respiratory depression. Quetiapine potentiates opioid sedation. Older patients: fall and aspiration risk.

Symptoms

Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.

Management

The combination is possible in palliative care with careful monitoring. Keep doses minimal. Older patients: cap quetiapine at 25–50 mg at night. Alternative antipsychotic for delirium: dexmedetomidine or low-dose haloperidol.

Mechanism

Rifampicin is the most potent CYP3A4 inducer available. Quetiapine plasma levels fall 5- to 8-fold – clinical inefficacy of the antipsychotic.

Symptoms

Return of positive symptoms: hallucinations, delusions, agitation. In bipolar disorder: manic episode risk.

Management

During anti-TB therapy, increase quetiapine 5-fold with clinical monitoring. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole. Alternative anti-TB drug: rifabutin (weaker CYP3A4 induction).

Mechanism

Additive CNS depression plus seizure threshold reduction (tramadol lowers it, quetiapine at high doses).

Symptoms

Deep sedation, drowsiness, ataxia. Seizures (especially with prior epilepsy) are possible. Older patients: fall risk.

Management

Avoid the combination with quetiapine above 300 mg. For analgesia on quetiapine, use paracetamol, an NSAID, or morphine/oxycodone (without serotonergic activity).

Mechanism

Trazodone prolongs the QT interval, and postmarketing reports include torsade de pointes at doses of 100 mg or less (trazodone label, US Food and Drug Administration, FDA). QT prolongation has been reported with quetiapine at therapeutic doses and in overdose (quetiapine summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The trazodone label warns that other QT-prolonging drugs may add to its QT effect (trazodone FDA label). Both drugs act on the central nervous system. Trazodone can intensify the sedative effect of antipsychotics, and both drugs cause somnolence and orthostatic hypotension (SmPCs of both drugs, AEMPS). Trazodone is a serotonergic agent, and quetiapine raises the risk of serotonin syndrome when combined with serotonergic drugs. Neuroleptic malignant syndrome, including fatal cases, has been reported when trazodone was given with neuroleptics (SmPCs of both drugs, AEMPS). Quetiapine and its metabolites do not inhibit the major cytochrome P450 (CYP) enzymes, and the labels give no pharmacokinetic study of this pair (quetiapine FDA label).

Symptoms

QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). A ventricular arrhythmia causes palpitations, dizziness and fainting. The added sedative and blood pressure-lowering effects cause somnolence, dizziness on standing, fainting and falls, more often in older people (summaries of product characteristics of both drugs). Serotonin syndrome presents with agitation, hallucinations, tremor, muscle jerks, fever and a fast pulse (trazodone label). Neuroleptic malignant syndrome presents with high fever, muscle rigidity, confusion and unstable pulse and blood pressure (quetiapine summary of product characteristics).

Management

The labels of both drugs from the US Food and Drug Administration (FDA) say to avoid combining them with drugs that prolong the QT interval. Each of the two prolongs QT according to its own documents (quetiapine and trazodone FDA labels; quetiapine summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The Spanish SmPCs of both drugs are softer and ask for caution with this combination (quetiapine and trazodone SmPCs, AEMPS). Avoid both drugs in bradycardia, low potassium or magnesium, congenital QT prolongation or a history of arrhythmias (quetiapine and trazodone FDA labels). Use quetiapine with caution in older people and in heart failure or cardiac hypertrophy (quetiapine SmPC, AEMPS). Trazodone can intensify the sedative effect of antipsychotics, and its SmPC recommends a dose reduction in that case (trazodone SmPC, AEMPS). If orthostatic hypotension occurs, consider a lower quetiapine dose or a slower titration (quetiapine SmPC, AEMPS). Monitor somnolence and blood pressure closely after the start and before and after each dose increase. Tell the patient not to drive until they know how the drugs affect them (trazodone SmPC, AEMPS; FDA labels of both drugs). If serotonin syndrome or neuroleptic malignant syndrome is suspected, stop trazodone at once and start supportive treatment (trazodone SmPC, AEMPS). In neuroleptic malignant syndrome, stop quetiapine as well (quetiapine SmPC, AEMPS).

Mechanism

Additive hypotension. Quetiapine blocks α1-adrenoceptors; amlodipine dilates vessels.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

The combination is acceptable at low quetiapine doses (≤300 mg/day). Check blood pressure 1–2 weeks after start. In older patients, olanzapine or aripiprazole (less α1-blockade) is preferable.

Mechanism

Additive QT prolongation (quetiapine prolongs QT at high doses).

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

For short azithromycin courses (3–5 days) with quetiapine ≤300 mg, the combination is acceptable. On high quetiapine doses or cardiovascular disease: ECG before start or alternative antibiotics.

Mechanism

Additive hypotension (quetiapine blocks α1-adrenoceptors) and additive bradycardia.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

The combination is acceptable at low quetiapine doses (≤300 mg/day). Check pulse and blood pressure 1–2 weeks after start. In older patients, olanzapine or aripiprazole (less α1-blockade) is preferable.