Barhemsys (amisulpride)
Antiemetic Intravenous Vial (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Amisulpride, a dopamine-2 (D2) and dopamine-3 (D3) antagonist, is an antiemetic.
Amisulpride, a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist, is an antiemetic. Amisulpride binds to D2/D3 receptors, and has no binding affinity for D1, D4, alpha-adrenergic, histaminergic, muscarinic,gamma-aminobutyric acid (GABA) type A, GABA type B or n-methyl-D-aspartic acid(NMDA)receptors, and little or no affinity for 5-HT2B and 5-HT7receptors. Dopamine D2 receptors are in the chemoreceptor trigger zone (CTZ) andrespond to the dopamine released from nerve endings.
Activation of the CTZ relays stimuli to the vomiting center, which is involved in emesis. Studies in multiple species indicate that D3receptors in the CTZ also play a role in emesis. Amisulpride inhibits hERG potassium ion channels (IC50approximately 100 microM) and exhibits dose- and concentration-dependent prolongation of the QT interval.
Following IV administration, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases to about 50% of the peak value within approximately 15 minutes. Amisulpride exposure (AUC) increases dose-proportionally in the dose range from 5 to 40 mg (4-times the maximum recommended dose). Plasma protein binding is 25 to 30%.
The mean elimination half-life is approximately 4 to 5 hours and similar between healthy subjects and surgical patients. No metabolites were detectable in plasma while 4 metabolites, accounting for less than 7% of the dose, were identified in urine and feces. In vitro studies suggest amisulpride is not metabolized by major cytochrome P-450 isoenzymes.
Following IV administration, 74 and 23% of the administered dose was recovered in urine and feces,respectively; 58 and 20% was excreted unchanged in urine and feces, respectively. Amisulpride clearance is 342 mL/minute, greater than a typical glomerular filtration rate of 125 mL/minute, which suggests that amisulpride undergoes active renal secretion; multidrug and toxin extrusion (MATE) 1and MATE2-K transporters may contribute to active renal secretion.
In subjects with severe renal impairment (estimated glomerular filtration rate (eGFR) less than 30 mL/minute per 1.73 m2) not requiring dialysis, amisulpride peak plasma concentraton after a single 10 mg IV dose was not greater than that in healthy subjects with normal renal function, and the AUC was approximately twice as high. In surgical patients with mild or moderate renal impairment (eGFR 30-89 mL/minute per 1.73 m2), amisulpride peak plasma concentraton after a single 5 or 10 mg IV dose was not significantly different and the AUC of amisulpride increased about 1.3-fold compared to patients with normal renal function. The changes in the pharmacokinetics of amisulpride following a single 5 or 10 mg IV dose in subjects or patients with mild, moderate, or severe renal impairment compared to subjects or patients with normal renal function are not considered to be clinically meaningful.
The effect of hepatic impairment was not studied. No clinically significant differences in the pharmacokinetics of amisulpride were observed based on age (18-90 years of age), sex, or race.
Generic name: amisulpride
Drug class: Antiemetic
Therapeutic class: Gastrointestinal Therapy Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Barhemsys
Indications
The following indications are listed for Barhemsys:
- Post-Operative Nausea And Vomiting
- Prevention Of Post-Operative Nausea And Vomiting
Also known as: Post Op Nausea And Vomiting, Postop Nausea And Vomiting Prophylaxis, Postoperative Nausea And Vomiting, Postoperative Nausea And Vomiting Prophylaxis.
Dosing
No dosing information is available for this tab.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Barhemsys 5 Mg/2 Ml Vial | Maintenance | Infuse 4 milliliters (10 mg) over 1-2 minute(s) by intravenous route once. |
| Barhemsys 10 Mg/4 Ml Vial | Maintenance | Infuse 4 milliliters (10 mg) over 1-2 minute(s) by intravenous route once. |
No dosing information is available for this tab.
Drug interactions
No clinical drug interaction studies have been conducted with amisulpride.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Antipsychotics/Sibutramine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Sibutramine has demonstrated antidepressant effects. (1)
CLINICAL EFFECTS: Concurrent use of sibutramine and an antipsychotic may result in additive or synergistic central nervous system (CNS) effects.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Australian,(2) Canadian,(1) and UK(3) manufacturers of sibutramine state that concurrent use with antipsychotics is contraindicated.
DISCUSSION: The use of sibutramine with other CNS-active agents has not been evaluated.(1-3)
Neuroleptics/Iomeprol
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Neuroleptics may lower seizure threshold.(1)
CLINICAL EFFECTS: Use of iomeprol in a patient receiving a neuroleptic may increase the risk of seizure.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of iomeprol states that neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1)
DISCUSSION: Because neuroleptics may lower seizure threshold, neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Antipsychotics; Phenothiazines/Opioids (Cough And Cold)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as antipsychotics, including phenothiazine derivatives.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Antipsychotics; Phenothiazines; Rivastigmine/Metoclopramide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: These agents block dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic malignant syndrome may also occur in patients receiving D2 blockers. The risk of these adverse effects may be increased by concurrent use.(1-3)
CLINICAL EFFECTS: Concurrent use may increase the risk of extrapyramidal reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which may be permanent, typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs.(1-3) Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, an autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias), elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.(1)
PREDISPOSING FACTORS: Patients with Parkinson's or Lewy Body Disease may be more likely to have extrapyramidal reactions or unmasking of their primary disease symptoms. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1)
PATIENT MANAGEMENT: The concurrent use of metoclopramide and agents likely to cause extrapyramidal reactions should be avoided.(1) If concurrent use is warranted, monitor patients closely for extrapyramidal reactions and neuroleptic malignant syndrome. The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) Discontinue therapy if symptoms occur. Instruct patients to seek immediate medical attention if symptoms develop. Symptoms of extrapyramidal reactions, including tardive dyskinesia, include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.(3)
DISCUSSION: Both metoclopramide and phenothiazines can cause extrapyramidal reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome. The risk may be increased by concurrent use.(1,2) Extrapyramidal symptoms have been reported with concurrent metoclopramide and neuroleptics, prochlorperazine, and chlorpromazine.(4-6)
Possible Qt Prolonging Agents/Anagrelide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of anagrelide with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-4)
CLINICAL EFFECTS: The concurrent use of anagrelide with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-4)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(5)
PATIENT MANAGEMENT: The US manufacturer of anagrelide states that anagrelide should not be used in patients taking medications known to prolong the QT interval.(1) The Australian, Canadian, and UK manufacturers of anagrelide state use of anagrelide should be approached with caution in patients taking medications that can prolong the QTc interval.(2-4) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, dose-related QT changes were observed with anagrelide. The maximum mean change in QTcI (95% CI) in comparison to placebo was 7.0 (9.8) ms and 13.0 (15.7) msec following doses of 0.5 mg and 2.5mg, respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(6) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Artemether-Lumefantrine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of artemether-lumefantrine and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the use of artemether-lumefantrine in patients taking drugs that are known to prolong the QTc interval is contraindicated. These agents include class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some macrolides, fluoroquinolones, imidazole and triazole antifungals; terfenadine; astemizole; and cisapride.(1) The US manufacturer of artemether-lumefantrine states that the use of artemether-lumefantrine should be avoided in patients taking drugs that are known to prolong the QTc interval. These agents include class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some macrolides, fluoroquinolones, imidazole and triazole antifungals; terfenadine; astemizole; and cisapride.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Bepridil
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bepridil has shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of bepridil with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Hypokalemia, the use of potassium wasting diuretics, and the presence of antecedent bradycardia may increase the risk of torsades de pointes.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypomagnesemia, hypocalcemia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of bepridil states that under contraindications that bepridil is contraindicated in patients taking other drugs that prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Cisapride
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Torsades de pointes has been reported with cisapride. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of cisapride with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The Australian manufacturer of cisapride states that concurrent use of agents known to prolong the QTc interval with cisapride is contraindicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Disopyramide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of disopyramide and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The Australian manufacturer of disopyramide states that concurrent use with agents liable to produce torsades de pointes, including tricyclic or tetracyclic antidepressants, erythromycin, vincamine, and sultopride, is contraindicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Domperidone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of domperidone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of domperidone patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or female gender.(2) The elderly and patients taking dosages of domperidone greater than 30 mg may also be at increased risk. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of domperidone and agents known to prolong the QT interval is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Treatment with domperidone has been associated with increased risk of sudden cardiac death.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Possible Qt Prolonging Agents/Dronedarone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of dronedarone and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration of dronedarone and QT prolonging agents may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of dronedarone states that the use of drugs or herbal products that are known to prolong the QTc interval is contraindicated. These agents include phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class IA and III antiarrhythmics.(1) When concurrent therapy of dronedarone and possible QT prolonging agents is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Droperidol
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Droperidol has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of droperidol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, age over 65 years, alcohol abuse, and the use of agents such as benzodiazepines, volatile anesthetics, and intravenous opiates may predispose patients to the development of prolonged QT syndrome.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypocalcemia, or female gender.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of droperidol states under precautions/drug interactions that drugs known to have the potential to prolong the QT interval should not be used together with droperidol.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Halofantrine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Halofantrine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of halofantrine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of halofantrine states in a black box warning that halofantrine is not recommended for use in combination with drugs known to prolong the QTc interval. Under precautions, drug interactions, the manufacturer states that halofantrine should not be administered with drugs known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Levoketoconazole
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Levoketoconazole has been observed to prolong the QTc interval in a dose-dependent manner. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of levoketoconazole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of levoketoconazole states that levoketoconazole is contraindicated with other agents that prolong the QT interval.(1) Levoketoconazole is also contraindicated in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history). Use caution in patients with other risk factors for QT prolongation including congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities. Consider more frequent ECG monitoring. Prior to starting levoketoconazole, obtain a baseline ECG and correct hypokalemia or hypomagnesemia. If a patient develops QT prolongation with a QTc interval greater than 500 msec, temporarily discontinue levoketoconazole. After resolution of prolonged QTc interval, levoketoconazole may be resumed at a lower dose. If QTc interval prolongation recurs, permanently discontinue levoketoconazole.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: During phase 1 and 2 studies, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Pimozide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Pimozide has shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of pimozide with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of pimozide states that the use of pimozide is contraindicated in patients taking other drugs which prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Sertindole
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sertindole has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects of the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of sertindole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of sertindole state that sertindole is contraindicated in patients receiving drugs known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2)
Possible Qt Prolonging Agents/Sparfloxacin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sparfloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of sparfloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmics, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of sparfloxacin states under contraindications that sparfloxacin is contraindicated in patients being treated concomitantly with medications known to produce an increase in the QTc interval and/or torsades de pointes.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2)
Selected Antipsychotics That Prolong Qt/Apomorphine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of apomorphine with certain antipsychotics may have additive effects on the QTc interval.(1) In addition, apomorphine is used to treat Parkinson Disease (PD) by increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1,2)
CLINICAL EFFECTS: The concurrent use of apomorphine with certain antipsychotics may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) In addition, the efficacy of either agent may be decreased, leading to exacerbation of PD. Motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(3) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4) Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.
PATIENT MANAGEMENT: The US manufacturer of apomorphine states that patients with major psychotic disorders treated with neuroleptics should be treated with dopamine agonists only if the potential benefits outweigh the risks. Concurrent use with agents known to prolong the QT interval should be approached with caution.(1) The Canadian manufacturer of levomepromazine states concomitant use with other QT prolonging medications is not recommended.(5) The UK manufacturer of zuclopenthixol states that coadministration of other QT prolonging medications should be avoided.(6) Manufacturers of other QT-prolonging antipsychotics generally recommend using caution when coadministered with medications that prolong the QT interval. Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(2,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic. They also found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(3,4) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)
Selected Antipsychotics That Prolong Qt/Levomethadyl (Ir)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Levomethadyl has been shown to prolong the QTc interval. Concurrent use with selected antipsychotics may result in additive effects on the QTc interval.(1,2) Concurrent use of opioids such as levomethadyl and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(3)
CLINICAL EFFECTS: The concurrent use of levomethadyl with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2) Concurrent use of opioids such as levomethadyl and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: The manufacturer of levomethadyl states under contraindications that levomethadyl is contraindicated in patients being treated concomitantly with other drug products known to prolong the QT interval.(1,2) Limit prescribing opioid analgesics such as levomethadyl with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(3) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(6) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(8) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(9) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(10) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(11) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(12)
Selected Antipsychotics That Prolong Qt/Methadone (Non Mat)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Methadone has been shown to prolong the QTc interval. Concurrent use with selected antipsychotics may result in additive effects on the QTc interval. Concurrent use of methadone and antipsychotics may result in additive CNS depression.(1,2)
CLINICAL EFFECTS: Concurrent use of methadone with antipsychotics may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Concurrent use of methadone and other CNS depressants such as antipsychotics may result in profound sedation, respiratory depression, coma, and/or death.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Concurrent use of methadone with agents known to prolong the QT interval should be approached with extreme caution.(1) Limit prescribing methadone with CNS depressants such as antipsychotics to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)
DISCUSSION: Most cases of methadone-induced QT prolongation are associated with, but not limited to, higher dose treatment (greater than 200 mg daily) and most involve patients being treated for pain with large, multiple daily doses. Cases have been reported in patients treated with doses commonly used for maintenance treatment of opioid addiction.(1) A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(6) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(8) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(9) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(10) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(11) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(12) Selected antipsychotics linked include: amsulpride, chlorpromazine, chlorprothixene, clozapine, iloperidone, mesoridazine, paliperidone, perphenazine, pimavanserin, pipamperone, promethazine, quetiapine, sulpiride, sultopride, thioridazine, ziprasidone, and zuclopenthixol.
Selected Antipsychotics That Prolong Qt/Methadone For Mat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Methadone has been shown to prolong the QTc interval. Concurrent use with selected antipsychotics may result in additive effects on the QTc interval.(1-3) Concurrent use of methadone and antipsychotics may result in additive CNS depression.(1-3)
CLINICAL EFFECTS: The concurrent use of methadone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2) Concurrent use of opioids and other CNS depressants such as antipsychotics may result in profound sedation, respiratory depression, coma, and/or death.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4) Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Concurrent use of methadone with other agents known to prolong the QT interval should be approached with extreme caution.(1,2) Limit prescribing methadone with CNS depressants such as antipsychotics to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Medication assisted treatment (MAT) with methadone is not contraindicated in patients taking CNS depressants; however, gradual tapering or decreasing to the lowest effective dose of antipsychotics may be appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's methadone treatment.(5) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(3) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(6) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7)
DISCUSSION: Most cases of methadone-induced QT prolongation are associated with, but not limited to, higher dose treatment (greater than 200 mg daily) and most involve patients being treated for pain with large, multiple daily doses. Cases have been reported in patients treated with doses commonly used for maintenance treatment of opioid addiction.(2) Levomethadone should be used with caution in patients with a history of QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or electrolyte abnormalities. Cases of QT prolongation and torsades de pointes have been reported, most commonly with high doses.(1) A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(8) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(9) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(10) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(11) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(12) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(13) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(14) Selected antipsychotics that prolong QT include: amsulpride, chlorpromazine, chlorprothixene, clozapine, haloperidol, iloperidone, mesoridazine, paliperidone, pimavanserin, pipamperone, promethazine, quetiapine, sulpiride, sultopride, thioridazine, ziprasidone, and zuclopenthixol.
Selected Dopamine Blockers/Cabergoline
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Dopamine (D2) blockers such as the phenothiazines, butyrophenones, thioxanthenes and atypical antipsychotics may decrease the effects of cabergoline, a dopamine agonist.(1)
CLINICAL EFFECTS: Concurrent administration of cabergoline with dopamine blockers (e.g. phenothiazines, butyrophenones, or thio xanthines) may decrease the effectiveness of cabergoline.(1) Cabergoline may decrease the effectiveness of antipsychotic treatment.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of cabergoline states cabergoline(1) should not be administered concurrently with dopamine antagonists. Avoid concurrent use when possible. If cabergoline is started in a patient receiving long term antipsychotic treatment, monitor closely for loss of antipsychotic efficacy. If an antipsychotic is required for a patient on long term cabergoline therapy, consider use of a shorter half-life, less potent dopamine (D2) blocking atypical antipsychotic (e.g. clozapine, quetiapine) and monitor closely.
DISCUSSION: The manufacturer of cabergoline state that it should not be administered concurrently with dopamine antagonists.
Selected Qt Prolonging Agents/Ziprasidone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ziprasidone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ziprasidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1,3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QT interval such as dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.(1) It would be prudent to avoid the use of ziprasidone with medicines suspected of prolonging the QT interval. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Slt Antipsychotics/Selected Dopaminergic Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Selected dopaminergic agents are used to treat neurologic conditions such as Parkinson Disease (PD) or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)
CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination.
PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.
PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the dopaminergic agent. The US manufacturer of ropinirole recommends treatment with dopaminergic agents only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)
DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Amisulpride/Qt Prolonging Agents
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Amisulpride has been shown to prolong the QT interval. Concurrent use with QT prolonging agents may result in additive effects on the QT interval.(1)
CLINICAL EFFECTS: The concurrent use of amisulpride with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Use caution when using amisulpride concurrently with other agents that can prolong the QT interval. Amisulpride may cause a dose and concentration dependent increase in the QTc interval. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. ECG monitoring is recommended in patients with pre-existing arrhythmias or cardiac conduction disorders; electrolyte abnormalities; congestive heart failure; or in patients taking medications or with other medical conditions known to prolong the QT interval. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)
DISCUSSION: QT prolongation and torsades de pointes have been reported with amisulpride. In a study in 40 patients with post operative nausea and vomiting, amisulpride increased baseline QTcF by 5 msec after a 2-minute intravenous infusion of 5 mg and by 23.4 msec after an 8-minute intravenous infusion of 40 mg. Based on an exposure-response relationship, it is expected that a 10 mg intravenous infusion over 1 minute may increase the QTcF by 13.4 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Antipsychotics/Bupropion
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Both bupropion and the antipsychotics are known to lower the seizure threshold.(1,2) Bupropion is also a strong inhibitor of CYP2D6.(3)
CLINICAL EFFECTS: Concurrent use of bupropion and an antipsychotic may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2)
PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)
PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)
DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1)
Antipsychotics; Phenothiazines/Opioids (Extended Release)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Antipsychotics; Phenothiazines/Tramadol (Extended Release)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as tramadol with antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as tramadol with other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as tramadol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Antipsychotics;Phenothiazine/Slt Opioids (Immediate Release)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Possible Qt Prolonging Agents/Adagrasib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Adagrasib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)
CLINICAL EFFECTS: The concurrent use of adagrasib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of adagrasib states that the concurrent use of QT prolonging agents should be avoided.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1)
DISCUSSION: Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1) Agents that are linked to this monograph may have been associated with Torsade de Pointes and/or QT prolongation but at this time lack substantial evidence for causing Torsade de Pointes.(3)
Possible Qt Prolonging Agents/Ajmaline
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ajmaline has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ajmaline with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: If possible, avoid the use of ajmaline with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Ajmaline has been associated with case reports of QT prolongation and torsades de pointes (TdP).(1,3-8) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(9)
Possible Qt Prolonging Agents/Aumolertinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)
DISCUSSION: A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Dexmedetomidine Sublingual
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Dexmedetomidine sublingual has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of dexmedetomidine sublingual with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of dexmedetomidine sublingual states that concurrent use should be avoided with other agents known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a QT study, dexmedetomidine sublingual had a concentration dependent effect on the QT interval. The mean QTc (95% confidence interval) increased from baseline by 6 (7) msec with a 120 mcg single dose, 8 (9) msec with 120 mcg followed by 2 additional doses of 60 mcg (total 3 doses), 8 (11) msec with a single 180 mcg dose, and 11 (14) msec with 180 mcg followed by 2 additional doses of 90 mcg (total 3 doses), respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Dordaviprone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Dordaviprone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of dordaviprone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: If possible, avoid the use of dordaviprone with other agents known to prolong the QTc interval. If current use cannot be avoided, separate administration of dordaviprone and the QT-prolonging agent. The manufacturer does not provide details about how to separate administration and states that the exposure-response relationship and time course of pharmacodynamic response is not fully characterized. Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours (0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1) Baseline and periodic monitoring of ECG and electrolytes is recommended.(1) Increase the frequency of monitoring in patients with congenital long QT syndrome, existing QTc prolongation, history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or are taking strong or moderate CYP3A4 inhibitors.(1) If QTc interval prolongation occurs, dose modifications are warranted. If QTc is >500 msec or the change from baseline is >60 msec, interrupt dordaviprone therapy until QTc interval is <= 480 msec or returns to baseline. If the patient has Torsades de pointes, polymorphic ventricular tachycardia, or signs or symptoms of serious or life-threatening arrhythmia, permanently discontinue dordaviprone.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Dordaviprone causes concentration-dependent QTc prolongation.(1) In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8, 13.7) with dordaviprone (1.2 times the maximum recommended dose).(1) In a pooled safety analysis, out of 82 patients with baseline ECG, 6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had an increase in QTc >500 msec. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Fexinidazole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Fexinidazole has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of fexinidazole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of fexinidazole states that fexinidazole should be avoided in patients receiving other drugs known to cause QT prolongation.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to prolong QTcF interval or to induce bradycardia do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Firmonertinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Firmonertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of firmonertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of firmonertinib states that firmonertinib should be avoided in patients with risk factors that may increase the risk of QTc interval prolongation or arrhythmic events, such as heart failure, hypokalemia, or congenital long QT syndrome.(1) Concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating firmonertinib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. The manufacturer of firmonertinib states patients with at least two independent ECG tests indicating a QTc > 500 ms should temporarily discontinue firmonertinib until QTc < 481 ms or returns to baseline levels (e.g., baseline QTc > or = 481 ms). Patients with QTc prolongation and severe arrhythmic symptoms or signs should permanently discontinue firmonertinib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical trials, among 446 patients treated with firmonertinib at a dose of 80 mg, 57 (12.8%) experienced QT interval prolongation on an ECG, of which 6 (1.3%) were grade 3 and the rest were grade 1-2. Of these, 7 (1.6%) experienced dose interruption, 5 (1.1%) experienced dose reduction, and 1 (0.2%) experienced permanent discontinuation of treatment.(1) In another study, QTc interval prolongation was reported as an adverse event in 6% of 130 patients (in 20 mg, 40 mg, 80 mg, and 160 mg groups; n=2 each). All were classified as grade 1 or grade 2 and assessed as possibly related to treatment. Two events (grade 2 at 80 mg, grade 2 at 160 mg) led to dose interruption before resolution. QT prolongation in the remaining patients was resolved without intervention, except for one event (grade 1) reported as worsening.(3)
Possible Qt Prolonging Agents/Gadofosveset
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: QT prolongation has been reported following gadofosveset administration. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of gadofosveset in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: In patients maintained on agents known to prolong the QT interval, consider a baseline ECG prior to administration of gadofosveset to asses the risk/benefit of gadofosveset. If gadofosveset is used, consider ECG monitoring for 72 hours until the majority of gadofosveset is eliminated. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Counsel patients to report any irregular heartbeat, dizziness, or fainting episodes during this time frame.(1)
DISCUSSION: In clinical trials, 6% of patients experienced an increase in QTc of 30 msec to 60 msec 45 minutes after the administration of gadofosveset and 0.4% of patients experienced a QTc increase of greater than 60 msec at 45 minutes post-administration.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Gepotidacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Gepotidacin may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of gepotidacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of gepotidacin states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating gepotidacin, during concomitant use, and as clinically indicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: The effect of gepotidacin on the QTc interval was evaluated in a randomized, active (moxifloxacin 400 mg) and placebo-controlled, double-blind cross-over trial in healthy subjects who received single intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and concentration-dependent QTc prolongation effect of gepotidacin was observed. The mean placebo-corrected change from baseline QTcF values around Tmax were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing regimens and route of administration). Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Givinostat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Givinostat may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of givinostat with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of givinostat states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating givinostat, during concomitant use, and as clinically indicated.(1) If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold givinostat therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a QT study, the largest mean increase in QTc interval of 13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after administration of givinostat 265.8 mg (approximately 5 times the recommended 53.2 mg dose in patients weighing 60 kg or more).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Hydroxychloroquine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Hydroxychloroquine has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of hydroxychloroquine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of hydroxychloroquine states that hydroxychloroquine should not be administered with other agents that prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: The manufacturer states that hydroxychloroquine has been shown to prolong the QT interval;(1) however, conditions that hydroxychloroquine treats have also been associated with QT prolongation. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Iloperidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Iloperidone has been shown to prolong the QTc interval by 9 msec at dosages of 12 mg twice daily. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of iloperidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age or with concurrent use of inhibitors of CYP3A4 or CYP2D6, which metabolize iloperidone.(1,3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. co-administration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of iloperidone states that the concurrent administration of other drugs that are known to prolong the QTc interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) Coadministration of ketoconazole (200 mg twice daily, an inhibitor of CYP3A4) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Coadministration of paroxetine (20 mg daily, an inhibitor of CYP2D6) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1)
Possible Qt Prolonging Agents/Levomepromazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Levomepromazine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of levomepromazine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of levomepromazine states that levomepromazine is not recommended in patients receiving other drugs known to cause QT prolongation.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Case reports of QTc prolongation associated with levomepromazine have been reported.(1,3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Possible Qt Prolonging Agents/Lonafarnib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Lonafarnib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of lonafarnib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of lonafarnib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs when initiating, during concurrent use, and as clinically indicated.(1) Lonafarnib dose modification recommendation: if the QTc interval is greater than or equal to 500 msec, withhold lonafarnib until the QTc interval is less than 470 msec, then resume lonafarnib at the same dosage.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive days and a single 200 mg dose on day 10 increased the mean QTc interval by 19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48 hours after administration of the morning dose of lonafarnib 200 mg. The maximum concentration (Cmax) on Day 10 was 2233 ng/ml, which is similar to the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford Progeria Syndrome patient population.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Milsaperidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Milsaperidone may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of milsaperidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and with concurrent use of inhibitors of CYP3A4 or CYP2D6, which metabolize milsaperidone.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of milsaperidone states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval is consistently above 500 msec, discontinue milsaperidone.(1)
DISCUSSION: Milsaperidone and iloperidone rapidly interconvert in vivo. In a study of 160 patients with psychiatric disorders, coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Mobocertinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Mobocertinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of mobocertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of mobocertinib states that mobocertinib may cause life-threatening QTc prolongation, including torsades de pointes. Mobocertinib should be avoided in patients receiving other drugs known to cause QT prolongation.(1) If patients develop QTc prolongation during mobocertinib therapy, dose modifications are recommended: - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the same dose. - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60 msec from baseline) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 and recurrence: permanently discontinue mobocertinib. - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Increase the frequency of ECG monitoring in patients with risk factors for QTc prolongation, including congenital long QT syndrome, heart disease, or electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a clinical study, mobocertinib 160 mg once daily was associated with a concentration-dependent increase in QTc, with the largest mean increase in QTc of 23 msec.(1) In clinical studies, patients were excluded if baseline QTc was greater than 470 msec. In a subset of 250 patient with scheduled and unscheduled electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and 11% of patients had a change-from-baseline QTc interval >60 msec. Grade 4 Torsades de Pointes occurred in 1 patient (0.4%).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Oxaliplatin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of oxaliplatin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of oxaliplatin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of oxaliplatin in patients with congenital long QT syndrome. ECG monitoring is recommended if oxaliplatin therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Prescribing information for oxaliplatin states post-marketing cases of QT prolongation and ventricular arrhythmias, including fatal Torsades de Pointes, have been reported.(1) Case reports have documented QT prolongation in patients with varying cancer indications for oxaliplatin.(3-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)
Possible Qt Prolonging Agents/Pacritinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Pacritinib has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of pacritinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of pacritinib states concurrent use with agents known to prolong the QT interval should be avoided. Avoid the use of pacritinib in patients with a baseline QTc > 480 msec. Correct hypokalemia prior to initiation and during therapy with pacritinib.(1) If patients develop QTc prolongation >500 msec or >60 msec from baseline, hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline within 1 week, resume pacritinib at the same dose. If time to resolution of the QTc interval takes greater than 1 week to resolve, reduce the pacritinib dose.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a 24 week clinical study, patients treatment with pacritinib 200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1) Pacritinib has been associated with QTc interval prolongation. In clinical trials, patients with QTc prolongation >500 msec occurred in 1.4% of patients in the treatment arm compared to 1% in the control arm. The treatment arm had a greater incidence of an increase in QTc > 60 msec from baseline than the control arm (1.9% vs 1%, respectively). QTc prolongation adverse reactions were higher in the treatment arm than the control group (3.8% vs 2%, respectively).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Quizartinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Quizartinib has been shown to prolong the QTc interval in a dose- and concentration dependent manner. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)
CLINICAL EFFECTS: The concurrent use of quizartinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of quizartinib states that the concurrent use of QT prolonging agents should be avoided.(1) Quizartinib is only available through a restricted REMS program due to the serious risk of QT prolongation, torsades de pointes, and cardiac arrest. The manufacturer recommends monitoring as follows: -Initiate quizartinib only if the QTcF is less than or equal to 450 ms. -During induction and consolidation, monitor ECGs prior to initiation and then at minimum once weekly during treatment. -During maintenance, monitor ECGs prior to initiation and then at minimum once weekly for the first month following dose initiation and escalation and clinically therafter. Dose escalation may occur only if the QTcF is less than or equal to 450 ms. The manufacturer recommends the following dose modifications for adverse reactions: -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose. -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of quizartinib without interruption based on prescribing information. Resume the previous dose in the next cycle if the QTcF has decreased to less than 450 ms. -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib. Resume at a reduced dose based on prescribing information when the QTcF is less than 450 ms. Maintain the dose of 26.5 mg once daily during maintenance if the QTcF is greater than 500 ms during induction or consolidation. -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently discontinue quizartinib if QTcF is greater than 500 ms despite dose reduction and correction/elimination of other risk factors. -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of life-threatening arrhythmia occur (Grade 4) - Permanently discontinue quizartinib. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Quizartinib has been associated with QTc interval prolongation, Torsades de Pointes, ventricular arrhythmias, cardiac arrest, and sudden death. Quizartinib increased QTc in a dose- and concentration-dependent manner.(1) In an exposure-response analysis, quizartinib had a predicted concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of 2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg and 53 mg during maintenance therapy.(1) In patients administered quizartinib, 2.3% of 265 patients had a QTcF greater than 500 msec and 10% of patients had a increase from baseline QTcF greater than 60 msec.(1) In patients administered quizartinib during the induction phase, torsades de pointes occurred in approximately 0.2% of patients, cardiac arrest occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients experienced ventricular fibrillation.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Revumenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Revumenib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of revumenib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of revumenib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib, during concomitant use, and as clinically indicated.(1) If the QTc interval is greater than 480 ms, withhold revumenib therapy. Resume revumenib after the QTc interval drops to 480 msec or less.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical trials, QTc interval prolongation was reported as an adverse event in 29% of 135 patients treated with the recommended dosage of revumenib; 12% of patients had Grade 3 QTc prolongation. Revumenib increased the QTc interval in a concentration-dependent manner. At the mean steady-state Cmax using the highest approved recommended dosage of revumenib without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper bound of 90% confidence interval = 30 msec). At the steady-state Cmax using the highest approved recommended dosage of revumenib with CYP3A4 inhibitors, QTc increase was predicted to be 19 msec (upper bound of 90% confidence interval = 22 msec).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Selpercatinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Selpercatinib prolongs the QTc interval.(1) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2,3)
CLINICAL EFFECTS: The concurrent use of selpercatinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2,3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Selpercatinib prolongs the QT interval. An increase in QT interval to > 500 ms was measured in 6% of patients and increase in the QT interval of at least 60 ms over baseline was measured in 15% of patients. Monitor patients at significant risk of developing QT prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes, and TSH at baseline and periodically during treatment. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiation and during treatment. Dose adjustments (1): For grade 3 QT interval prolongation, withhold selpercatinib until recovery to baseline or grade 0 or 1. Resume at a reduced dose. -1st dose reduction: For patients weighing less than 50 kg: 80 mg twice daily. For patients weighing 50 kg or greater: 120 mg twice daily. -2nd dose reduction: For patients weighing less than 50 kg: 40 mg twice daily. For patients weighing 50 kg or greater: 80 mg twice daily. -3rd dose reduction: For patients weighing less than 50 kg: 40 mg once daily. For patients weighing 50 kg or greater: 40 mg twice daily. -For grade 4 QT prolongation, discontinue selpercatinib.
DISCUSSION: The effect of selpercatinib on the QT interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QT is predicted to be 10.6 ms (upper 90% confidence interval: 12.1 ms) at the mean steady state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QT was concentration-dependent. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Possible Qt Prolonging Agents/Taletrectinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Taletrectinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of taletrectinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Taletrectinib should be taken on an empty stomach. Administration with food may increase the risk of QT prolongation or torsade de pointes.
PATIENT MANAGEMENT: If possible, avoid the use of taletrectinib with other agents known to prolong the QT interval.(1) If concurrent therapy cannot be avoided, adjust the frequency of monitoring as recommended in the prescribing information. If QTc is >500 msec or the change from baseline is >60 msec, withhold taletrectinib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Taletrectinib causes concentration-dependent QTc prolongation. At steady state maximal concentration, taletrectinib (600 mg daily) increased the QTc interval by 12.8 msec (upper confidence interval 15.4 msec). At plasma concentrations achieved with taletrectinib (600 mg daily) with high fat food (1.5-fold higher than on an empty stomach), the predicted QTc interval increase is 20.5 (16.3, 24.7) msec.(1) In a clinical trial including 351 evaluable patients, 13% experienced an increase in QTcF of >60 msec compared to baseline and 2.6% had an increase in QTcF to >500 msec. Overall, 3.4% of patients had Grade 3 QTc interval prolongation. The median time from the first dose of taletrectinib to the onset of QT prolongation was 22 days (range: 1 day to 38.7 months). Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(9)
Possible Qt Prolonging Agents/Thioridazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Thioridazine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of thioridazine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Hypokalemia, bradycardia, the presence of congenital prolongation of the QT interval, or use of thioridazine in patients with reduced CYP2D6 activity (either through genetic predisposition or use of drugs that inhibit CYP2D6 activity) may increase the risk of torsades de pointes and/or sudden death in patients taking thioridazine.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes), hypomagnesemia, hypocalcemia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of thioridazine states under contraindications that the use of thioridazine should be avoided in combination with other drugs that are known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with Torsades de Pointes and/or QT prolongation but at this time lack substantial evidence for causing Torsades de Pointes.(4) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Vepdegestrant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Vepdegestrant may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of vepdegestrant with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of vepdegestrant states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If concurrent therapy is warranted, monitor ECG when initiating vepdegestrant, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG monitoring. Do not initiate vepdegestrant in patients with a baseline QTc >470 ms. Withhold vepdegestrant if the QTc is >480 ms or the change from baseline is >60 ms.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Vepdegestrant 200 mg daily increased QTc by 12 ms (upper confidence interval = 15 ms) in patients with ESR1 mutation-positive breast cancer.(1) In VERITAC-2, QTc prolongation occurred in 10% of patients, with 1.6% of patients having Grade 3 events. QTc was >500 ms in 1.6% of patients and QTc increase from baseline of >60 ms occurred in 2.6% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Ziftomenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ziftomenib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ziftomenib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of ziftomenib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating ziftomenib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. Do not initiate ziftomenib if baseline QTcF > 480 ms.(1) Perform ECG at least once weekly for the first 4 weeks on treatment, then at least monthly thereafter. If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold ziftomenib therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical trials, QTc interval prolongation was reported as an adverse event in 12% of 112 patients treated with the recommended dosage of ziftomenib. QTc was >500 ms in 9% of patients and the increase from baseline QTcF was >60 ms in 12% of patients. Ziftomenib increased the QTc interval in a concentration-dependent manner. At a dose of 600 mg daily, the largest mean increase in QTc was 7.7 ms (upper bound of confidence interval = 12.6 ms).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Anamorelin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Anamorelin may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of anamorelin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of anamorelin states that the concurrent use of QT prolonging agents should be approached with caution, especially in the early stages (i.e., the first 3 weeks) of drug administration.(1,3) Obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. If abnormalities are found, take appropriate measures, including discontinuing anamorelin.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Anamorelin blocks sodium channels and may suppress cardiac conduction, resulting in prolongation of the QRS width or QT interval. A study of 7 healthy volunteers receiving single-dose anamorelin 400 mg found that 1 patient experienced QRS width prolongation. In 60 healthy adults recieving anamorelin, the maximum difference (upper limit of 95% one-sided confidence interval) in the change from baseline in QTcF interval compared to placebo was 6.16 (7.73) msec in patients on 100 mg and 7.38 (10.31) msec in patients on 300 mg.(1) The Japanese pharmacovigilance database was reviewed to evaluate disproportionality of conduction defects related to anamorelin. Out of 537 cases of adverse reactions, there were 51 cases of conduction defects (36 cases of prolonged QT, 5 cases of prolonged QRS complex, 2 cases of long QT syndrome). When adjusted for concomitant use of QT prolonging agents, the reporting odds ratio (ROR) of anamorelin-related conduction defects was 20.00 (95% CI 14.86-26.91).(3) There have been several case reports of widened QRS complexes following anamorelin exposure, usually accompanied by worsening hepatic function.(4-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)
Qt Prolonging Agents/Catequentinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Catequentinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of catequentinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of catequentinib with other agents known to prolong the QTc interval should be monitored closely. Monitor ECG and electrolytes regularly (every 3-6 weeks) if catequentinib is administered with concurrent QTc prolonging drugs.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Catequentinib causes QTc prolongation. In clinical studies, QTc prolongation was reported as a very common adverse effect.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Clofazimine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Clofazimine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of clofazimine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of clofazimine with other agents known to prolong the QTc interval should be approached with caution and monitored closely. Monitor ECG and electrolytes regularly if clofazimine is administered with concurrent QTc prolonging drugs.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Clofazimine has been reported to cause QTc prolongation and torsades de pointes when combined with medications that also prolong the QT interval.(1) In a pharmacovigilance analysis based on FAERS data from 2004-2025, a disproportionality analysis identified multiple serious and consistent safety signals associated with clofazimine. The most prominent safety signals included QT prolongation (ROR 37.61).(3) In an observational cohort of 321 patients with rifampin-resistant tuberculosis (RR-TB), the mean maximum increase of QTcF was 27.1 ms (IQR 13.8-42.4) for treatment with fluoroquinolones, 43.3 ms (IQR 31.3-65.9) for clofazimine, and 53.2 ms (IQR 36.2-73.2) for clofazimine with fluoroquinolone. Clofazimine was significantly associated with QTcF >=501 ms in multivariable analysis (adjusted HR 4.35, 95% CI 2.01-9.44).(4) A post-hoc analysis of an open label phase 2/3 randomized controlled trial compared QTcF associated with RR-TB therapies using bedaquiline/pretomanid/linezolid (BPaL), BPaL with clofazimine (BPaLC), or BPaL with moxifloxacin (BPaLM). Only 1 incidence of QTcF >500 ms occurred in the BPaLC arm. Peak QTcF values were higher in the BPaLC arm than in the BPaL or BPaLM arms (446.5 ms +/- 19.4 ms, 436 ms +/- 22.2 ms, 439.5 ms +/- 20.7 ms, respectively), but the differences were considered to be small and not clinically important.(5) An analysis of a phase 3 randomized controlled trial (STREAM) compared the effects of a short 9-month regimen (moxifloxacin + clofazimine) with a long 20-month regimen (moxifloxacin or levofloxacin) on the QT interval. The long regimen had a median maximum QTcF change of 30 ms (IQR 22-41) compared to 50 ms (IQR 36-65 ms) on the short regimen. Thirty-one patients (11%) on the short regimen had a maximum QTcF >=500 ms, compared to seven patients (5%) on the long regimen.(6) In a case report, a 66 year old male on clofazimine 300 mg daily for 11 days for leprosy developed torsades de pointe. Although his magnesium level was also low, it was believed that clofazimine alone or with the electrolyte disturbance was responsible for his arrhythmia.(7) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(8)
Qt Prolonging Agents/Fingolimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. Initiation of fingolimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1-3) Fingolimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.(1-3)
CLINICAL EFFECTS: The heart rate lowering effect of fingolimod is biphasic with an initial decrease usually within 6 hours, followed by a second decrease 12 to 24 hours after the first dose. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment.(1-3)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to fingolimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to fingolimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: Patients with a baseline QTc interval greater than or equal to 500 milliseconds should not be started on fingolimod. Patients with pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, or a prolonged QTc interval prior to fingolimod initiation should receive cardiologist consultation to evaluate the risks of fingolimod therapy. In all patients, first dose monitoring is recommended to monitor for bradycardia for the first 6 hours. Check blood pressure and pulse hourly. ECG monitoring is recommended prior to dosing and at the end of the observation period. US monitoring recommendations include additional monitoring for the following patients:(1) If heart rate (HR) is less than 45 beats per minute (bpm), the heart rate 6 hours postdose is at the lowest value postdose, or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. Continuous overnight ECG monitoring is recommended in patients requiring pharmacologic intervention for symptomatic bradycardia, some preexisting heart and cerebrovascular conditions, prolonged QTc before dosing or during 6 hours observation, concurrent therapy with QT prolonging drugs, or concurrent therapy with drugs that slow heart rate or AV conduction. Consult the prescribing information for full monitoring recommendations. United Kingdom recommendations:(3) Obtain a 12-lead ECG prior to initiating fingolimod therapy. Consult a cardiologist for pretreatment risk-benefit assessment if patient has a resting heart rate less than 55 bpm, history of syncope, second degree or greater AV block, sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or other significant cardiovascular disease. Perform continuous ECG monitoring, measure blood pressure and heart rate every hour, and perform a 12-lead ECG 6 hours after the first dose. Monitoring should be extended beyond 6 hours if symptomatic bradycardia or new onset of second degree AV block, Mobitz Type II or third degree AV block has occurred at any time during the monitoring period. If heart rate 6 hours after the first dose is less than 40 bpm, has decreased more than 20 bpm compared with baseline, or if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists, then monitoring should also be continued. If fingolimod treatment is discontinued for more than two weeks, the effects on heart rate and conduction could recur. Thus, first dose monitoring precautions should be followed upon reintroduction of fingolimod. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: After the first dose of fingolimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 6 hours followed by a second decrease 12 to 24 hours after the first dose. The second dose may further decrease heart rate, but the magnitude of change is smaller than the first dose. With continued, chronic dosing, heart rate gradually returns to baseline in about one month.(1,2) In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper boundary of the 90% confidence interval (CI) of 14.0 msec. The cause of death in a patient who died within 24 hour after taking the first dose of fingolimod was not conclusive; however a link to fingolimod or a drug interaction with fingolimod could not be ruled out.(1)
Qt Prolonging Agents/Galantamine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Galantamine may reduce heart rate by increasing acetylcholine in the heart and increasing vagal tone. Bradycardia has been associated with increased risk of QTc interval prolongation.(1) Concurrent use of galantamine with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2)
CLINICAL EFFECTS: The use of galantamine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age or when receiving concomitant treatment with an inhibitor of CYP3A4.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The UK manufacturer of galantamine states that it should be used with caution in patients treated with drugs that affect the QTc interval.(2) If concurrent therapy is warranted, monitor ECG more frequently and consider obtaining serum calcium, magnesium, and potassium levels at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Therapeutic doses of galantamine have been reported to cause QTc prolongation in patients.(2) An 85 year old male with dementia was restarted on galantamine 8 mg daily after a 2-week treatment interruption due to a syncopal episode that occurred 3 months previously. During his prior syncopal episode, he was hypotensive and bradycardic, but QTc interval was normal. After restarting galantamine, he was found to be hypotension and bradycardiac again, and QTc interval was significantly prolonged to 503 msec, over 60 msec longer than when he was off galantamine. Galantamine was discontinued and his QTc interval returned to baseline.(4) A 47 year old schizophrenic male experienced prolongation of the QTc interval to 518 msec after galantamine was increased from 8 mg daily to 12 mg daily. Although he was also on quetiapine and metoprolol, he had been stable on his other medications. His QTc interval normalized after galantamine was stopped.(5) The European pharmacovigilance (Eudravigilance) database contains 14 reports of torsades de pointe in patients on galantamine as of October 2019.(1) A pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS) database found that, of a total of 33,626 cases of TdP/QT prolongation reported between January 2004 and September 2022, 54 cases occurred in patients on galantamine. The disproportionality analysis found a ROR = 5.12, 95% CI (3.92,6.68) and a PRR = 5.11, chi-square = 175.44.(6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(7)
Qt Prolonging Agents/Gepirone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Gepirone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of gepirone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of gepirone states that gepirone should be used with caution and ECGs should be monitored more frequently when used with other agents known to prolong the QTc interval.(1) If QTcF is > 450 msec at baseline, do not initiate gepirone. If QTc increases to > 450 msec during treatment, monitor ECGs more frequently and do not increase the dose of gepirone.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, 100 mg per day of immediate-release gepirone increased the mean QTc 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and 16.1 msec (upper 90% CI = 20.7) on day 7. The dose of gepirone was 2-fold the exposure of the recommended maximum daily dose.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Mavorixafor
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Mavorixafor has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of mavorixafor with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of mavorixafor states that concurrent use of mavorixafor with other agents known to prolong the QTc interval should be approached with caution. ECG monitoring is recommended prior to initiation, during concurrent therapy, and as clinically indicated with other agents known to prolong the QTc interval.(1) If QT prolongation occurs, a dose reduction or discontinuation of mavorixafor may be required.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, a dose of mavorixafor 800 mg increased the mean QTc 15.6 msec (upper 90% CI = 19.9 msec). The dose of mavorixafor was 2 times the recommended maximum daily dose.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Osilodrostat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Osilodrostat has been shown to prolong the QT interval. Concurrent use with QT prolonging agents may result in additive effects on the QT interval.(1)
CLINICAL EFFECTS: The concurrent use of osilodrostat with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Use caution when using osilodrostat concurrently with other agents that can prolong the QT interval and consider more frequent ECG monitoring. A dose-dependent QT interval prolongation was noted in clinical studies. Prior to initiating therapy with osilodrostat, obtain a baseline ECG and monitor for QTc interval changes thereafter. Consider temporary discontinuation of therapy if the QTc interval increases > 480 msec. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)
DISCUSSION: QTc prolongation has been reported with osilodrostat. In a thorough QT study in 86 healthy patients, osilodrostat increased baseline QTcF by 1.73 msec at a 10 mg dose and 25.38 msec at a 150 mg dose (up to 2.5 times the maximum recommended dosage). The predicted mean placebo-corrected QTcF at the highest recommended dose in clinical practice (30 mg twice daily) was estimated as 5.3 msec.(1) In a clinical study, five patients (4%) were reported to have an event of QT prolongation, three patients (2%) had a QTcF increase of > 60 msec from baseline, and 18 patients (13%) had a new QTcF value of > 450 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Ozanimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator. Initiation of ozanimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1,2) Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.
CLINICAL EFFECTS: The initial heart rate lowering effect of ozanimod usually occurs within 5 hours. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ozanimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ozanimod.(1,2) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Prior to initiation of ozanimod, obtain an ECG to determine if preexisting conduction abnormalities are present. Patients with preexisting cardiac conditions, significant QT prolongation (QTc >450 msec in males, >470 msec in females), concurrent Class Ia or Class III antiarrhythmics, or receiving concurrent treatment with a QT prolonging agent at the time ozanimod is initiated or resumed should be referred to a cardiologist.(1) The US recommendations state: Dose titration is recommended with initiation of ozanimod due to transient decrease in heart rate and AV conduction delays.(1) United Kingdom recommendations:(2) Due to the risk of transient decreases in HR with the initiation of ozanimod, first dose, 6-hour monitoring for signs and symptoms of symptomatic bradycardia is recommended in patients with resting HR <55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction or heart failure. Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hour period. An ECG prior to and at the end of this 6-hour period is recommended. Additional monitoring after 6 hours is recommended in patients with: heart rate less than 45 bpm, heart rate at the lowest value post-dose (suggesting that the maximum decrease in HR may not have occurred yet), evidence of a new onset second-degree or higher AV block at the 6-hour post dose ECG, or QTc interval greater than 500 msec. In these cases, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2,3)
DISCUSSION: After the first dose of ozanimod heart rate decline is usually maximal at approximately 5 hours, returning to baseline at 6 hours. With continued, chronic dosing, maximum heart rate effect occurred on day 8.(1,2)
Qt Prolonging Agents/Ponesimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator. Initiation of ponesimod has a negative chronotropic effect leading to a mean decrease in heart rate of 6 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1)
CLINICAL EFFECTS: After a dose of ponesimod, a decrease in heart rate typically begins within an hour and reaches its nadir within 2-4 hours. The heart rate typically recovers to baseline levels 4-5 hours after administration. All patients recovered from bradycardia. The conduction abnormalities typically were transient, asymptomatic, and resolved within 24 hours. Second- and third-degree AV blocks were not reported. With up-titration after Day 1, the post-dose decrease in heart rate is less pronounced. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ponesimod initiation, factors associated with QTc prolongation, or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ponesimod.(1) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Prior to initiation of ponesimod, obtain an ECG to determine if preexisting conduction abnormalities are present. Ponesimod is generally not recommended in patients who are receiving concurrent treatment with a QT prolonging agent, anti-arrhythmic drugs, or drugs that may decrease heart rate. Consultation with a cardiologist is recommended.(1) In patients with heart rate (HR) less than 55 beats per minute (bpm), first- or second-degree AV block, or history of myocardial infarction or heart failure, monitor patients for 4 hours after the first dose for signs and symptoms of bradycardia with a minimum of hourly pulse and blood pressure measurements. Obtain an ECG in these patients prior to dosing and at the end of the 4-hour observation period.(1) Additional US monitoring recommendations include: If HR is less than 45 bpm, the heart rate 4 hours post-dose is at the lowest value post-dose or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, second-degree or higher AV block, or QTc interval greater than or equal to 500 msec, perform continuous overnight ECG monitoring and repeat the first dose monitoring strategy for the second dose of ponesimod. Consult the prescribing information for full monitoring recommendations. If fewer than 4 consecutive doses are missed during titration: resume treatment with the first missed titration dose and resume the titration schedule at that dose and titration day. If fewer than 4 consecutive doses are missed during maintenance: resume treatment with the maintenance dosage. If 4 or more consecutive daily doses are missed during treatment initiation or maintenance treatment, reinitiate Day 1 of the dose titration (new starter pack) and follow first-dose monitoring recommendations. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: After the first dose of ponesimod, heart rate decrease may begin within the first hour. Decline is usually maximal at approximately 4 hours. With continued, chronic dosing, post-dose decrease in heart rate is less pronounced. Heart rate gradually returns to baseline in about 4-5 hours.(1)
Qt Prolonging Agents/Savolitinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Savolitinib has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of savolitinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of savolitinib states concurrent use with agents known to prolong the QT interval should be used with caution.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, patients treatment with savolitinib 600 mg had a mean change in QTc from baseline of 11.93 msec at 3-6 hours postdose.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Qt Prolonging Agents/Siponimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Initiation of siponimod has a negative chronotropic effect. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.(1,2)
CLINICAL EFFECTS: The heart rate lowering effect of siponimod starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. This leads to a mean decrease in heart rate of 5-6 beats per minute after the first dose. The first dose has also been associated with heart block. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. Symptomatic bradycardia has been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to siponimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Prior to initiation of siponimod, obtain an ECG to determine if preexisting conduction abnormalities are present.(1) Advice from a cardiologist is recommended in patients with preexisting heart and cerebrovascular conditions, prolonged QTc interval before or during the 6 hour observation, risk factors for QT prolongation, concurrent therapy with QT prolonging drugs or drugs that slow the heart rate or AV conduction.(1) In patients with heart rate (HR) less than 55 beats per minute (bpm), first- or second-degree AV block, or history of myocardial infarction or heart failure, first dose monitoring is recommended with hourly pulse and blood pressure to monitor for bradycardia for the first 6 hours. ECG monitoring is recommended prior to dosing and at the end of the observation period.(1) Additional US monitoring recommendations include: If HR is less than 45 bpm, the heart rate 6 hours postdose is at the lowest value postdose or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, second-degree or higher AV block, or QTc interval greater than or equal to 500 msec, perform continuous overnight ECG monitoring. Repeat the first dose monitoring strategy for the second dose of siponimod. If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations. Patient will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods. Consult the prescribing information for full monitoring recommendations. United Kingdom recommendations:(3) In certain patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post-dose bradyarrhythmia or conduction-related symptoms occur or if ECG 6 hours post-dose shows new onset second-degree or higher AV block or QTc > 500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6-hour monitoring should be repeated after the second dose. During the first 6 days of treatment, if a titration dose is missed on one day, treatment needs to be re-initiated with a new titration pack. If there is a missed dose after day 6 the prescribed dose should be taken at the next scheduled time; the next dose should not be doubled. If maintenance treatment is interrupted for 4 or more consecutive daily doses, siponimod needs to be re-initiated with a new titration pack.(1,2)
DISCUSSION: After the first dose of siponimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 3-4 hours. With continued, chronic dosing, heart rate gradually returns to baseline in about 10 days.(1,2) A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of siponimod, which plateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detected at a higher incidence under siponimod treatment than placebo. AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions.(1)
Qt Prolonging Agents/Triclabendazole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Triclabendazole has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Triclabendazole is partially metabolized by CYP1A2. Ciprofloxacin, propafenone, and vemurafenib are CYP1A2 inhibitors and may inhibit the CYP1A2 mediated metabolism of triclabendazole.
CLINICAL EFFECTS: The concurrent use of triclabendazole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Hepatic impairment and concurrent use of CYP1A2 inhibitors may raise triclabendazole levels and increase the risk of QT prolongation.(1)
PATIENT MANAGEMENT: The manufacturer of triclabendazole states concurrent use with agents known to prolong the QT interval should be used with caution. Monitor ECG in patients with a history of QTc prolongation, symptoms of long QT interval, electrolyte imbalances, concurrent CYP1A2 inhibitors, or hepatic impairment. If signs of a cardiac arrhythmia develop, stop treatment with triclabendazole and monitor ECG.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, a dose-dependent prolongation in the QTc interval was observed with triclabendazole. The largest placebo-corrected mean increase in QTc was 9.2 msec (upper limit of confidence interval (UCI): 12.2 msec) following oral administration of 10 mg/kg triclabendazole twice daily (at the recommended dose), and the largest placebo-corrected mean increase in QTc was 21.7 msec (UCI: 24.7 msec) following oral administration of 10 mg/kg triclabendazole twice daily for 3 days (3 times the approved recommended dosing duration).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Tucidinostat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of tucidinostat with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of tucidinostat in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Concurrent use of tucidinostat and other agents that are known to prolong the QTc interval should be used with caution. The manufacturer of tucidinostat recommends monitoring ECG and electrolytes every three weeks.(1) If the QTc interval exceeds 500 ms, tucidinostat should be suspended and the ECG should be monitored more frequently. After the QTc interval prolongation has resolved, tucidinostat may be restarted at a reduced dose.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Zidesamtinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Zidesamtinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of zidesamtinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of zidesamtinib states that concurrent use of other drugs that are known to prolong the QTc interval should be monitored more frequently.(1) If concurrent use is warranted, monitor ECG and electrolytes when initiating zidesamtinib, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG and electrolyte monitoring. Withhold, then resume at same or reduced dose, or permanently discontinue zidesamtinib based on severity.(1) If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval 481-500 ms): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at same dose. - Grade 3 (QTc interval >= 501 ms or QTc interval increase of > 60 ms from baseline): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at reduced dose. - Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; or signs/symptoms of serious arrhythmia): Permanently discontinue zidesamtinib. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Zidesamtinib 100 mg once daily increased the QTc by 13 ms (upper confidence interval = 19 ms) in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors.(1) In a pooled safety study, QTc increase >60 ms occurred in 2% of patients and 0.2% of patients had an increase in QTcF > 500 ms.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Selected Antipsychotics/Selected Opioids For Mat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of buprenorphine or diacetylmorphine and antipsychotics may result in additive CNS depression.(1-3)
CLINICAL EFFECTS: Concurrent use of buprenorphine or diacetylmorphine and antipsychotics may result in profound sedation, respiratory depression, coma, and/or death.(1-3)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine or diacetylmorphine is not contraindicated in patients taking CNS depressants, such as antipsychotics; however, gradual tapering or decreasing to the lowest effective dose of the antipsychotic may be appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine or diacetylmorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(6) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(8) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(9) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(10) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(11) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(12) Selected antipsychotics linked include: amsulpride, chlorpromazine, chlorprothixene, clozapine, droperidol, haloperidol, iloperidone, mesoridazine, paliperidone, pimavanserin, pimozide, pipamperone, promethazine, quetiapine, sertindole, sulpiride, sultopride, thioridazine, ziprasidone, and zuclopenthixol.
Selected Antipsychotics; Phenothiazines/Meperidine (Ir)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as meperidine and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as meperidine and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as meperidine with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Selected Antipsychotics; Phenothiazines/Oliceridine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as oliceridine with antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as oliceridine with other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as oliceridine with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Selected Antipsychotics; Phenothiazines/Tramadol (Ir)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as tramadol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as tramadol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as tramadol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Slt Antipsychotics; Phenothiazines/Codeine; Levorphanol (Ir)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as codeine and levorphanol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as codeine and levorphanol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as codeine and levorphanol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Contraindications
*Known hypersensitivity to amisulpride.
- Congenital long QT syndrome
- Prolonged QT interval
- Torsades de pointes
- Bradycardia
- Chronic heart failure
- Hypokalemia
- Hypomagnesemia
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse reactions reported in >=2% of patients receiving amisulpridefor prevention of PONV were increased blood prolactin concentrations, chills, hypokalemia, procedural hypotension, and abdominal distension.
The most common adverse reaction reported in >=2% of patients receiving amisulpride for treatment of PONV wasinfusion site pain.
Less Frequent
- Diabetes mellitus
Rare or Very Rare
- Abnormal hepatic function tests
- Acquired dystonia
- Agranulocytosis
- Akathisia
- Allergic reaction
- Angioedema
- Bradycardia
- Cerebrovascular accident
- Extrapyramidal disease
- Hypersensitivity drug reaction
- Hypotension
- Leukopenia
- Neuroleptic malignant syndrome
- Neutropenic disorder
- Prolonged QT interval
- Rhabdomyolysis
- Seizure disorder
- Suicidal
- Tardive dyskinesia
- Thromboembolic disorder
- Torsades de pointes
More Frequent
- Weight gain
Less Frequent
- Agitation
- Amenorrhea
- Drowsy
- Erectile dysfunction
- Galactorrhea not associated with childbirth
- Gynecomastia
- Headache disorder
- Hyperglycemia
- Hyperprolactinemia
- Insomnia
- Orgasm disorder
- Symptoms of anxiety
- Tremor
Rare or Very Rare
- Acute cognitive impairment
- Increased creatine kinase level
- Tachycardia
- Urticaria
- Ventricular tachycardia
Precautions
No enhanced messaging available.
Safety and effectiveness of amisulpride have not been established in pediatric patients.
There are insufficient data on the use of amisulpride in pregnant women to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adverse developmental effects wereobserved with oral administration of amisulpride in rats and rabbits during the period of organogenesis at exposures about 43 (160 mg/kg per day) and 645 (210 mg/kg per day) times, respectively, the exposure delivered by the highest recommended human dose of 10 mg.
Amisulpride is present in human milk at concentrations that are 11- to 20-fold higher than human plasma in patients taking multiple oral (not available in the US) doses of amisulpride (200 to 400 mg/day). There are no reports of adverse effects on the breastfed child and no information on the effects of amisulpride on milk production.
The pharmacological action of amisulpride, a dopamine-2 receptor antagonist, may result in an increase in serum prolactin levels, which may lead to a reversible increase in maternal milk production. The manufacturer states that the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for amisulpride and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after amisulpride administration to minimize drug exposure to a breastfed infant.
The manufacturer makes no specific dosage recommendations for geriatric patients.
Of the total number of patients enrolled in controlled clinical trials who received amisulpride 5 mg for prevention of PONV or 10 mg for treatment of PONV, 235 (17%) were 65 years of age and older and 59 (4%) were 75 years of age and older. No overall differences in safety or effectiveness of amisulpide were observed between such patients compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
ICD codes
| Code | Type | Description |
|---|---|---|
| Post-operative nausea and vomiting | ||
| K91.0 | ICD10CM | Vomiting following gastrointestinal surgery |
| R11.2 | ICD10CM | Nausea with vomiting, unspecified |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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