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Drug overview for GEODON (ziprasidone hcl):
Generic name: ZIPRASIDONE HCL (zi-PRAS-i-done)
Drug class: Antipsychotics
Therapeutic class: Central Nervous System Agents
Ziprasidone has been referred to as an atypical or second-generation antipsychotic agent.
Ziprasidone hydrochloride is used orally for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder. Ziprasidone mesylate is used IM for acute agitation in schizophrenic patients. When deciding among the alternative treatments available for the condition requiring treatment, clinicians should consider ziprasidone's greater capacity to prolong the QT or QTc (QT interval corrected for rate) interval compared with several other antipsychotic agents.
QTc-interval prolongation has been associated in some other drugs with the ability to cause torsades de pointes and sudden death. In many cases, this would lead clinicians to the conclusion that other drugs should be tried first. The manufacturer states that it is not yet known whether ziprasidone will cause torsades de pointes or increase the rate of sudden death.
In one large observational study (Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC)), the incidence of nonsuicide mortality was not found to be higher in ziprasidone-treated patients compared with olanzapine-treated patients; however, the study design did not allow for evaluation of possible differences in the incidence of more uncommon outcomes, such as torsades de pointes and sudden death. (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Generic name: ZIPRASIDONE HCL (zi-PRAS-i-done)
Drug class: Antipsychotics
Therapeutic class: Central Nervous System Agents
Ziprasidone has been referred to as an atypical or second-generation antipsychotic agent.
Ziprasidone hydrochloride is used orally for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder. Ziprasidone mesylate is used IM for acute agitation in schizophrenic patients. When deciding among the alternative treatments available for the condition requiring treatment, clinicians should consider ziprasidone's greater capacity to prolong the QT or QTc (QT interval corrected for rate) interval compared with several other antipsychotic agents.
QTc-interval prolongation has been associated in some other drugs with the ability to cause torsades de pointes and sudden death. In many cases, this would lead clinicians to the conclusion that other drugs should be tried first. The manufacturer states that it is not yet known whether ziprasidone will cause torsades de pointes or increase the rate of sudden death.
In one large observational study (Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC)), the incidence of nonsuicide mortality was not found to be higher in ziprasidone-treated patients compared with olanzapine-treated patients; however, the study design did not allow for evaluation of possible differences in the incidence of more uncommon outcomes, such as torsades de pointes and sudden death. (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
DRUG IMAGES
GEODON 20 MG CAPSULE
GEODON 60 MG CAPSULE
GEODON 80 MG CAPSULE
The following indications for GEODON (ziprasidone hcl) have been approved by the FDA:
Indications:
Bipolar disorder
Schizophrenia
Professional Synonyms:
Bipolar affective disorder
Bipolar affective illness
Bipolar mood disorder
Dementia praecox
Manic-depressive illness
Parergasia
Indications:
Bipolar disorder
Schizophrenia
Professional Synonyms:
Bipolar affective disorder
Bipolar affective illness
Bipolar mood disorder
Dementia praecox
Manic-depressive illness
Parergasia
The following dosing information is available for GEODON (ziprasidone hcl):
Dosage of ziprasidone hydrochloride is expressed in terms of the hydrochloride monohydrate. Dosage of ziprasidone mesylate is expressed in terms of ziprasidone.
For the symptomatic management of schizophrenia, the recommended initial adult dosage of ziprasidone hydrochloride is 20 mg orally twice daily. In some patients, dosage may be increased based on clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, generally should occur at intervals of not less than 2 days, since steady-state concentrations of the drug are achieved within 1-3 days.
To ensure use of the lowest effective dosage, however, it is recommended that patients be observed for several weeks prior to upward titrations of ziprasidone dosage. The effective dosage of ziprasidone hydrochloride in short-term clinical studies generally ranged from 20-100 mg twice daily. Although there were trends toward a dose response within a dosage range of 20-80 mg twice daily, results were not consistent.
The manufacturer states that dosages exceeding 80 mg twice daily generally are not recommended, and safety of dosages exceeding 100 mg twice daily has not been established.
The optimum duration of ziprasidone therapy currently is not known, but maintenance therapy with ziprasidone hydrochloride 20-80 mg twice daily has been shown to be effective for up to 52 weeks. However, the manufacturer states that no additional benefit has been demonstrated for ziprasidone hydrochloride dosages beyond 20 mg twice daily. Patients responding to ziprasidone therapy should continue to receive the drug as long as clinically necessary and tolerated, but at the lowest possible effective dosage, and the need for continued therapy with the drug should be reassessed periodically.
The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first episodes or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.
For the prompt control of acute agitation in patients with schizophrenia, the recommended initial adult IM dose of ziprasidone is 10-20 mg given as a single dose. Depending on patient response, doses of 10 or 20 mg may be repeated every 2 or 4 hours, respectively, up to a maximum cumulative dose of 40 mg daily.
Oral therapy should replace IM therapy as soon as possible. Safety and efficacy of administering ziprasidone mesylate IM injection for longer than 3 consecutive days have not been evaluated. Because there is no experience regarding the safety of administering ziprasidone mesylate IM injection to patients with schizophrenia who already are receiving oral ziprasidone hydrochloride, the concomitant use of oral and IM formulations of ziprasidone is not recommended by the manufacturer.
For the acute treatment of manic or mixed episodes associated with bipolar disorder (with or without psychotic features), the recommended initial adult dosage of ziprasidone hydrochloride is 40 mg orally twice daily on the first day of therapy. Dosage may then be increased to 60 or 80 mg twice daily on the second day of therapy. Subsequent dosage adjustments based on efficacy and tolerability may be made within a dosage range of 40-80 mg twice daily.
In the flexible-dosage clinical trials, the mean dosage of ziprasidone hydrochloride was approximately 120 mg daily.
For the maintenance treatment of bipolar I disorder (as adjunctive therapy to either lithium or valproate) in adults, ziprasidone should be continued at the same dosage on which the patient was initially stabilized within the dosage range of 40-80 mg orally twice daily. The manufacturer of ziprasidone states that the need for continued maintenance therapy should be reassessed periodically.
For the symptomatic management of schizophrenia, the recommended initial adult dosage of ziprasidone hydrochloride is 20 mg orally twice daily. In some patients, dosage may be increased based on clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, generally should occur at intervals of not less than 2 days, since steady-state concentrations of the drug are achieved within 1-3 days.
To ensure use of the lowest effective dosage, however, it is recommended that patients be observed for several weeks prior to upward titrations of ziprasidone dosage. The effective dosage of ziprasidone hydrochloride in short-term clinical studies generally ranged from 20-100 mg twice daily. Although there were trends toward a dose response within a dosage range of 20-80 mg twice daily, results were not consistent.
The manufacturer states that dosages exceeding 80 mg twice daily generally are not recommended, and safety of dosages exceeding 100 mg twice daily has not been established.
The optimum duration of ziprasidone therapy currently is not known, but maintenance therapy with ziprasidone hydrochloride 20-80 mg twice daily has been shown to be effective for up to 52 weeks. However, the manufacturer states that no additional benefit has been demonstrated for ziprasidone hydrochloride dosages beyond 20 mg twice daily. Patients responding to ziprasidone therapy should continue to receive the drug as long as clinically necessary and tolerated, but at the lowest possible effective dosage, and the need for continued therapy with the drug should be reassessed periodically.
The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first episodes or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.
For the prompt control of acute agitation in patients with schizophrenia, the recommended initial adult IM dose of ziprasidone is 10-20 mg given as a single dose. Depending on patient response, doses of 10 or 20 mg may be repeated every 2 or 4 hours, respectively, up to a maximum cumulative dose of 40 mg daily.
Oral therapy should replace IM therapy as soon as possible. Safety and efficacy of administering ziprasidone mesylate IM injection for longer than 3 consecutive days have not been evaluated. Because there is no experience regarding the safety of administering ziprasidone mesylate IM injection to patients with schizophrenia who already are receiving oral ziprasidone hydrochloride, the concomitant use of oral and IM formulations of ziprasidone is not recommended by the manufacturer.
For the acute treatment of manic or mixed episodes associated with bipolar disorder (with or without psychotic features), the recommended initial adult dosage of ziprasidone hydrochloride is 40 mg orally twice daily on the first day of therapy. Dosage may then be increased to 60 or 80 mg twice daily on the second day of therapy. Subsequent dosage adjustments based on efficacy and tolerability may be made within a dosage range of 40-80 mg twice daily.
In the flexible-dosage clinical trials, the mean dosage of ziprasidone hydrochloride was approximately 120 mg daily.
For the maintenance treatment of bipolar I disorder (as adjunctive therapy to either lithium or valproate) in adults, ziprasidone should be continued at the same dosage on which the patient was initially stabilized within the dosage range of 40-80 mg orally twice daily. The manufacturer of ziprasidone states that the need for continued maintenance therapy should be reassessed periodically.
Ziprasidone hydrochloride is available as capsules and is administered orally twice daily with food for optimal absorption. Absorption of ziprasidone is increased up to twofold in the presence of food. Ziprasidone mesylate is administered only by IM injection and should not be administered IV.
The commercially available lyophilized powder of ziprasidone mesylate for injection must be reconstituted prior to administration by adding 1.2 mL of sterile water for injection to single-dose vials of ziprasidone to provide a solution containing 20 mg/mL. Other solutions should not be used to reconstitute ziprasidone mesylate injection, and the drug should not be admixed with other drugs.
The vials should then be shaken vigorously to ensure complete dissolution. Strict aseptic technique must be observed since the drug contains no preservative or bacteriostatic agent. Following reconstitution, ziprasidone mesylate for injection is stable for 24 hours when protected from light and stored at 15-30degreesC or for up to 7 days when refrigerated at 2-8degreesC. Ziprasidone mesylate injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
The commercially available lyophilized powder of ziprasidone mesylate for injection must be reconstituted prior to administration by adding 1.2 mL of sterile water for injection to single-dose vials of ziprasidone to provide a solution containing 20 mg/mL. Other solutions should not be used to reconstitute ziprasidone mesylate injection, and the drug should not be admixed with other drugs.
The vials should then be shaken vigorously to ensure complete dissolution. Strict aseptic technique must be observed since the drug contains no preservative or bacteriostatic agent. Following reconstitution, ziprasidone mesylate for injection is stable for 24 hours when protected from light and stored at 15-30degreesC or for up to 7 days when refrigerated at 2-8degreesC. Ziprasidone mesylate injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| GEODON 20 MG CAPSULE | Maintenance | Adults take 1 capsule (20 mg) by oral route 2 times per day with food |
| GEODON 60 MG CAPSULE | Maintenance | Adults take 1 capsule (60 mg) by oral route 2 times per day with food |
| GEODON 80 MG CAPSULE | Maintenance | Adults take 1 capsule (80 mg) by oral route 2 times per day with food |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ZIPRASIDONE HCL 20 MG CAPSULE | Maintenance | Adults take 1 capsule (20 mg) by oral route 2 times per day with food |
| ZIPRASIDONE HCL 60 MG CAPSULE | Maintenance | Adults take 1 capsule (60 mg) by oral route 2 times per day with food |
| ZIPRASIDONE HCL 80 MG CAPSULE | Maintenance | Adults take 1 capsule (80 mg) by oral route 2 times per day with food |
The following drug interaction information is available for GEODON (ziprasidone hcl):
There are 7 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Ziprasidone/Selected Antiarrhythmics 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: Dofetilide, quinidine, sotalol and ziprasidone have been shown to prolong the QTc interval. The concurrent use of ziprasidone with these agents may result in additive effects on the QTc interval.(1) CLINICAL EFFECTS: The concurrent use of ziprasidone with dofetilide, quinidine, or sotalol may result in additive prolongation of the QTc interval and potentially life-threatening arrhythmias.(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 ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including dofetilide, quinidine, or sotalol.(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: Ziprasidone has been shown to prolong the QTc interval in a dose-related fashion. Therefore, the manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including dofetilide, quinidine, or sotalol.(1) |
BETAPACE, BETAPACE AF, DOFETILIDE, NUEDEXTA, QUINIDINE GLUCONATE, QUINIDINE SULFATE, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE, TIKOSYN |
| Ziprasidone/Pimozide; Thioridazine 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: Pimozide, thioridazine and ziprasidone have all been shown to prolong the QTc interval. The concurrent use of ziprasidone with these agents may result in additive effects on the QTc interval.(1) CLINICAL EFFECTS: The concurrent use of ziprasidone with pimozide or thioridazine may result in additive prolongation of the QTc interval and potentially life-threatening arrhythmias.(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 ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including pimozide or thioridazine.(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: Ziprasidone has been shown to prolong the QTc interval in a dose-related fashion. Therefore, the manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including pimozide or thioridazine.(1) |
PIMOZIDE, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE |
| Ziprasidone/Moxifloxacin; Sparfloxacin 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: Moxifloxacin, sparfloxacin, and ziprasidone have been shown to prolong the QTc interval. The concurrent use of ziprasidone with these agents may result in additive effects on the QTc interval.(1) CLINICAL EFFECTS: The concurrent use of ziprasidone with moxifloxacin or sparfloxacin may result in additive prolongation of the QTc interval and potentially life-threatening arrhythmias.(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 ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including moxifloxacin and sparfloxacin.(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: Ziprasidone has been shown to prolong the QTc interval in a dose-related fashion. Therefore, the manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QTc interval, including moxifloxacin or sparfloxacin.(1) |
AVELOX IV, MOXIFLOXACIN, MOXIFLOXACIN HCL |
| Ziprasidone/Selected QT Prolonging Agents 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: 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: Bradycardia, hypokalemia, hypomagnesemia, and the presence of congenital prolongation of the QT interval may increase the risk of torsades de pointes and/or sudden death.(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), 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 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) 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: 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) |
AMIODARONE HCL, AMIODARONE HCL-D5W, ARSENIC TRIOXIDE, ASTAGRAF XL, CESIUM CHLORIDE, CHLORPROMAZINE HCL, CORVERT, DISOPYRAMIDE PHOSPHATE, DROPERIDOL, ENVARSUS XR, GATIFLOXACIN SESQUIHYDRATE, IBUTILIDE FUMARATE, MEFLOQUINE HCL, NEXTERONE, NORPACE, NORPACE CR, OXALIPLATIN, PACERONE, PENTAM 300, PENTAMIDINE ISETHIONATE, PROCAINAMIDE HCL, PROGRAF, TACROLIMUS, TACROLIMUS XL, TRISENOX |
| Iomeprol/Neuroleptics 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) |
IOMERON 350 |
| Ziprasidone/MAOIs 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: Combination of MAOIs, which decrease the breakdown of serotonin, and ziprasidone, a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor, may cause an increase in endogenous serotonin.(1-2) CLINICAL EFFECTS: Concurrent use of ziprasidone and MAOIs may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1) PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) PATIENT MANAGEMENT: The concurrent use of ziprasidone with MAOIs is contraindicated. At least 14 days must elapse between discontinuation of an MAOI and initiation of therapy with ziprasidone. Conversely, at least 3 days must be allowed after stopping ziprasidone before starting an MAOI.(1) Do not initiate ziprasidone in a patient being treated with MAOIs such as intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as intravenous methylene blue in a patient taking ziprasidone, discontinue ziprasidone before initiating treatment with the MAOI. DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(7,8) Metaxalone is a weak inhibitor of MAO.(9,10) |
AZILECT, EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, VUEBLU, XADAGO, ZELAPAR |
| Ziprasidone/Serotonergic Agents that Prolong QT 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: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity. Current use may also result in additive effects on the QTc interval.(1,2) CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1) Additive QTc prolongation may also occur, resulting in potentially life-threatening arrhythmias like torsades de pointes.(1) PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) 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: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1) 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 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: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(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) |
CELEXA, CITALOPRAM HBR, ESCITALOPRAM OXALATE, LEXAPRO |
There are 14 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Cabergoline/Selected Dopamine Blockers 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. |
CABERGOLINE |
| Ziprasidone/Selected QT Prolonging Agents 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) |
ADLARITY, ADVAIR DISKUS, ADVAIR HFA, AIRDUO DIGIHALER, AIRDUO RESPICLICK, ALFUZOSIN HCL ER, ARICEPT, ASPRUZYO SPRINKLE, ATOMOXETINE HCL, AZITHROMYCIN, BARHEMSYS, BESPONSA, BRAFTOVI, CHLOROQUINE PHOSPHATE, CILOSTAZOL, CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W, CLARITHROMYCIN, CLARITHROMYCIN ER, CLOZAPINE, CLOZAPINE ODT, CLOZARIL, CORLANOR, DANZITEN, DASATINIB, DAURISMO, DIFLUCAN, DIPRIVAN, DONEPEZIL HCL, DONEPEZIL HCL ODT, E.E.S. 200, E.E.S. 400, EFAVIRENZ, EFAVIRENZ-EMTRIC-TENOFOV DISOP, EFAVIRENZ-LAMIVU-TENOFOV DISOP, EGATEN, ELLENCE, EPIRUBICIN HCL, ERIBULIN MESYLATE, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, FARESTON, FARYDAK, FLECAINIDE ACETATE, FLUCONAZOLE, FLUCONAZOLE-NACL, FLUTICASONE-SALMETEROL, FLUTICASONE-SALMETEROL HFA, GALANTAMINE ER, GALANTAMINE HBR, GALANTAMINE HYDROBROMIDE, GRANISETRON HCL, HALAVEN, HALDOL DECANOATE 100, HALDOL DECANOATE 50, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL DECANOATE 100, HALOPERIDOL LACTATE, HYDROXYCHLOROQUINE SULFATE, HYDROXYZINE HCL, HYDROXYZINE PAMOATE, ISRADIPINE, ISTODAX, ISTURISA, IVABRADINE HCL, KISQALI, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LAPATINIB, LENVIMA, LEVOFLOXACIN, LEVOFLOXACIN HEMIHYDRATE, LEVOFLOXACIN-D5W, LOFEXIDINE HCL, LUCEMYRA, MEMANTINE HCL-DONEPEZIL HCL ER, NAMZARIC, NEXAVAR, NILOTINIB HCL, NOXAFIL, NUPLAZID, OFLOXACIN, OMECLAMOX-PAK, ONDANSETRON HCL, ONDANSETRON HCL-0.9% NACL, PAZOPANIB HCL, PLAQUENIL, POSACONAZOLE, PROPAFENONE HCL, PROPAFENONE HCL ER, PROPOFOL, QUALAQUIN, QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, QUININE HCL, QUININE SULFATE, RANOLAZINE ER, RETEVMO, REVUFORJ, ROMIDEPSIN, ROZLYTREK, RUBRACA, RYDAPT, SANCUSO, SEREVENT DISKUS, SEROQUEL, SEROQUEL XR, SIGNIFOR, SIGNIFOR LAR, SIRTURO, SORAFENIB, SOVUNA, SPRYCEL, STRATTERA, SUNITINIB MALATE, SUSTOL, SUTENT, SYMFI, SYMFI LO, TAGRISSO, TASIGNA, TIBSOVO, TOLTERODINE TARTRATE, TOLTERODINE TARTRATE ER, TOREMIFENE CITRATE, TYKERB, UROXATRAL, VANFLYTA, VERSACLOZ, VFEND, VFEND IV, VIBATIV, VONJO, VOQUEZNA TRIPLE PAK, VORICONAZOLE, VOTRIENT, WAKIX, WIXELA INHUB, XALKORI, XENLETA, XOSPATA, ZELBORAF, ZITHROMAX, ZITHROMAX TRI-PAK, ZOKINVY, ZUNVEYL, ZYKADIA |
| Paliperidone/QT Prolonging Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Paliperidone has been shown to cause a modest increase in the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2) CLINICAL EFFECTS: The concurrent use of paliperidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2) 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, 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) PATIENT MANAGEMENT: The US manufacturer of paliperidone states that the use of paliperidone should be avoided with other drugs that are known to prolong the QTc interval, including Class IA and Class III antiarrhythmics, antipsychotics, antibiotics such as gatifloxacin and moxifloxacin, or any other class of medications known to prolong the QTc interval.(1,2) 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) |
ERZOFRI, INVEGA, INVEGA HAFYERA, INVEGA SUSTENNA, INVEGA TRINZA, PALIPERIDONE ER |
| Serotonin Reuptake Inhibitors/Linezolid SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Serotonin reuptake inhibitors and linezolid, which inhibits MAO, may act synergistically to increase central nervous system (CNS) serotonin concentrations, leading to toxicity. CLINICAL EFFECTS: Concurrent use or switching between agents without a sufficient washout period may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) Serotonin syndrome may result in death. PREDISPOSING FACTORS: High doses of serotonin reuptake inhibitors or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome. PATIENT MANAGEMENT: If linezolid is required for urgent or life threatening treatment, the FDA states the interacting serotonergic drug should be stopped. Although discontinued, serotonin toxicity due to the interaction is still possible. Patients should be monitored for CNS serotonin toxicity for two weeks (five weeks if fluoxetine, 3 weeks if vortioxetine, 7 days if desvenlafaxine or venlafaxine, or 5 days if duloxetine was taken) or until 24 hours after the last linezolid dose, whichever comes first. Therapy with the SSRI may be resumed 24 hours after the last dose of linezolid.(1,3-13) DISCUSSION: Serotonin syndrome has been reported in four patients receiving concurrent citalopram and linezolid, in a patient in whom linezolid was initiated 18 days after fluoxetine discontinuation, in a patient receiving concurrent linezolid and fluoxetine, in a patient in whom linezolid was initiated three days after the discontinuation of paroxetine, in three patients receiving concurrent linezolid and sertraline, and in a patient receiving concurrent linezolid and venlafaxine. Many authors state that linezolid is a weak MAOI and rarely causes serotonin toxicity. Cases of serotonin toxicity were rapidly reversible with discontinuation of the offending agent(s) and supportive care. Some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(24-29) |
LINEZOLID, LINEZOLID-0.9% NACL, LINEZOLID-D5W, ZYVOX |
| Artemether-Lumefantrine/Possible QT Prolonging Agents 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) |
COARTEM |
| Dronedarone/Possible QT Prolonging Agents 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. |
MULTAQ |
| Lopinavir/QT Prolonging Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lopinavir has been shown to prolong the QTc interval by 5 msec. 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 lopinavir 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, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: The US manufacturer of lopinavir 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: In a randomized, placebo and active controlled crossover study in 39 healthy subjects designed to evaluated QTc intervals, lopinavir/ritonavir increased QTc by 5.3 msec and 15.2 msec for 400/100 mg twice daily and 800/200 mg twice daily, 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.(2) |
KALETRA, LOPINAVIR-RITONAVIR |
| Metoclopramide/Antipsychotics; Phenothiazines; Rivastigmine 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) |
GIMOTI, METOCLOPRAMIDE HCL, REGLAN |
| Anagrelide/Possible QT Prolonging Agents 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) 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) 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: The US manufacturer of anagrelide states that anagrelide should not be used in patients taking medications 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: 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.(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. |
AGRYLIN, ANAGRELIDE HCL |
| Apomorphine/Ziprasidone SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of apomorphine and ziprasidone may have additive effects on the QTc interval.(1,2) In addition, apomorphine is a dopamine agonist. Ziprasidone may decrease apomorphine's effectiveness by blocking dopamine activity at CNS D2 receptors.(1) CLINICAL EFFECTS: The concurrent use of apomorphine with ziprasidone may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated, e.g. Parkinson disease or a psychotic disorder. 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).(3) 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 ziprasidone states other agents known to prolong the QT interval should not be used concomitantly.(2) 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.(1) 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.(4,5) 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 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.(4,5) 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) |
APOKYN, APOMORPHINE HCL, ONAPGO |
| Levoketoconazole/Possible QT Prolonging Agents 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) |
RECORLEV |
| Ziprasidone/Serotonergic Agents that Prolong QT SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity. Current use may also result in additive effects on the QTc interval.(1,2) CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1) Additive QTc prolongation may also occur, resulting in potentially life-threatening arrhythmias like torsades de pointes.(1) PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) 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: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1) 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 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: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(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) |
RALDESY, TRAZODONE HCL |
| Methadone for MAT/Ziprasidone 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 ziprasidone may result in additive effects on the QTc interval.(1-3, 19) Concurrent use of methadone and ziprasidone may result in additive CNS depression.(1-3,19) Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Methadone may inhibit neural uptake of serotonin. Concurrent use may increase serotonin effects, resulting in serotonin toxicity.(19) 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 ziprasidone may result in profound sedation, respiratory depression, coma, and/or death.(1-3) Concurrent use of ziprasidone and methadone may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(15) 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. Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(15) 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 inadequate.(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. Consider this risk 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) Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(19) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(16-18) |
DISKETS, METHADONE HCL, METHADONE INTENSOL, METHADOSE |
| Methadone (non MAT)/Ziprasidone 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 ziprasidone may result in additive effects on the QTc interval.(1-3, 14) Concurrent use of methadone and ziprasidone may result in additive CNS depression.(1-3,14) Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Methadone may inhibit neural uptake of serotonin. Concurrent use may increase serotonin effects, resulting in serotonin toxicity.(14) 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 ziprasidone may result in profound sedation, respiratory depression, coma, and/or death.(1-3) Concurrent use of ziprasidone and methadone may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(13) 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. Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(13) 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 inadequate.(2) Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(14) 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. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(15-17) |
METHADONE HCL, METHADONE HCL-0.9% NACL, METHADONE HCL-NACL |
There are 19 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Bupropion/Antipsychotics 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) |
APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FORFIVO XL, WELLBUTRIN SR, WELLBUTRIN XL |
| Iloperidone/Possible QT Prolonging Agents 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 CYP P-450-3A4) 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 CYP P-450-2D6) 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) |
FANAPT |
| Vandetanib/Possible QT Prolonging Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Vandetanib 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 vandetanib 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 vandetanib states that the use of vandetanib with other agents known to prolong the QT interval should be avoided.(1) The manufacturer of vandetanib states therapy should be interrupted if Corrected QT interval, Frederica (QTcF) is greater than 500 ms; resume at a reduced dose when the QTcF returns to less than 450 ms. Consult current prescribing information for further details.(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: Vandetanib has been shown to prolong the QTc interval in a dose-dependent manner. Vandetanib has a long half-life (19 days) and effects on the QTc interval may not resolve quickly following vandetanib discontinuation.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received vandetanib, QTc prolongation was identified in 4 (80%) with 0 (0%) having Grade 1 (QTc 450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 1 (25%) having QTc greater than or equal to 500 ms and 2 (50%) having QTc change greater than or equal to 60 ms. No patients had ventricular tachycardia, sudden cardiac death, or TdP.(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.(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. |
CAPRELSA |
| Selected Dopamine Agonists/Select Atypical Antipsychotics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Selected dopamine agonists 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, e.g. Parkinson disease or a psychotic disorder. Dopamine agonists linked to this monograph are: bromocriptine, entacapone, levodopa, pergolide, pramipexole, ropinirole and rotigotine. Atypical antipsychotics linked to this monograph are: aripiprazole, asenapine, iloperidone, lumateperone, lurasidone, paliperidone, quetiapine, risperidone, ziprasidone and zotepine. 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 dopamine agonist. The US manufacturer of ropinirole recommends treatment with dopamine agonists 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) Two clozapine trials showed significant improvement in psychosis without worsening of motor symptoms. In contrast, two olanzapine trials were associated with unacceptable worsening of motor symptoms. Risperidone has also been associated with motor worsening in case reports. Quetiapine evaluations have been conflicting with several small studies showing improvement in psychotic symptoms while a more rigorous trial showed no improvement.(6) |
BROMOCRIPTINE MESYLATE, CARBIDOPA-LEVODOPA, CARBIDOPA-LEVODOPA ER, CARBIDOPA-LEVODOPA-ENTACAPONE, CREXONT, CYCLOSET, DHIVY, DUOPA, INBRIJA, LEVODOPA, MIRAPEX ER, NEUPRO, PRAMIPEXOLE DIHYDROCHLORIDE, PRAMIPEXOLE ER, ROPINIROLE ER, ROPINIROLE HCL, RYTARY, SINEMET, VYALEV |
| Fingolimod/QT Prolonging Agents 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) |
FINGOLIMOD, GILENYA, TASCENSO ODT |
| Sevoflurane/QT Prolonging Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of multiple agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) CLINICAL EFFECTS: The concurrent use of multiple 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) 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).(1) PATIENT MANAGEMENT: Sevoflurane should be used with caution in patients taking agents known to prolong the QT interval.(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 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) 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. |
SEVOFLURANE, ULTANE |
| Codeine; Levorphanol (IR)/Slt Antipsychotics; Phenothiazines 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
ACETAMIN-CAFF-DIHYDROCODEINE, ACETAMINOPHEN-CODEINE, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, CARISOPRODOL-ASPIRIN-CODEINE, CODEINE PHOSPHATE, CODEINE SULFATE, DIHYDROCODEINE BITARTRATE, FIORICET WITH CODEINE, HYDROCODONE BITARTRATE, LEVORPHANOL TARTRATE, TREZIX |
| Selected Opioids for MAT/Selected Antipsychotics 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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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. |
BRIXADI, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, SUBLOCADE, SUBOXONE, ZUBSOLV |
| Siponimod/QT Prolonging Agents 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) |
MAYZENT |
| Ponesimod/QT Prolonging Agents 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) |
PONVORY |
| Ozanimod/QT Prolonging Agents 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) |
ZEPOSIA |
| Etrasimod/QT Prolonging Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Etrasimod is a sphingosine-1-phosphate (S1P) receptor modulator. Initiation of etrasimod has a negative chronotropic effect, which may increase the risk of developing QT prolongation. CLINICAL EFFECTS: Initiation of etrasimod may result in a transient decrease in heart rate. A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to 3 hours after the first dose. The first dose has also been associated with heart block. 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 etrasimod 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 etrasimod. 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 etrasimod, 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, risk factors for QT prolongation, concurrent therapy with QT prolonging drugs or drugs that slow the heart rate or AV conduction.(1) Monitor blood pressure during treatment.(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: Initiation of etrasimod may result in a transient decrease in heart rate or transient AV conduction delays.(1) A transient decrease in heart rate was observed during the initial dosing phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a higher incidence under etrasimod treatment than placebo.(1) |
VELSIPITY |
| Dexmedetomidine Sublingual/Possible QT Prolonging Agents 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) |
IGALMI |
| Mavorixafor/QT Prolonging Agents 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) |
XOLREMDI |
| Givinostat/Possible QT Prolonging Agents 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) |
DUVYZAT |
| Ziprasidone/Serotonergic Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2) CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1) PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) PATIENT MANAGEMENT: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1) DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6) |
AA 2%-D10W-CALCIUM, AA 2%-D10W-CALCIUM-HEPARIN, AA 2%-D10W-LOW CALCIUM-HEPARIN, AA 2%-D5W-CALCIUM-HEPARIN, AA 2.5%-D10W-CALCIUM-HEPARIN, AA 3%-D10W-CALCIUM, AA 3%-D10W-CALCIUM-HEPARIN, AA 3%-D10W-LOW CALCIUM-HEPARIN, AA 3%-D5W-CALCIUM, AA 3%-D5W-CALCIUM-HEPARIN, AA 3%-D5W-LOW CALCIUM-HEPARIN, AA 3.5%-D10W-CALCIUM, AA 3.5%-D10W-CALCIUM-HEPARIN, AA 3.5%-D10W-LO CALCIUM-HEPARN, AA 4%-D10W-CALCIUM-HEPARIN, AA 6%-D10W-CALCIUM-HEPARIN, ADDERALL, ADDERALL XR, ADIPEX-P, ADZENYS XR-ODT, AMINO ACID 3%-D10W, AMINO ACID 3.5%-D10W, AMINO ACID 3.5%-D10W-HEPARIN, AMINO ACID 4%-D10W, AMINO ACID 4.5%-D10W-HEPARIN, AMINO ACIDS 2.5%-D10W, AMINOSYN II, AMINOSYN-PF, AMPHETAMINE SULFATE, ANAFRANIL, AUVELITY, BROMFED DM, BROMPHENIRAMINE-PSEUDOEPHED-DM, BUSPIRONE HCL, CLINIMIX, CLINIMIX E, CLINISOL, CLOMIPRAMINE HCL, CYMBALTA, DESOXYN, DESVENLAFAXINE ER, DESVENLAFAXINE SUCCINATE ER, DEXEDRINE, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DEXTROMETHORPHAN HBR, DRIZALMA SPRINKLE, DULOXETINE HCL, DULOXICAINE, DYANAVEL XR, EFFEXOR XR, EVEKEO, FETZIMA, FINTEPLA, FLUOXETINE DR, FLUOXETINE HCL, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, HYDROXYAMPHETAMINE HBR, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, KABIVEN, LISDEXAMFETAMINE DIMESYLATE, LITHIUM CARBONATE, LITHIUM CARBONATE ER, LITHIUM CITRATE, LITHIUM CITRATE TETRAHYDRATE, LITHOBID, LOMAIRA, METHAMPHETAMINE HCL, MYDAYIS, NUEDEXTA, OLANZAPINE-FLUOXETINE HCL, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PERIKABIVEN, PHENTERMINE HCL, PLENAMINE, PREMASOL, PRISTIQ, PROCENTRA, PROMETHAZINE-DM, PROSOL, PROZAC, QSYMIA, SAVELLA, SERTRALINE HCL, TRAVASOL, TRINTELLIX, VENLAFAXINE BESYLATE ER, VENLAFAXINE HCL, VENLAFAXINE HCL ER, VIIBRYD, VILAZODONE HCL, VYVANSE, XELSTRYM, ZENZEDI, ZOLOFT |
| Selected Serotonergic Opioids/Ziprasidone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of serotonergic opioids such as meperidine or tramadol and antipsychotics such as ziprasidone may result in additive CNS depression or additive risk of serotonin syndrome.(1) CLINICAL EFFECTS: Concurrent use of serotonergic opioids such as meperidine or tramadol and antipsychotics such as ziprasidone 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. Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity. Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as meperidine or tramadol with CNS depressants such as antipsychotics, including ziprasidone, to patients for whom alternatives are inadequate.(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. Consider this risk 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) as well as for signs of serotonin syndrome. Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(12-14) |
CONZIP, DEMEROL, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL, NUCYNTA, NUCYNTA ER, PENTAZOCINE-NALOXONE HCL, QDOLO, TRAMADOL HCL, TRAMADOL HCL ER, TRAMADOL HCL-ACETAMINOPHEN |
| Opioids (Extended Release)/Ziprasidone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and ziprasidone may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as ziprasidone, 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 ziprasidone to patients for whom alternatives are inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
BUPRENORPHINE, BUTRANS, FENTANYL, HYDROCODONE BITARTRATE ER, HYDROMORPHONE ER, HYSINGLA ER, MORPHINE SULFATE ER, MS CONTIN, OXYCODONE HCL ER, OXYCONTIN, OXYMORPHONE HCL ER, XTAMPZA ER |
| Slt Opioids (Immediate Release)/Ziprasidone 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 such as ziprasidone may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants such as ziprasidone 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 ziprasidone, to patients for whom alternatives are inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
APADAZ, BELBUCA, BELLADONNA-OPIUM, BENZHYDROCODONE-ACETAMINOPHEN, BUPRENORPHINE HCL, BUTORPHANOL TARTRATE, DILAUDID, DSUVIA, DURAMORPH, ENDOCET, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL, HYDROCODONE BITARTRATE, HYDROCODONE-ACETAMINOPHEN, HYDROCODONE-IBUPROFEN, HYDROMORPHONE HCL, HYDROMORPHONE HCL-0.9% NACL, HYDROMORPHONE HCL-D5W, HYDROMORPHONE HCL-NACL, HYDROMORPHONE HCL-WATER, INFUMORPH, MITIGO, MORPHINE SULFATE, MORPHINE SULFATE-0.9% NACL, MORPHINE SULFATE-NACL, NALBUPHINE HCL, NALOCET, OLINVYK, OPIUM TINCTURE, OXYCODONE HCL, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYMORPHONE HCL, PERCOCET, PRIMLEV, PROLATE, REMIFENTANIL HCL, ROXICODONE, ROXYBOND, SUFENTANIL CITRATE, ULTIVA |
The following contraindication information is available for GEODON (ziprasidone hcl):
Drug contraindication overview.
Known history of QT-interval prolongation (including congenital long QT syndrome), recent acute myocardial infarction, or uncompensated heart failure. (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) Concomitant therapy with drugs that prolong the QT interval. (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Drugs that Prolong QT Interval.) Known hypersensitivity to ziprasidone.
Known history of QT-interval prolongation (including congenital long QT syndrome), recent acute myocardial infarction, or uncompensated heart failure. (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) Concomitant therapy with drugs that prolong the QT interval. (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Drugs that Prolong QT Interval.) Known hypersensitivity to ziprasidone.
There are 8 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| 30 day risk period post-myocardial infarction |
| Acute decompensated heart failure |
| Congenital long QT syndrome |
| Lactation |
| Neuroleptic malignant syndrome |
| Parkinsonism |
| Serotonin syndrome |
| Torsades de pointes |
There are 15 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acquired dystonia |
| Agranulocytosis |
| Bradycardia |
| Cardiac arrhythmia |
| Cerebrovascular disorder |
| Dehydration |
| Diabetes mellitus |
| Extrapyramidal disease |
| Hypokalemia |
| Hypomagnesemia |
| Metabolic syndrome x |
| Myocardial ischemia |
| Senile dementia |
| Suicidal ideation |
| Tardive dyskinesia |
There are 11 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Carcinoma of breast |
| Dysphagia |
| Hyperlipidemia |
| Hyperprolactinemia |
| Leukopenia |
| Neutropenic disorder |
| Obesity |
| Orthostatic hypotension |
| Seizure disorder |
| Severe diarrhea |
| Severe hepatic disease |
The following adverse reaction information is available for GEODON (ziprasidone hcl):
Adverse reaction overview.
Adverse effects occurring in 5% or more of patients with schizophrenia receiving oral ziprasidone and at a frequency at least twice the that reported with placebo include somnolence and respiratory tract infection. Adverse effects occurring in 5% or more of patients with bipolar mania receiving oral ziprasidone and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, and vomiting. Adverse effects occurring in 5% or more of patients with schizophrenia receiving IM ziprasidone 10 or 20 mg and at a frequency at least twice that reported among those receiving IM ziprasidone 2 mg include somnolence, headache, and nausea.
Adverse effects occurring in 5% or more of patients with schizophrenia receiving oral ziprasidone and at a frequency at least twice the that reported with placebo include somnolence and respiratory tract infection. Adverse effects occurring in 5% or more of patients with bipolar mania receiving oral ziprasidone and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, and vomiting. Adverse effects occurring in 5% or more of patients with schizophrenia receiving IM ziprasidone 10 or 20 mg and at a frequency at least twice that reported among those receiving IM ziprasidone 2 mg include somnolence, headache, and nausea.
There are 66 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Skin rash |
Chest pain Hypokalemia Tachycardia |
| Rare/Very Rare |
|---|
|
Accidental fall Agranulocytosis Anemia Angina Angioedema Atrial fibrillation Atrioventricular block Bloody vomit Bradycardia Bundle branch block Cataracts Cerebrovascular accident Chorea Diabetes mellitus DRESS syndrome Dysphagia Eosinophilia Esophageal dysmotility Exfoliative dermatitis Facial edema Fecal impaction First degree atrioventricular heart block Hemoptysis Hepatitis Hostility Hyperglycemia Hyperprolactinemia Hypersensitivity pneumonitis Hyperthyroidism Hypomagnesemia Hypothyroidism Jaundice Laryngismus Leukopenia Lymphadenopathy Manic disorder Myocarditis Myoclonus Myopathy Nephritis Neuroleptic malignant syndrome Neutropenic disorder Obstructive hyperbilirubinemia Ocular hemorrhage Pericarditis Priapism Prolonged QT interval Pulmonary thromboembolism Rectal bleeding Seizure disorder Serotonin syndrome Sleep apnea Steatosis of liver Stevens-johnson syndrome Syncope Tardive dyskinesia Tenosynovitis Thrombocytopenic disorder Thrombocytosis Thyroiditis Tongue swelling Torsades de pointes |
There are 72 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Akathisia Constipation Dizziness Drowsy Extrapyramidal disease General weakness Headache disorder Nausea Sialorrhea Weight gain |
Anorexia Cough Diarrhea Dyspepsia Hyperlipidemia Hypertonia Myalgia Orthostatic hypotension Pruritus of skin Rhinitis Tremor Upper respiratory infection Visual changes Vomiting Xerostomia |
| Rare/Very Rare |
|---|
|
Abnormal vaginal bleeding Acquired dystonia Acute abdominal pain Acute cognitive impairment Agitation Amenorrhea Anticholinergic toxicity Arthralgia Ataxia Black tarry stools Blepharitis Chills Delirium Depression Diplopia Dry eye Dysarthria Dysphasia Dyspnea Ecchymosis Erectile dysfunction Fever Flank pain Flu-like symptoms Galactorrhea not associated with childbirth Gingival bleeding Gynecomastia Hypertension Hypothermia Insomnia Keratoconjunctivitis Leucoplakia of oral mucosa Lymphedema Maculopapular rash Nocturia Nystagmus Oral hypoesthesia Phlebitis Photophobia Skin photosensitivity Sleep walking disorder Thrombophlebitis Tinnitus Trismus Urinary incontinence Urinary retention Urticaria |
The following precautions are available for GEODON (ziprasidone hcl):
Safety and efficacy of ziprasidone have not been established in pediatric patients younger than 18 years of age.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Category C. (See Users Guide.) In animals, ziprasidone demonstrated developmental toxicity, including possible teratogenic effects at dosages similar to human therapeutic dosages. Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.
Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.
For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.
National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388; clinicians are encouraged to enroll women from 18-45 years of age exposed to ziprasidone during pregnancy. The effect of ziprasidone on labor and delivery is unknown.
Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.
For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.
National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388; clinicians are encouraged to enroll women from 18-45 years of age exposed to ziprasidone during pregnancy. The effect of ziprasidone on labor and delivery is unknown.
The manufacturer states that it is not known whether ziprasidone or its metabolites are distributed into milk. However, a low concentration of ziprasidone in breast milk was reported in one woman; the milk to plasma ratio was 0.06 and the relative infant dose was estimated to be 1.2%
of the weight-normalized maternal dose. The manufacturer recommends that women receiving ziprasidone not breast-feed.
of the weight-normalized maternal dose. The manufacturer recommends that women receiving ziprasidone not breast-feed.
In clinical studies evaluating oral ziprasidone hydrochloride, 2.4% of patients were 65 years of age and older. Although no overall differences in safety or efficacy of oral ziprasidone were observed between geriatric and younger adults and other reported clinical experience has not identified differences in responses between geriatric and younger patients receiving the drug, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.
Because multiple factors may increase the pharmacodynamic response to ziprasidone or cause poorer tolerance or orthostasis, lower initial dosages, slower titration, and careful monitoring during the initial dosing period should be considered in some geriatric patients. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.) Ziprasidone mesylate IM injection has not been systematically evaluated in geriatric patients. In a multiple-dose study and a population pharmacokinetic evaluation of oral ziprasidone, no clinically important differences in pharmacokinetics were observed between geriatric and younger adults.
Geriatric patients with dementia-related psychosis treated with ziprasidone are at an increased risk of death compared with those treated with placebo. The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions). For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.
Because multiple factors may increase the pharmacodynamic response to ziprasidone or cause poorer tolerance or orthostasis, lower initial dosages, slower titration, and careful monitoring during the initial dosing period should be considered in some geriatric patients. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.) Ziprasidone mesylate IM injection has not been systematically evaluated in geriatric patients. In a multiple-dose study and a population pharmacokinetic evaluation of oral ziprasidone, no clinically important differences in pharmacokinetics were observed between geriatric and younger adults.
Geriatric patients with dementia-related psychosis treated with ziprasidone are at an increased risk of death compared with those treated with placebo. The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions). For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.
The following prioritized warning is available for GEODON (ziprasidone hcl):
WARNING: There may be a slightly increased risk of serious, possibly fatal side effects (such as stroke, heart failure, fast/irregular heartbeat, pneumonia) when this medication is used by older adults with dementia. This medication is not approved for the treatment of dementia-related behavior problems. Discuss the risks and benefits of this medication, as well as other effective and possibly safer treatments for dementia-related behavior problems, with the doctor. If you are using ziprasidone in combination with other medication to treat depression, also carefully read the drug information for the other medication.
WARNING: There may be a slightly increased risk of serious, possibly fatal side effects (such as stroke, heart failure, fast/irregular heartbeat, pneumonia) when this medication is used by older adults with dementia. This medication is not approved for the treatment of dementia-related behavior problems. Discuss the risks and benefits of this medication, as well as other effective and possibly safer treatments for dementia-related behavior problems, with the doctor. If you are using ziprasidone in combination with other medication to treat depression, also carefully read the drug information for the other medication.
The following icd codes are available for GEODON (ziprasidone hcl)'s list of indications:
| Bipolar disorder | |
| F31 | Bipolar disorder |
| F31.0 | Bipolar disorder, current episode hypomanic |
| F31.1 | Bipolar disorder, current episode manic without psychotic features |
| F31.10 | Bipolar disorder, current episode manic without psychotic features, unspecified |
| F31.11 | Bipolar disorder, current episode manic without psychotic features, mild |
| F31.12 | Bipolar disorder, current episode manic without psychotic features, moderate |
| F31.13 | Bipolar disorder, current episode manic without psychotic features, severe |
| F31.2 | Bipolar disorder, current episode manic severe with psychotic features |
| F31.3 | Bipolar disorder, current episode depressed, mild or moderate severity |
| F31.30 | Bipolar disorder, current episode depressed, mild or moderate severity, unspecified |
| F31.31 | Bipolar disorder, current episode depressed, mild |
| F31.32 | Bipolar disorder, current episode depressed, moderate |
| F31.4 | Bipolar disorder, current episode depressed, severe, without psychotic features |
| F31.5 | Bipolar disorder, current episode depressed, severe, with psychotic features |
| F31.6 | Bipolar disorder, current episode mixed |
| F31.60 | Bipolar disorder, current episode mixed, unspecified |
| F31.61 | Bipolar disorder, current episode mixed, mild |
| F31.62 | Bipolar disorder, current episode mixed, moderate |
| F31.63 | Bipolar disorder, current episode mixed, severe, without psychotic features |
| F31.64 | Bipolar disorder, current episode mixed, severe, with psychotic features |
| F31.7 | Bipolar disorder, currently in remission |
| F31.70 | Bipolar disorder, currently in remission, most recent episode unspecified |
| F31.71 | Bipolar disorder, in partial remission, most recent episode hypomanic |
| F31.72 | Bipolar disorder, in full remission, most recent episode hypomanic |
| F31.73 | Bipolar disorder, in partial remission, most recent episode manic |
| F31.74 | Bipolar disorder, in full remission, most recent episode manic |
| F31.75 | Bipolar disorder, in partial remission, most recent episode depressed |
| F31.76 | Bipolar disorder, in full remission, most recent episode depressed |
| F31.77 | Bipolar disorder, in partial remission, most recent episode mixed |
| F31.78 | Bipolar disorder, in full remission, most recent episode mixed |
| F31.8 | Other bipolar disorders |
| F31.81 | Bipolar II disorder |
| F31.89 | Other bipolar disorder |
| F31.9 | Bipolar disorder, unspecified |
| Schizophrenia | |
| F20 | Schizophrenia |
| F20.0 | Paranoid schizophrenia |
| F20.1 | Disorganized schizophrenia |
| F20.2 | Catatonic schizophrenia |
| F20.3 | Undifferentiated schizophrenia |
| F20.5 | Residual schizophrenia |
| F20.8 | Other schizophrenia |
| F20.81 | Schizophreniform disorder |
| F20.89 | Other schizophrenia |
| F20.9 | Schizophrenia, unspecified |
Formulary Reference Tool