Abilify Asimtufii (aripiprazole)
Antipsychotics Intramuscular Suspension,Extended Release Syringe (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Aripiprazole is considered an atypical or second-generation antipsychotic agent.
Aripiprazole is a quinolinone derivative antipsychotic agent that differs chemically from other currently available antipsychotic agents (e.g., butyrophenones, phenothiazines) and has been referred to as an atypical or second-generation antipsychotic agent. The exact mechanism of action of aripiprazole in schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, Tourette's syndrome, and agitation associated with schizophrenia or bipolar mania has not been fully elucidated but, like that of other drugs with efficacy in these conditions (e.g., olanzapine, risperidone, ziprasidone), may involve the drug's activity at dopamine D2 and serotonin type 1 (5-HT1A) and type 2 (5-HT2A) receptors. However, aripiprazole appears to differ from other atypical antipsychotic agents because the drug demonstrates partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.
Antagonism at other receptors (e.g., alpha1-adrenergic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence) observed with aripiprazole.
Aripiprazole is well absorbed following oral administration; peak plasma concentrations following oral administration of conventional tablets occur within 3-5 hours. Following administration of aripiprazole oral film, peak plasma concentrations are attained in a median of 1.5 hours. Administration with a high-fat meal does not affect peak plasma concentration or systemic exposure of aripiprazole or dehydro-aripiprazole.
Absolute oral bioavailability of conventional tablets is 87%. Following administration of the oral solution, plasma aripiprazole concentrations are higher than those after administration of equivalent dosages of the conventional tablets. Steady-state plasma concentrations of both aripiprazole and dehydro-aripiprazole are achieved within 14 days with oral administration.
Aripiprazole is extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by the cytochrome P-450 (CYP) 3A4 and 2D6 isoenzymes. The major active metabolite of aripiprazole, dehydro-aripiprazole, exhibits affinity for D2 receptors similar to that of the parent compound and represents approximately 40% of aripiprazole area under the concentration-time curve (AUC) in plasma. Poor CYP2D6 metabolizers have substantially increased aripiprazole and dehydro-aripiprazole exposures compared with extensive metabolizers.
Approximately 18% of an orally administered dose of aripiprazole is excreted unchanged in feces and less than 1% is excreted unchanged in urine. The mean elimination half-life of aripiprazole and dehydro-aripiprazole is approximately 75 and 94 hours, respectively. In poor metabolizers of CYP2D6, the mean elimination half-life is approximately 146 hours.
Following IM administration of extended-release aripiprazole (Abilify Maintena(R)), the low solubility of aripiprazole particles results in prolonged aripiprazole absorption. Following multiple IM doses, peak plasma aripiprazole concentrations occur after a median of 4 or 5-7 days when administered into the deltoid or gluteal muscle, respectively. Single IM injections into the deltoid result in 31% higher peak plasma concentrations compared with the gluteal site; however, aripiprazole systemic exposures and peak plasma concentrations at steady state were similar for both injection sites.
Dose-proportional increases in aripiprazole and dehydro-aripiprazole systemic exposures were observed following extended-release aripiprazole IM doses of 300 or 400 mg given every 4 weeks. Steady-state plasma concentrations of aripiprazole are achieved by the fourth dose of extended-release aripiprazole for both sites of administration. Following gluteal administration of multiple 300- or 400-mg doses of extended-release aripiprazole every 4 weeks, the mean terminal half-life of aripiprazole is 29.9 or 46.5 days, respectively.
Following gluteal injection of extended-release aripiprazole (Abilify Asimtufii(R)), the low solubility of aripiprazole particles results in prolonged aripiprazole absorption. The release profile of aripiprazole results in prolonged plasma concentrations over a 2-month period. Over the approved dosage range, extended-release aripiprazole exhibits linear pharmacokinetics.
It demonstrates a flat plasma concentration profile, with the time to maximum plasma concentrations occurring after 1-49 days. Steady-state plasma concentrations of aripiprazole are achieved by the fourth dose of extended-release aripiprazole. Steady state plasma concentrations are similar for Abilify Maintena(R) 400 mg once monthly and Abilify Asimtufii(R) 960 mg every 2 months.
Aripiprazole lauroxil is a prodrug of aripiprazole. Following IM injection, aripiprazole lauroxil is probably converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. Following IM administration of extended-release aripiprazole lauroxil (Aristada(R)), aripiprazole begins to appear in the systemic circulation in 5-6 days and is continually released for an additional 36 days.
Plasma concentrations of aripiprazole increase with consecutive doses and reach steady-state concentrations following the fourth monthly injection. With the addition of a single IM injection of extended-release aripiprazole lauroxil (Aristada Initio(R)) and 30 mg of oral aripiprazole at the time of the first Aristada(R) injection, aripiprazole concentrations reach therapeutic plasma levels within 4 days. A similar effect is achieved when oral aripiprazole is administered for 21 days following the first Aristada injection.
IM injection of extended-release aripiprazole lauroxil (441 mg) into the deltoid and gluteal areas results in similar systemic exposure; therefore, these injection sites are considered interchangeable. In addition, IM administration of aripiprazole lauroxil 882 mg every 6 weeks or 1064 mg every 2 months results in plasma aripiprazole concentrations that are within the established therapeutic range for dosages of 441 and 882 mg once monthly. The mean elimination half-life of aripiprazole ranges from about 54-57 days following monthly, every 6 week, or every 2 month injections of extended-release aripiprazole lauroxil (Aristada Initio(R)) .
Aripiprazole is commercially available in the US as aripiprazole and aripiprazole lauroxil.
Generic name: aripiprazole
Pronunciation: (AR-i-PIP-ra-zole)
Drug class: Antipsychotics
Therapeutic class: Central Nervous System Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Abilify Asimtufii
Indications
The following indications are listed for Abilify Asimtufii:
- Bipolar Disorder In Remission
- Schizophrenia
Also known as: Dementia Praecox, Parergasia.
Dosing
Aripiprazole oral solution may be given at the same dose on a mg-per-mg basis as the tablet strengths of the medication up to a dose of 25 mg. However, if the oral solution is used in patients who were receiving aripiprazole 30 mg as tablets, a dose of 25 mg of the oral solution should be used.
Conventional tablets and orally disintegrating tablets of aripiprazole are bioequivalent; therefore, dosing for the orally disintegrating tablets is the same as for the conventional tablets.
Dosage of aripiprazole lauroxil is expressed in terms of aripiprazole lauroxil.
Extended-release aripiprazole lauroxil (Aristada(R)) doses of 441, 662, 882, and 1064 mg correspond to aripiprazole doses of 300, 450, 600, and 724 mg, respectively.
Of the available oral dosage forms of aripiprazole, aripiprazole oral film (Opipza(R)) is not indicated for use in pediatric or adult patients with manic and mixed episodes associated with bipolar I disorder.
Aripiprazole is administered orally or by IM injection. Aripiprazole lauroxil is administered only by IM injection.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Abilify Asimtufii 720 Mg/2.4Ml | Maintenance | Inject 720 mg by intramuscular route every 2 months. |
| Abilify Asimtufii 960 Mg/3.2Ml | Maintenance | Inject 960 mg by intramuscular route every 2 months. |
No dosing information is available for this tab.
Drug interactions
There is no enhanced messaging for this drug.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Antipsychotics/Sibutramine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Sibutramine has demonstrated antidepressant effects. (1)
CLINICAL EFFECTS: Concurrent use of sibutramine and an antipsychotic may result in additive or synergistic central nervous system (CNS) effects.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Australian,(2) Canadian,(1) and UK(3) manufacturers of sibutramine state that concurrent use with antipsychotics is contraindicated.
DISCUSSION: The use of sibutramine with other CNS-active agents has not been evaluated.(1-3)
Neuroleptics/Iomeprol
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Neuroleptics may lower seizure threshold.(1)
CLINICAL EFFECTS: Use of iomeprol in a patient receiving a neuroleptic may increase the risk of seizure.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of iomeprol states that neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1)
DISCUSSION: Because neuroleptics may lower seizure threshold, neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1)
Selected Cyp2d6 Substrates/Mavorixafor
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: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)
CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)
PREDISPOSING FACTORS: With tricyclic antidepressants, 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 and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, 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.(2)
PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) The US manufacturer of doxepin states if concurrent use of doxepin and strong CYP2D6 inhibitors such as mavorixafor is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)
DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, atomoxetine, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Antipsychotics; Phenothiazines/Opioids (Cough And Cold)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as antipsychotics, including phenothiazine derivatives.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Antipsychotics; Phenothiazines; Rivastigmine/Metoclopramide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: These agents block dopamine (D2) receptors. D2 blockade can cause extrapyramidal reactions, such acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia. Neuroleptic malignant syndrome may also occur in patients receiving D2 blockers. The risk of these adverse effects may be increased by concurrent use.(1-3)
CLINICAL EFFECTS: Concurrent use may increase the risk of extrapyramidal reactions (e.g. acute dystonic reactions, pseudoparkinsonian tremors, akathisia, or tardive dyskinesia) and neuroleptic malignant syndrome. Tardive dyskinesia, which may be permanent, typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs.(1-3) Symptoms of neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, an autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias), elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.(1)
PREDISPOSING FACTORS: Patients with Parkinson's or Lewy Body Disease may be more likely to have extrapyramidal reactions or unmasking of their primary disease symptoms. The risk of extrapyramidal symptoms is also increased in patients on metoclopramide for longer than 12 weeks. Elderly patients, especially elderly women, and diabetics are at higher risk of developing tardive dyskinesia. Other extrapyramidal symptoms, like acute dystonia, have occurred more frequently in patients younger than 30 years old.(1)
PATIENT MANAGEMENT: The concurrent use of metoclopramide and agents likely to cause extrapyramidal reactions should be avoided.(1) If concurrent use is warranted, monitor patients closely for extrapyramidal reactions and neuroleptic malignant syndrome. The manufacturer of metoclopramide says to avoid treatment with metoclopramide for longer than 12 weeks, and to use the lowest possible dose.(1) Discontinue therapy if symptoms occur. Instruct patients to seek immediate medical attention if symptoms develop. Symptoms of extrapyramidal reactions, including tardive dyskinesia, include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, and/or dystonic reactions resembling tetanus/stridor/dyspnea.(3)
DISCUSSION: Both metoclopramide and phenothiazines can cause extrapyramidal reactions, such as tardive dyskinesia, and neuroleptic malignant syndrome. The risk may be increased by concurrent use.(1,2) Extrapyramidal symptoms have been reported with concurrent metoclopramide and neuroleptics, prochlorperazine, and chlorpromazine.(4-6)
Selected Dopamine Blockers/Cabergoline
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Dopamine (D2) blockers such as the phenothiazines, butyrophenones, thioxanthenes and atypical antipsychotics may decrease the effects of cabergoline, a dopamine agonist.(1)
CLINICAL EFFECTS: Concurrent administration of cabergoline with dopamine blockers (e.g. phenothiazines, butyrophenones, or thio xanthines) may decrease the effectiveness of cabergoline.(1) Cabergoline may decrease the effectiveness of antipsychotic treatment.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of cabergoline states cabergoline(1) should not be administered concurrently with dopamine antagonists. Avoid concurrent use when possible. If cabergoline is started in a patient receiving long term antipsychotic treatment, monitor closely for loss of antipsychotic efficacy. If an antipsychotic is required for a patient on long term cabergoline therapy, consider use of a shorter half-life, less potent dopamine (D2) blocking atypical antipsychotic (e.g. clozapine, quetiapine) and monitor closely.
DISCUSSION: The manufacturer of cabergoline state that it should not be administered concurrently with dopamine antagonists.
Slt Long-Acting Aripiprazole Injection/Strong Cyp3a4 Inducer
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of aripiprazole.(1,2)
CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of aripiprazole.(1,2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of the extended release injectable aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding use of strong CYP3A4 inducers with Aristada Initio. Aristada Initio is only available in a single strength as a single-dose prefilled syringe.(1) For patients receiving aripiprazole extended-release injection (Abilify Maintena or Abilify Asimtuffi), dose adjustments are not recommended by the manufacturer if the duration of strong CYP3A4 inducer treatment is less than 14 days. Concurrent use of Abilify Maintena or Abilify Asimtuffi with strong CYP3A4 inducers for greater than 14 days should be avoided.(2-3)
DISCUSSION: Drug interaction studies have not been conducted with Aristada Initio,(1) Abilify Maintena,(2) or Abilify Asimtuffi.(3) Aristada Initio has a long half-life (15-18 days).(1) Abilify Maintena has a half-life of 29.9 days and 46.5 days after multiple injections for every 4-week injection with the 300 mg and 400 mg dose, respectively.(2) The concurrent administration of carbamazepine (200 mg twice daily) with aripiprazole (30 mg daily) resulted in 70% decreases in the area-under-curve (AUC) and maximum concentration (Cmax) of both aripiprazole and dehydro-aripiprazole, its active metabolite.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(4-5)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Antipsychotics/Selected Opioids For Mat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics may result in additive CNS depression.(1-3) Levomethadone is an enantiomer of methadone.(4)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, may result in profound sedation, respiratory depression, coma, and/or death.(1-3)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine, diacetylmorphine, or methadone is not contraindicated in patients taking CNS depressants; however, gradual tapering or decreasing to the lowest effective dose of the CNS depressant may be appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine, diacetylmorphine, or methadone treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6)
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.(7) 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.(8) 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.(9) 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.(10) 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.(11) 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.(12) 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.(13)
Antipsychotics; Phenothiazines/Opioids (Extended Release)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Antipsychotics; Phenothiazines/Tramadol (Extended Release)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as tramadol with antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as tramadol with other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as tramadol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Antipsychotics;Phenothiazine/Slt Opioids (Immediate Release)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Aripiprazole Im Every 2 Months/Bupropion
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors such as bupropion may inhibit the metabolism of aripiprazole. Both agents are also known to lower the seizure threshold.(1-3)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole. Concurrent use may also result in additive effects on the seizure threshold, increasing the risk of seizures.(1-3)
PREDISPOSING FACTORS: The pharmacokinetic interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1) 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).(2-3)
PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics such as aripiprazole should be undertaken only with extreme caution and with low initial bupropion dosing, small gradual dosage increases of bupropion,(2-3) and reduced dosages of aripiprazole.(1) Single doses of bupropion should not exceed 150 mg.(2-3) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(3) or 450 mg for depression.(2) The US manufacturer of aripiprazole IM every 2 months injection (Abilify Asimtufii) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 960 mg every 2 months and a strong CYP2D6 inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2 months. - if the patient is taking both a strong CYP2D6 inhibitor AND a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.
DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold.(1)
Aripiprazole Im Every 2 Months/Slt Strong Cyp2d6 Inhibitors
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)
PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)
PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM every 2 months injection (Abilify Asimtufii) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 960 mg every 2 months and a strong CYP2D6 inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2 months. - if the patient is taking both a strong CYP2D6 inhibitor AND a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.
DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold.(1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)
Aripiprazole Im Every 2 Months/Str Cyp3a4 Inhib;Atazan;Darun
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of aripiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from aripiprazole.(1)
PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a strong CYP3A4 inhibitor.(1)
PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM every 2 months injection (Abilify Asimtufii) makes the following recommendations for patients who receive a strong CYP3A4 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 960 mg every 2 months and a strong CYP3A4 inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2 months. - if the patient is taking both a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, avoid use of Abilify Asimtufii. - if the patient is a poor CYP2D6 metabolizer and receives treatment with a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.
DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The coadministration of ketoconazole (200 mg daily for 14 days) with a single oral dose of aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and 77%, respectively. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold. The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6 metabolizers is predicted to increase aripiprazole Cmax and AUC by 3-fold.(1) CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)
Select Atypical Antipsychotics/Apomorphine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Apomorphine is a dopamine agonist. Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1)
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.
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.(2,3) The US manufacturer of apomorphine states patients with major psychotic disorders treated with neuroleptics should be treated with dopamine agonists only if the potential benefits outweigh the risks.(1)
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.(2,3) 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.(2)
Select Atypical Antipsychotics/Selected Dopamine Agonists
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)
Selected Antipsychotics; Phenothiazines/Levomethadyl (Ir)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as levomethadyl and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as levomethadyl and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(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 levomethadyl with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Selected Antipsychotics; Phenothiazines/Meperidine (Ir)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as meperidine and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as meperidine and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as meperidine with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Selected Antipsychotics; Phenothiazines/Methadone (Non Mat)
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 methadone and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as methadone 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 methadone with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Selected Antipsychotics; Phenothiazines/Oliceridine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as oliceridine with antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as oliceridine with other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as oliceridine with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Selected Antipsychotics; Phenothiazines/Tramadol (Ir)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as tramadol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as tramadol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as tramadol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Slt Antipsychotics; Phenothiazines/Codeine; Levorphanol (Ir)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of opioids such as codeine and levorphanol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as codeine and levorphanol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.
PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as codeine and levorphanol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)
Contraindications
*Known hypersensitivity to aripiprazole; hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis.
- Parkinsonism
- Chronic heart failure
- CYp2d6 poor metabolizer
- Metabolic syndrome x
- Neuroleptic malignant syndrome
- Senile dementia
- Suicidal ideation
- Tardive dyskinesia
- Acute cognitive impairment
- Agranulocytosis
- Alzheimer's disease
- Cerebrovascular disorder
- Diabetes mellitus
- Esophageal dysmotility
- Hypotension
- Leukopenia
- Lower seizure threshold
- Myocardial ischemia
- Neutropenic disorder
- Obesity
- Orthostatic hypotension
- Predisposition to aspiration
- Seizure disorder
- Weight gain
Adverse reactions
In adults with schizophrenia receiving oral aripiprazole in clinical trials, akathisia was the only adverse effect that occurred in >=5% of patients and at an incidence at least twice that for placebo.
Adverse effects occurring in >=5% of adolescents (13 to 17 years of age) with schizophrenia receiving oral aripiprazole in clinical trials and at an incidence at least twice that of placebo include extrapyramidal disorder, somnolence, and tremor.
Adverse effects occurring in >=5% of adults with bipolar mania receiving oral aripiprazole as monotherapy in clinical trials and at an incidence at least twice that of placebo include akathisia, sedation, restlessness, tremor, and extrapyramidal disorder.
Adverse effects occurring in >=5% of adults with bipolar mania receiving oral aripiprazole as adjunctive therapy with lithium or valproate in clinical trials and at an incidence at least twice that of placebo include akathisia, insomnia, and extrapyramidal disorder.
Adverse effects occurring in >=5% of pediatric patients 10 to 17 years of age with bipolar mania receiving oral aripiprazole in clinical trials and at an incidence at least twice that of placebo include somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness.
Adverse effects occurring in >=5% of adults with major depressive disorder receiving oral aripiprazole in clinical trials and at an incidence at least twice that of placebo include akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.
Adverse effects occurring in >=5% of pediatric patients 6 to 17 years of age with autistic disorder receiving oral aripiprazole in clinical trials and at an incidence at least twice that of placebo include sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy.
Adverse effects occurring in >=5% of pediatric patients 6 to 18 years of age with Tourette's Disorder receiving oral aripiprazole in clinical trials and at an incidence at least twice that of placebo include sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, and increased appetite.
In clinical trials with aripiprazole tablets with sensor and other components of the digital ingestion tracking system (Abilify MyCite(R)), skin rash localized at the application site of the wearable sensor (patch) was reported in 12.4% of patients.
Adverse effects occurring in >=5% of adults receiving extended-release IM aripiprazole injection in clinical trials and at an incidence at least twice that for placebo include increased weight, akathisia, injection site pain, and sedation.
In patients receiving extended-release IM aripiprazole lauroxil injection (Aristada(R)) in clinical trials, akathisia was the only adverse effect that occurred in >=5% of patients and at an incidence at least twice that for placebo.
More Frequent
- Akathisia
Less Frequent
- Acquired dystonia
- Extrapyramidal disease
- Fever
- Hyperglycemia
- Orthostatic hypotension
- Skin rash
- Tardive dyskinesia
Rare or Very Rare
- Abnormal hepatic function tests
- Accidental fall
- Acute myocardial infarction
- Agranulocytosis
- Anaphylaxis
- Angioedema
- Aspiration pneumonia
- Atrial flutter
- Atrioventricular block
- Biliary calculus
- Bradycardia
- Chest pain
- Cholecystitis
- Diabetes mellitus
- Diabetic ketoacidosis
- DRESS syndrome
- Dysglycemia
- Dysphagia
- Esophageal dysmotility
- Heat stroke
- Hepatic failure
- Hepatitis
- Hepatomegaly
- Homicidal ideation
- Hypertension
- Hypoglycemic disorder
- Hypokalemia
- Hyponatremia
- Hypoprolactinemia
- Hypotension
- Increased creatine kinase level
- Jaundice
- Laryngismus
- Leukopenia
- Myocardial ischemia
- Neuroleptic malignant syndrome
- Neutropenic disorder
- Oculogyric crisis
- Pancreatitis
- Parkinsonism
- Peripheral edema
- Pneumonia
- Priapism
- Rhabdomyolysis
- Seizure disorder
- Serotonin syndrome
- Sleep apnea
- Splenomegaly
- Steatosis of liver
- Stevens-johnson syndrome
- Suicidal ideation
- Tachycardia
- Thrombocytopenic disorder
- Upper respiratory infection
- Urinary retention
- Ventricular tachycardia
More Frequent
- Agitation
- Constipation
- Dizziness
- Dyspepsia
- Headache disorder
- Hypertriglyceridemia
- Increased appetite
- Insomnia
- Nausea
- Symptoms of anxiety
- Vomiting
Less Frequent
- Acute abdominal pain
- Anorexia
- Arthralgia
- Cough
- Diarrhea
- Dysmenorrhea
- Fatigue
- Fecal incontinence
- General weakness
- Hyperlipidemia
- Hyperprolactinemia
- Injection site pain
- Injection site sequelae
- Myalgia
- Nasal congestion
- Nervousness
- Pain
- Pharyngitis
- Toothache
- Tremor
- Weight gain
Rare or Very Rare
- Amenorrhea
- Anticholinergic toxicity
- Ataxia
- Blurred vision
- Compulsive gambling
- Diplopia
- Drowsy
- Dyspnea
- Erectile dysfunction
- Eyelid edema
- Facial edema
- Gastroesophageal reflux disease
- Gynecomastia
- Hiccups
- Hirsutism
- Hyperhidrosis
- Hypokinesia
- Impulse control disorder
- Increased libido
- Lethargy
- Mastalgia
- Memory impairment
- Menstrual disorder
- Muscle rigidity
- Muscle weakness
- Myoclonus
- Nocturia
- Orgasm disorder
- Palpitations
- Photophobia
- Pruritus of skin
- Sedation
- Sialorrhea
- Skin photosensitivity
- Sleep walking disorder
- Urinary incontinence
- Urticaria
- Weight loss
- Xerostomia
Precautions
No enhanced messaging available.
Safety and efficacy of oral aripiprazole have not been established in pediatric patients with major depressive disorder.
Safety and efficacy of oral aripiprazole have not been established in pediatric patients with agitation associated with schizophrenia or bipolar mania.
Safety and efficacy of extended-release IM formulations of aripiprazole and aripiprazole lauroxil have not been evaluated in pediatric patients <18 years of age.
Safety and efficacy of aripiprazole tablets with sensor have not been established in pediatric patients.
Safety and efficacy of oral aripiprazole for the acute management of schizophrenia in pediatric patients 13 to 17 years of age have been established in a placebo-controlled study of 6 weeks' duration. Although the efficacy of oral aripiprazole for maintenance treatment of schizophrenia in pediatric patients has not been systematically evaluated, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
Safety and efficacy of oral aripiprazole monotherapy for the acute management of bipolar mania in pediatric patients 10 to 17 years of age have been established in a placebo-controlled study of 4 weeks' duration.
The efficacy of oral aripiprazole as an adjunct to lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar disorder in pediatric patients has not been systematically evaluated. However, efficacy can be extrapolated from adult data in addition to pharmacokinetic comparisons of aripiprazole between adult and pediatric populations.
Safety and efficacy of oral aripiprazole for the treatment of irritability associated with autistic disorder have been established in 2 placebo-controlled clinical trials of 8 weeks' duration in pediatric patients 6 to 17 years of age. Efficacy of the drug as maintenance therapy for irritability associated with autistic disorder was not established in a longer-term, placebo-controlled relapse prevention trial in pediatric patients 6 to 17 years of age.
Safety and efficacy of oral aripiprazole for the treatment of Tourette's syndrome have been established in one 8-week, placebo-controlled trial in pediatric patients 7 to 17 years of age and one 10-week, placebo-controlled trial in pediatric patients 6 to 18 years of age. Efficacy of the drug as maintenance therapy in pediatric patients with Tourette's syndrome has not been systematically evaluated.
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients 10 to 17 years of age are similar to those in adults after correcting for differences in body weight.
Mean weight gain of 1.6 kg was reported in pediatric patients with schizophrenia or bipolar disorder receiving oral aripiprazole compared with a gain of 0.3 kg in those receiving placebo in 2 short-term studies. After 24 weeks of therapy, the mean change from baseline in body weight in the aripiprazole-treated patients was 5.8 kg compared with 1.4 kg in placebo recipients. Similar gains in weight were observed in short-term studies in pediatric patients with irritability associated with autistic disorder and Tourette's syndrome.
A greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants). No suicides occurred in these pediatric trials. These findings should be carefully considered when assessing potential benefits and risks of aripiprazole in a child or adolescent for any clinical use.
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 and managed appropriately. The complications have varied in severity; some neonates recovered within hours to days without specific treatment, while others have required prolonged hospitalization.
There is a pregnancy registry that monitors pregnancy outcomes in females exposed to atypical antipsychotics during pregnancy. Clinicians are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 and https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/atypicalantipsychotic/.
Limited data indicate that aripiprazole is present in human milk at a relative infant dose (RID) ranging from 0.7-8.3% of the maternal weight-adjusted dosage. Poor weight gain in breast-fed infants exposed to aripiprazole and inadequate milk supply in lactating women have been reported. The manufacturers of aripiprazole state that the benefit of aripiprazole therapy to the mother as well as the benefits of breast-feeding to the infant should be weighed against the potential risk to the infant resulting from exposure to the drug or from the underlying maternal condition.
No dosage adjustment is necessary in geriatric patients..
The manufacturer of extended-release IM aripiprazole (Abilify Asimtufii(R)) states that an insufficient number of patients >=65 years of age were included in clinical trials to assess differences in response compared to younger adults; however, dosage selection for elderly patients should be undertaken with caution and dosages should be initiated at the lower end of the dosage range.
The safety and efficacy of Aristada(R) or Aristada Initio(R) have not been established in patients >65 years of age.
In clinical studies, approximately 8% of over 13,000 patients treated with oral aripiprazole were >=65 years of age and approximately 6% were >=75 years of age. Experience from placebo-controlled trials with oral aripiprazole in patients with schizophrenia, bipolar mania, or major depressive disorder who are >=65 years of age is insufficient to determine whether they respond differently than younger adults.
The manufacturer of oral and extended-release IM formulations of aripiprazole states that dosage adjustment is not necessary in geriatric patients on the basis of age alone. The manufacturer of extended-release IM aripiprazole lauroxil states that the safety and efficacy of the drug have not been evaluated in patients >65 years of age and makes no specific dosage recommendations for geriatric patients.
The manufacturer of extended-release IM aripiprazole (Abilify Asimtufii(R)) states that an insufficient number of patients >=65 years of age were included in clinical trials to assess differences in response compared to younger adults; however, dosage selection for elderly patients should be undertaken with caution and dosages should be initiated at the lower end of the dosage range.
Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with aripiprazole in placebo-controlled studies. Aripiprazole is not approved for the treatment of dementia-related psychosis.
In pooled data analyses, a reduced risk of suicidality was observed in adults >=65 years of age with antidepressant therapy compared with placebo.
ICD codes
| Code | Type | Description |
|---|---|---|
| Bipolar disorder in remission | ||
| F31.7 | ICD10CM | Bipolar disorder, currently in remission |
| F31.70 | ICD10CM | Bipolar disorder, currently in remission, most recent episode unspecified |
| F31.71 | ICD10CM | Bipolar disorder, in partial remission, most recent episode hypomanic |
| F31.72 | ICD10CM | Bipolar disorder, in full remission, most recent episode hypomanic |
| F31.73 | ICD10CM | Bipolar disorder, in partial remission, most recent episode manic |
| F31.74 | ICD10CM | Bipolar disorder, in full remission, most recent episode manic |
| F31.75 | ICD10CM | Bipolar disorder, in partial remission, most recent episode depressed |
| F31.76 | ICD10CM | Bipolar disorder, in full remission, most recent episode depressed |
| F31.77 | ICD10CM | Bipolar disorder, in partial remission, most recent episode mixed |
| F31.78 | ICD10CM | Bipolar disorder, in full remission, most recent episode mixed |
| Schizophrenia | ||
| F20 | ICD10CM | Schizophrenia |
| F20.0 | ICD10CM | Paranoid schizophrenia |
| F20.1 | ICD10CM | Disorganized schizophrenia |
| F20.2 | ICD10CM | Catatonic schizophrenia |
| F20.3 | ICD10CM | Undifferentiated schizophrenia |
| F20.5 | ICD10CM | Residual schizophrenia |
| F20.8 | ICD10CM | Other schizophrenia |
| F20.81 | ICD10CM | Schizophreniform disorder |
| F20.89 | ICD10CM | Other schizophrenia |
| F20.9 | ICD10CM | Schizophrenia, unspecified |
ICD code information from First Databank (FDB).
Formulary status
Search health-plan coverage for this drug by ZIP code.
Choose the first character of a health plan name.
Last reviewed · Source: First Databank (FDB) drug data
On this page
Actions
Sign in to save favorites
Saving this drug requires a free Physicians Office Resource account.