Risperidone (risperidone)
Antipsychotics Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Risperidone, a benzisoxazole-derivative, is an atypical antipsychotic agent.
Risperidone is a benzisoxazole-derivative antipsychotic agent. The drug has been described as an atypical antipsychotic agent. The principal active metabolite of risperidone is 9-hydroxyrisperidone (paliperidone); the clinical effects of risperidone result from the combined concentrations of risperidone and 9-hydroxyrisperidone.
The exact mechanism of antipsychotic action of risperidone has not been fully elucidated but may involve antagonism of both type 2 serotonergic (5-HT2) receptors and dopamine D2 receptors. Antagonism at other receptors (e.g., alpha1- and alpha2-adrenergic receptors, histamine H1 receptors) may contribute to other effects of risperidone.
Risperidone is a monoaminergic antagonist which exhibits high affinity for 5-HT2, dopamine D2, alpha1- and alpha2-adrenergic, and histamine H1 receptors. Risperidone exhibits low to moderate affinity for other serotonin receptor subtypes (e.g., 5HT1C, 5HT1A, 5HT1D), and weak affinity for dopamine D1 receptors and the haloperidol-sensitive sigma site. The drug possesses no affinity for cholinergic muscarinic or beta1- and beta2-adrenergic receptors.
Risperidone is well absorbed after oral administration, with peak drug plasma concentrations attained in approximately 1 hour. The absolute oral bioavailability of risperidone is 70%; the relative oral bioavailability from a tablet is 94% compared with a solution. Commercially available risperidone conventional and orally disintegrating tablets and oral solution are bioequivalent.
The mean peak plasma concentrations of the major active metabolite, 9-hydroxyrisperidone (paliperidone), occur at about 3 and 17 hours in patients who are extensive and poor metabolizers of cytochrome P-450 (CYP) 2D6, respectively. Steady state of risperidone is reached in 1 day in extensive metabolizers and expected in 5 days in poor metabolizers; 9-hydroxyrisperidone steady state is reached in 5-6 days in extensive metabolizers. Food does not affect the rate or extent of risperidone absorption.
After IM administration of risperidone (Risperdal(R) Consta(R)), there is a small initial release of the drug (<1% of dose) followed by a 3-week lag time; the main drug release starts from 3 weeks onward and is maintained for 4-6 weeks and then subsides by 7 weeks after the injection. Therefore, oral antipsychotic supplementation should be administered during the first 3 weeks of treatment with IM risperidone to maintain therapeutic levels until the main release of risperidone from the injection site has started. IM risperidone injections (Risperdal(R) Consta(R)) into the deltoid and gluteal areas are bioequivalent and therefore interchangeable.
With IM administration of extended-release risperidone injection every 2 weeks, steady-state plasma concentrations are achieved after 4 doses and are maintained 4-6 weeks after the last injection.
After a single IM risperidone injection (Rykindo(R)), the release profile consists of an initial release of the drug followed by a stable release phase of 2--4 weeks. The median time to peak concentration of risperidone and 9-hydroxyrisperidone combined are 14 and 17 days following administration of 25 mg and 50 mg of the drug, respectively. The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of Rykindo(R) results in sustained concentrations within the dosing interval (every 2 weeks).
Steady-state plasma concentrations are reached after 2 injections and can be maintained for 2--3 weeks after the last injection.
Subcutaneous risperidone (Uzedy(R)) contains risperidone in a liquid delivery system. A depot forms following subcutaneous injection, providing sustained plasma levels of risperidone and 9-hydroxyrisperidone combined over 1 or 2 months. After subcutaneous administration, the median time to peak plasma concentrations for risperidone and 9-hydroxyrisperidone combined ranges from 8--14 days.
Therapeutic concentrations in plasma are achieved within 6--24 hours following the first injection. Steady-state levels of risperidone and 9-hydroxyrisperidone are approached within 2 months of Uzedy(R) initiation. Administration in the abdomen and upper arm results in similar pharmacokinetic profiles for all doses, therefore these injection sites can be used interchangeably.
Similar to Uzedy(R), subcutaneous risperidone (Perseris(R)) contains risperidone in a liquid delivery system. A depot forms following subcutaneous injection, providing sustained plasma levels of risperidone over the monthly dosing interval. After single subcutaneous injection, there are 2 absorption peaks for risperidone in plasma; the first peak is due to an initial release of the drug during the depot formation process, and the second peak (observed at 10 to 14 days after administration) is associated with the slow release of risperidone from the depot.
For both 9-hydroxyrisperidone and total active moiety, the median time to peak plasma concentrations of the first and second peak ranges from 4--48 hours and 7--11 days, respectively. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and total active moiety approach steady-state levels after the first dose of Perseris(R).
Risperidone is rapidly distributed. The drug is approximately 90% protein bound (mainly to albumin and alpha1-acid glycoprotein); the major active metabolite (9-hydroxyrisperidone) is 77% protein bound. Risperidone is extensively metabolized, principally in the liver via CYP2D6, to the active metabolite (9-hydroxyrisperidone) which has similar pharmacologic activity to parent drug.
N-Dealkylation is a minor metabolic pathway. Risperidone is excreted principally in the urine (70%) and to much lesser extent, in the feces (14%).
After oral administration, overall mean elimination half-life for active moiety (risperidone plus 9-hydroxyrisperidone) is about 20 hours. After IM risperidone administration, the apparent half-life of the active moiety is 3-6 days. The elimination phase is complete approximately 7-8 and 6 weeks after the last injection of Risperdal(R) Consta(R) and Rykindo(R), respectively.
Following administration of Uzedy(R), the mean apparent half-life ranges between 14--22 days for risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined. Following a single subcutaneous injection of Perseris(R), the mean apparent terminal half-life of risperidone ranges between 9--11 days; the mean apparent terminal half-life ranges between 8--9 days for both 9-hydroxyrisperidone and total active moiety.
Notably, CYP2D6 is subject to genetic polymorphism; extensive metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, while poor metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations, the pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) are similar after single and multiple doses in extensive and poor metabolizers. Following subcutaneous administration, plasma exposure to risperidone and 9-hydroxyrisperidone combined was similar in CYP2D6 extensive, intermediate, poor and non-poor metabolizers.
USES: This medication is used to treat certain mental/mood disorders (such as schizophrenia, bipolar disorder, irritability associated with autistic disorder). Risperidone belongs to a class of drugs known as atypical antipsychotics. It works by helping to restore the balance of certain natural substances in the brain.
Generic name: risperidone
Pronunciation: (riss-PAIR-ih-doan)
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 Risperidone
Indications
The following indications are listed for Risperidone:
- Infantile Autism
- Mania Associated With Bipolar Disorder
- Mixed Bipolar I Disorder
- Schizophrenia
Also known as: Autism, Bipolar Mania, Childhood Autism, Dementia Praecox, Kanner's Syndrome, Mania Associated With Bipolar Affective Disorder, Manic Episode Associated With Bipolar Disorder, Manic Phase Bipolar Mood Disorder, Manic Phase Of Bipolar Mood Disorder, Manic Phase Of Manic-Depression, Parergasia.
Dosing
For patients who have never taken oral risperidone, tolerability should be established with oral risperidone prior to initiating treatment with IM or subcutaneous risperidone.
Risperidone is administered orally or by subcutaneous or IM injection. Risperidone is available as oral tablets, oral solution, and orally disintegrating tablets; extended-release IM injection (Risperdal(R) Consta(R); Rykindo(R)); and extended-release subcutaneous injection (Uzedy(R); Perseris(R)).
| Drug label | Dosing type | Instructions |
|---|---|---|
| Risperidone 2 Mg Tablet | Maintenance | Take 1 tablet (2 mg) by oral route 2 times per day. |
| Risperidone 1 Mg Tablet | Maintenance | Take 1 tablet (1 mg) by oral route 2 times per day. |
| Risperidone 0.5 Mg Tablet | Maintenance | Take 2 tablets (1 mg) by oral route 2 times per day. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Risperidone 0.5 Mg Tablet | Maintenance | Take 2 tablets (1 mg) by oral route 2 times per day. |
| Risperidone 1 Mg Tablet | Maintenance | Take 1 tablet (1 mg) by oral route 2 times per day. |
| Risperidone 2 Mg Tablet | Maintenance | Take 1 tablet (2 mg) by oral route 2 times per day. |
Drug interactions
In vitro studies indicate that risperidone is a relatively weak inhibitor of cytochrome P-450 (CYP) 2D6. Risperidone is metabolized by CYP2D6 to 9-hydroxyrisperidone (paliperidone), which has similar pharmacologic activity to risperidone; the clinical effects of risperidone result from the combined concentrations of risperidone and 9-hydroxyrisperidone.
In vitro, drugs metabolized by CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP3A4 only weakly inhibit risperidone metabolism.
The interactions of IM or subcutaneous risperidone with coadministration of other drugs have not been studied. The following drug interaction data are based on studies with oral risperidone.
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 Antipsychotics/Strong Cyp3a4 Inducers
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), brexpiprazole(2), and risperidone.(3)
CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of aripiprazole, brexpiprazole, and risperidone.(1-3)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The dose of immediate release aripiprazole should be doubled over 1-2 weeks if a CYP3A4 inducer is added to aripiprazole therapy. Additional dosage increases should be based on clinical observation of the patient. If the inducer is withdrawn from concurrent therapy, the dosage of aripiprazole should be gradually reduced to the original level over 1-2 weeks.(1) The dose of brexpiprazole should be doubled over 1-2 weeks in patients taking strong CYP3A4 inducers. If the inducer is discontinued, reduce the dosage of brexpiprazole to the original level over 1-2 weeks.(2) The US manufacturer of risperidone (Risperdal) recommends that patients increase the dose of risperidone up to double the patient's usual dose when taken concurrently with a CYP3A4 inducer. Do not exceed twice the patient's usual dose. It may be necessary to decrease the risperidone dose when the CYP3A4 inducer is discontinued.(3)
DISCUSSION: 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) Rifampin decreased the AUC of brexpiprazole by approximately 75%.(2) A study in 11 schizophrenic inpatients examined the effects of the addition of carbamazepine (200 mg twice daily) for one week to risperidone (3 mg twice daily). Concurrent carbamazepine decreased plasma concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by 50%, 44%, and 45%, respectively.(4) A study compared 23 patients receiving risperidone alone to 11 patients receiving concurrent risperidone and carbamazepine. The groups were matched for sex, age, body weight, and risperidone dosage. Plasma concentrations of 9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone were significantly lower in patients receiving concurrent carbamazepine. Five subjects received risperidone with and without carbamazepine. In these patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone concentrations were lower during concurrent carbamazepine.(5) In a case report, a patient developed an exacerbation of psychotic symptoms four weeks after the addition of carbamazepine (800 mg daily) to his regimen. Plasma levels of risperidone and 9-hydroxyrisperidone had decreased by 77% and 63%, respectively.(6) In an open, randomized cross-over study in 10 healthy males, pretreatment with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg) by 72% and 50%, respectively.(7) In a study in 10 healthy males, pretreatment with rifampin (600 mg daily for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone (1 mg) by 51% and 38%, respectively. The AUC of 9-hydroxyrisperidone and the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43% and 45%, respectively. The Cmax of 9-hydroxyrisperidone and the active moieties decreased by 46% and 41%, respectively.(8) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(9,10)
Selected Cyp1a2 Or Cyp2d6 Substrates/Givosiran
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Givosiran interferes with the first and rate-limiting step in hepatic heme biosynthesis, which may lower hepatic heme levels and decrease production and/or activity of cytochrome P450 enzymes.(1,2)
CLINICAL EFFECTS: Concurrent use of givosiran may result in elevated levels of and toxicity from agents metabolized by CYP1A2 or 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.(3)
PATIENT MANAGEMENT: Avoid the concurrent use of givosiran with agents that are sensitive substrates of CYP1A2 or CYP2D6, or CYP1A2 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is unavoidable, decrease the dose of the CYP1A2 or CYP2D6 substrate and monitor patients for toxicity.
DISCUSSION: A study of 9 patients with acute intermittent porphyria found that givosiran decreased the maximum concentration (Cmax) and area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and 3.1-fold, respectively, compared to caffeine alone. Givosiran also decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2- and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, nefazodone, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, and venlafaxine. Selected CYP1A2 substrates linked to this monograph include: agomelatine, aminophylline, rasagiline, tacrine, theophylline, tizanidine, and yohimbine.
Selected Cyp2d6 Substrates/Panobinostat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Panobinostat is a moderate inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)
CLINICAL EFFECTS: Concurrent use of panobinostat 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.(4)
PATIENT MANAGEMENT: Avoid the concurrent use of panobinostat with agents that are sensitive CYP2D6 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is warranted, monitor patients for toxicity.(1)
DISCUSSION: In a study in 14 subjects with advanced cancer, panobinostat (20 mg daily on Days 3, 5, and 8) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dextromethorphan (60 mg) by 20-200% and 20-130%, respectively. Dextromethorphan exposures were extremely variable.(1) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.
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.
Moderate Interaction: Assess the risk to the patient and take action as needed.
Antipsychotics/Bupropion
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Both bupropion and the antipsychotics are known to lower the seizure threshold.(1,2) Bupropion is also a strong inhibitor of CYP2D6.(3)
CLINICAL EFFECTS: Concurrent use of bupropion and an antipsychotic may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2)
PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1,2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)
PATIENT MANAGEMENT: The concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)
DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antipsychotics should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1)
Antipsychotics/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)
Risperidone/Codeine; Dihydrocodeine; 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 or levorphanol and antipsychotics such as risperidone may result in additive CNS depression.(1)
CLINICAL EFFECTS: Concurrent use of opioids such as codeine or levorphanol and other CNS depressants, such as risperidone, 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 or levorphanol with CNS depressants such as risperidone 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 opioid reversal agents (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: 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.(4) 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.(5) 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.(6) 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.(7) 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.(8) 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.(9)
Risperidone/Selected 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 risperidone by CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The US manufacturer of risperidone (Risperdal) recommends that when CYP2D6 inhibitors are co-administered with risperidone that the dose should be reduced. The risperidone dose should not exceed 8 mg per day when co-administered with CYP2D6 inhibitors. When initiating therapy with risperidone, the dose of risperidone should be titrated slowly. It may be necessary to increase the risperidone dose, when CYP2D6 inhibitors are discontinued.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(2)
DISCUSSION: In a study in 7 patients maintained on risperidone (doses ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased risperidone levels by 25%. The mean plasma risperidone/9-hydroxyrisperidone ratio increased 1.95-fold. One patient developed mild extrapyramidal symptoms. His risperidone level at the time was 72 ng/ml.(3) In contrast, a retrospective chart review compared 7 patients receiving concurrent risperidone and duloxetine to control patients receiving only risperidone and found no significant effect on risperidone levels.(4) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(5) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(5) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(6) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(2) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(2) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(7)
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/Lithium
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The exact mechanism of the interaction is unknown. Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and EEG changes) may be due to potentiation or an additive effect of the antipsychotic agent and lithium.
CLINICAL EFFECTS: Concurrent use of lithium and selected antipsychotic agents may produce neurotoxic symptoms, including extrapyramidal symptoms, neuroleptic malignant syndrome, and encephalopathic syndrome.
PREDISPOSING FACTORS: Large doses of either drug, pre-existing brain damage or other conditions (e.g. infection, dehydration) may increase the risk for neurotoxicity.
PATIENT MANAGEMENT: Lithium and antipsychotic agents are commonly co-prescribed for the acute management of manic or mixed manic episodes associated with bipolar disorder. Concurrent use should be approached with caution. Consider additional clinical monitoring for signs and symptoms of neurotoxicity, including confusion, fever, lethargy, tremors, stupor, weakness, leukocytosis, and increased blood urea nitrogen. If signs of neurotoxicity appear, discontinuation of the antipsychotic agent may be required. The US manufacturer of lithium carbonate states concurrent use with antipsychotic agents, including chlorpromazine, clozapine, fluphenazine, haloperidol, perphenazine, risperidone, and thioridazine, should be monitored closely. Although uncommon to rare, cases of severe neurotoxicity have been reported with this combination. Monitoring plasma levels is not always beneficial in preventing neurotoxic symptoms. Patients may experience neurotoxic symptoms with plasma concentrations in the therapeutic ranges. Close monitoring for signs of neurotoxicity, EEG monitoring, adequate hydration, and electrolyte status are recommended to minimize toxic potential.
DISCUSSION: Lithium and antipsychotic agents are commonly co-prescribed for the acute management of manic or mixed manic episodes associated with bipolar disorder. Several case reports have been published describing acute and irreversible neurotoxicity with the combination of lithium and antipsychotic agents, though these episodes often resemble rare serious events that can be attributed to the administration of either agent alone (e.g., delirium, dysphoria, encephalopathy, dyskinesias, neuroleptic malignant syndrome, etc.). Signs and symptoms of neurotoxicity associated with concomitant use have included confusion, fever, lethargy, tremors, stupor, weakness, leukocytosis, and increased blood urea nitrogen. Extrapyramidal effects, which in some cases were irreversible, and permanent brain damage have also been reported. Selected antipsychotics linked to this monograph include: benperidol, clozapine, haloperidol, and risperidone.
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)
Contraindications
*Known hypersensitivity to either risperidone or paliperidone (metabolite of risperidone) or to any of the excipients in the risperidone formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported.
- Neuroleptic malignant syndrome
- Parkinsonism
- Acute myocardial infarction
- Atherosclerotic cardiovascular disease
- Cardiac arrhythmia
- Cataract surgery
- Cerebrovascular disorder
- Chronic heart failure
- Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
- Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
- Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
- Dehydration
- Diffuse lewy body disease
- Disease of liver
- Hypotension
- Hypovolemia
- Leukopenia
- Myocardial ischemia
- Neutropenic disorder
- Orthostatic hypotension
- Rhabdomyolysis
- Senile dementia
- Severe hepatic disease
- Tardive dyskinesia
- Acute cognitive impairment
- Carcinoma of breast
- Diabetes mellitus
- Dysphagia
- Fever
- Hyperlipidemia
- Hyperprolactinemia
- Hypothermia
- Intraoperative floppy iris syndrome
- Metabolic syndrome x
- Obesity
- Predisposition to aspiration
- Seizure disorder
- Weight gain
Adverse reactions
The most frequent adverse effects of oral risperidone reported in >=5% of patients who received the drug in clinical trials and with an incidence of at least twice that of those receiving placebo were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.
The most frequent adverse effects of IM risperidone in patients with schizophrenia (>=5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremity, and dry mouth. The most frequent adverse effects of IM risperidone in patients with bipolar disorder were weight increase (5% in monotherapy trial) and tremor and parkinsonism (>=10% in adjunctive therapy trial).
The most frequent adverse effects of subcutaneous risperidone (Uzedy(R)) reported in >=5% of patients who received the drug in clinical trials and with an incidence greater than placebo were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. The most frequent injection site reactions with subcutaneous risperidone (Uzedy(R)) (>=5% and greater than placebo) were pruritus and nodule.
The most frequent adverse effects of subcutaneous risperidone (Perseris(R)) reported in >=5% of patients who received the drug in clinical trials and with an incidence of at least twice that of those receiving placebo were increased weight, sedation/somnolence, and musculoskeletal pain.
More Frequent
- Akathisia
- Dyskinesia
- Extrapyramidal disease
- Parkinsonism
- Visual changes
Less Frequent
- Hypotension
- Orthostatic hypotension
Rare or Very Rare
- Abnormal ECG
- Abnormal hepatic function tests
- Accidental fall
- Agranulocytosis
- Altered consciousness
- Anaphylaxis
- Anemia
- Angioedema
- Aspiration pneumonia
- Atrial fibrillation
- Atrioventricular block
- Bradycardia
- Catatonia
- Cerebral ischemia
- Cerebrovascular accident
- Diabetes mellitus
- DRESS syndrome
- Esophageal dysmotility
- Fever
- Gastrointestinal obstruction
- Heart block
- Hypertension
- Hypothermia
- Ileus
- Influenza
- Intraoperative floppy iris syndrome
- Jaundice
- Leukopenia
- Neuroleptic malignant syndrome
- Neutropenic disorder
- Pancreatitis
- Pituitary neoplasm
- Pneumonia
- Priapism
- Pulmonary thromboembolism
- Rhabdomyolysis
- Seizure disorder
- SIADH syndrome
- Sinus tachycardia
- Sleep apnea
- Stevens-johnson syndrome
- Tardive dyskinesia
- Thrombocytopenic disorder
- Thrombotic thrombocytopenic purpura
- Tongue swelling
- Toxic epidermal necrolysis
- Transient cerebral ischemia
- Water intoxication
More Frequent
- Abnormal sexual function
- Acquired dystonia
- Agitation
- Altered mental status
- Appetite changes
- Blurred vision
- Constipation
- Cough
- Diarrhea
- Dizziness
- Drowsy
- Dyspepsia
- Fatigue
- Headache disorder
- Increased appetite
- Injection site sequelae
- Insomnia
- Libido changes
- Nasal congestion
- Nausea
- Nervousness
- Pharyngitis
- Pruritus of skin
- Rhinitis
- Rhinorrhea
- Sedation
- Sialorrhea
- Skin rash
- Sore throat
- Symptoms of anxiety
- Tremor
- Upper respiratory infection
- Urinary incontinence
- Vomiting
- Weight gain
- Xerostomia
Less Frequent
- Abdominal pain with cramps
- Acute cognitive impairment
- Arthralgia
- Ataxia
- Back pain
- Concentration difficulty
- Dyspnea
- Epistaxis
- Galactorrhea not associated with childbirth
- General weakness
- Hypercholesterolemia
- Hyperglycemia
- Hyperprolactinemia
- Hypertriglyceridemia
- Menstrual disorder
- Muscle weakness
- Myalgia
- Pain in extremities
- Palpitations
- Seborrhea
Rare or Very Rare
- Alopecia
- Amenorrhea
- Anorexia
- Anticholinergic toxicity
- Blepharospasm
- Cheilitis
- Complex sleep behavior
- Conjunctival hyperemia
- Disorder of ejaculation
- Disturbance of attention
- Dysarthria
- Dysgeusia
- Dysphagia
- Earache
- Edema
- Eyelid crusting
- Eyelid edema
- Fecal incontinence
- Flatulence
- Gastritis
- Gynecomastia
- Hypoesthesia
- Hypoglycemic disorder
- Infection of ear
- Joint stiffness
- Lip swelling
- Mastalgia
- Muscle spasm
- Musculoskeletal pain
- Non-cardiac chest pain
- Peripheral edema
- Photophobia
- Purpura
- Reduced visual acuity
- Retrograde ejaculation
- Sleep disorder
- Sleep walking disorder
- Syncope
- Tinnitus
- Urinary retention
- Urinary tract infection
- Urticaria
- Vertigo
Precautions
No enhanced messaging available.
Safety and efficacy of risperidone for IM or subcutaneous administration have not been established in pediatric patients.
Safety and efficacy of oral risperidone for the treatment of schizophrenia in adolescents 13-17 years of age were demonstrated in 2 short-term clinical trials in 417 patients. Efficacy and safety of oral risperidone for the treatment of acute manic or mixed episodes associated with bipolar I disorder in children and adolescents 10-17 years of age were demonstrated in a 3-week, placebo-controlled study in 169 patients. The safety and efficacy of oral risperidone in children younger than 13 years of age with schizophrenia or younger than 10 years of age with bipolar I disorder have not been established.
Efficacy and safety of oral risperidone in the treatment of irritability associated with autistic disorder have been evaluated in 3 placebo-controlled trials in pediatric patients 5 to 17 years of age.
In clinical trials in 1885 children and adolescents treated with risperidone, 2 patients (0.1%) reportedly developed tardive dyskinesia, which resolved upon discontinuance of therapy.
Weight gain has been observed in children and adolescents during treatment with oral risperidone; clinical monitoring of weight is recommended during treatment.
Somnolence frequently occurred in placebo-controlled trials of oral risperidone in pediatric patients with autistic disorder. Most cases were mild to moderate in severity, occurred early during therapy (peak incidence during the first 2 weeks of therapy), and were transient (median duration of 16 days). Somnolence also was the most common adverse effect in clinical trials in children and adolescents with bipolar disorder as well as in schizophrenia clinical trials in adolescents; as in the autistic disorder trials, somnolence usually occurred early during therapy and was transient. Pediatric patients experiencing persistent somnolence may benefit from a change in dosage regimen.
Oral risperidone has been shown to elevate prolactin concentrations in children and adolescents as well as adults. In double-blind, placebo-controlled trials of up to 8 weeks' duration in children and adolescents 5-17 years of age, 49% of oral risperidone-treated patients had elevated prolactin concentrations compared with 2% of those receiving placebo. Similarly, in placebo-controlled trials in children and adolescents 10-17 years of age with bipolar disorder or adolescents 13-17 years of age with schizophrenia, 82-87% of risperidone-treated patients had elevated prolactin concentrations compared with 3-7% of placebo recipients. Increases in prolactin concentrations were dose dependent and generally greater in female than male patients across indications. In clinical trials conducted in 1885 children and adolescents, galactorrhea and gynecomastia reportedly occurred in 0.8 and 2.3%, respectively, of oral risperidone-treated patients.
The manufacturers state that the long-term effects of oral risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.
A pregnancy exposure registry is available that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy. Clinicians are encouraged to enroll patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/.
Currently available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse outcomes in the mother or fetus. However, there are risks to the mother (e.g., risk of relapse, hospitalization, suicide) associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including risperidone, during pregnancy. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.
In animals, administration of oral risperidone to pregnant mice caused cleft palate at doses 3--4 times the maximum recommended human dose (MRHD), with maternal toxicity observed at 4 times the MRHD based on body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the MRHD based on body surface area. Oral risperidone administration to pregnant rats at 1.5 times the MRHD (based on body surface area) resulted in increased stillbirths and decreased birth weight. Impaired learning was observed in offspring of rats when the dams were dosed at 0.6 times the MRHD and offspring mortality increased at doses 0.1--3 times the MRHD based on body surface area. Subcutaneous administration of the risperidone delivery system to pregnant rats and rabbits during organogenesis caused developmental toxicity (e.g., post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations), at doses that are 52 (rat) and 43 (rabbit) times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on body surface area.
Neonates exposed to antipsychotic agents, including risperidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.
Risperidone and its principal active metabolite, 9-hydroxyrisperidone (paliperidone), are distributed into milk. Sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) have been reported in breast-fed infants exposed to risperidone. There are no data on the effects of risperidone on milk production.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for risperidone and any potential adverse effects on the breast-fed child from the drug or from the mother's underlying condition.
Monitor infants exposed to risperidone through breastmilk for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).
Oral risperidone: Like other alpha-adrenergic blocking agents, risperidone can induce orthostatic hypotension; the manufacturers state that the risk of this effect can be minimized by limiting the initial oral dosage of risperidone to 0.5 mg twice daily in geriatric patients followed by careful titration.
Risperdal(R) Consta(R): For otherwise healthy geriatric patients, the recommended IM risperidone dosage of the extended-release injection is 25 mg every 2 weeks. Oral risperidone (or another oral antipsychotic agent) should be given with the first risperidone extended-release injection and should be continued for 3 weeks to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site.
Rykindo(R): The manufacturer makes no specific dosage recommendations for this extended-release IM injection for geriatric patients.
Uzedy(R), Perseris(R): Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients, dosage selection for extended-release subcutaneous injections of risperidone should be cautious, usually initiated at lower dosages in such patients.
Clinical studies of oral risperidone for the management of schizophrenia did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Other clinical experience with oral risperidone has not identified differences in responses between geriatric and younger patients. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients, oral risperidone generally should be initiated at lower dosages in such patients. Although geriatric patients exhibit a greater tendency to orthostatic hypotension, the manufacturers state that its risk may be minimized by limiting the initial oral dosage to 0.5 mg twice daily, followed by careful titration and close monitoring of orthostatic vital signs in patients for whom this is of concern.
No differences in the tolerability of extended-release IM risperidone were observed in an open-label study in otherwise healthy geriatric patients and younger patients with schizophrenia or schizoaffective disorder. Therefore, the manufacturer states that extended-release IM risperidone dosage recommendations for otherwise healthy geriatric patients are the same as for younger adults.
Clinical studies of subcutaneous risperidone for the management of schizophrenia did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients, dosage selection for subcutaneous risperidone should be cautious, usually initiated at lower dosages in such patients.
ICD codes
| Code | Type | Description |
|---|---|---|
| Infantile autism | ||
| F84.0 | ICD10CM | Autistic disorder |
| Mania associated with bipolar disorder | ||
| F31.1 | ICD10CM | Bipolar disorder, current episode manic without psychotic features |
| F31.10 | ICD10CM | Bipolar disorder, current episode manic without psychotic features, unspecified |
| F31.11 | ICD10CM | Bipolar disorder, current episode manic without psychotic features, mild |
| F31.12 | ICD10CM | Bipolar disorder, current episode manic without psychotic features, moderate |
| F31.13 | ICD10CM | Bipolar disorder, current episode manic without psychotic features, severe |
| F31.2 | ICD10CM | Bipolar disorder, current episode manic severe with psychotic features |
| F31.73 | ICD10CM | Bipolar disorder, in partial remission, most recent episode manic |
| Mixed bipolar I disorder | ||
| F31.6 | ICD10CM | Bipolar disorder, current episode mixed |
| F31.60 | ICD10CM | Bipolar disorder, current episode mixed, unspecified |
| F31.61 | ICD10CM | Bipolar disorder, current episode mixed, mild |
| F31.62 | ICD10CM | Bipolar disorder, current episode mixed, moderate |
| F31.63 | ICD10CM | Bipolar disorder, current episode mixed, severe, without psychotic features |
| F31.64 | ICD10CM | Bipolar disorder, current episode mixed, severe, with psychotic features |
| 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).
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Last reviewed · Source: First Databank (FDB) drug data
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