Zyprexa (olanzapine)

Olanzapine is commercially available as the base and as the pamoate salt; the dosage of olanzapine pamoate is expressed in terms of olanzapine.

Conventional olanzapine tablets and orally disintegrating tablets of the drug are bioequivalent. However, IM administration of a 5-mg dose of the commercially available short-acting olanzapine injection results in a maximum plasma olanzapine concentration that is about 5 times higher than that resulting from a 5-mg oral dose of the drug.

Olanzapine is administered orally or by IM injection. Olanzapine pamoate is administered only by IM injection. Olanzapine is also available in fixed combination with fluoxetine or samidorphan. Refer to the prescribing information for olanzapine/samidorphan (Lybalvi(R)) for specific information on its administration and dosing.

Olanzapine is mainly metabolized via direct glucuronidation and cytochrome P-450 (CYP)-mediated oxidation. In vitro studies suggest that CYP isoenzymes 1A2 and 2D6 and the flavin-containing monooxygenase system are involved in oxidation; however, CYP2D6-mediated oxidation appears to be a minor pathway.

In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit metabolism of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A substrates. Therefore, clinically important drug interactions between olanzapine and drugs metabolized by these isoenzymes are considered unlikely.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antipsychotics/Sibutramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sibutramine has demonstrated antidepressant effects. (1)

CLINICAL EFFECTS: Concurrent use of sibutramine and an antipsychotic may result in additive or synergistic central nervous system (CNS) effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(2) Canadian,(1) and UK(3) manufacturers of sibutramine state that concurrent use with antipsychotics is contraindicated.

DISCUSSION: The use of sibutramine with other CNS-active agents has not been evaluated.(1-3)

Neuroleptics/Iomeprol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Neuroleptics may lower seizure threshold.(1)

CLINICAL EFFECTS: Use of iomeprol in a patient receiving a neuroleptic may increase the risk of seizure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of iomeprol states that neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1)

DISCUSSION: Because neuroleptics may lower seizure threshold, neuroleptics should be discontinued 48 hours before iomeprol use. Treatment with a neuroleptic should not be resumed until 24 hours post-procedure.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That May Cause Respiratory Depression/Sodium Oxybate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

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)

Intramuscular Olanzapine/Parenteral Benzodiazepines

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of intramuscular olanzapine with a parenteral benzodiazepine may result in excessive sedation, cardiorespiratory depression, and death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of olanzapine state that simultaneous injection of intramuscular olanzapine and parenteral benzodiazepines is not recommended. If parenteral benzodiazepine therapy is required in a patient who has received IM olanzapine, wait 1 hour after the administration of IM olanzapine.(2) IM olanzapine should only be considered in patients who have received parenteral benzodiazepines after careful evaluation and they should be closely monitored for excessive sedation and cardiorespiratory depression.(2)

DISCUSSION: In post-marketing reports, temporal association of IM olanzapine with respiratory depression, hypotension, bradycardia, and death have been rarely reported (<0.01%). Many of the patients also received parenteral benzodiazepines.(2) In an analysis of 160 spontaneous reports of adverse events during a review of the first 21 months of olanzapine usage, benzodiazepines were used concurrently in 27% of non serious reports (21/77), 44% of serious nonfatal reports (24/54), and in 66% (19/29) fatal reports.(4) Concurrent use with diazepam has shown to increase orthostatic hypotension. There was no effect on the pharmacokinetics of diazepam or its active metabolite, N-desmethyldiazepam.(3) Concurrent use with intramuscular lorazepam did not affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. Somnolence was increased.(3)

Selected Antipsychotics/Selected Dopamine Agonists

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

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. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the 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)

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)

Olanzapine/Ciprofloxacin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ciprofloxacin may inhibit the CYP1A2 mediated metabolism of olanzapine.(1-6)

CLINICAL EFFECTS: Concurrent use of ciprofloxacin may result in elevated levels of and toxicity from olanzapine.

PREDISPOSING FACTORS: Cytokines or other immune modulators secreted in response to infection or inflammation may also inhibit CYP1A2, resulting in additive suppression of CYP1A2 activity.(3-5)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for olanzapine side effects. The dose of olanzapine may need to be adjusted if ciprofloxacin is initiated or discontinued.

DISCUSSION: In a study with fluvoxamine, another CYP1A2 inhibitor, 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(6) In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(7) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(8) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(9,10)

Olanzapine/Marijuana Smoke

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Olanzapine is primarily metabolized by CYP1A2.(1) Marijuana, when consumed by smoking, has been shown to induce CYP1A2.(2)

CLINICAL EFFECTS: Smoking marijuana may lower serum olanzapine concentrations resulting in reduced pharmacologic effects.

PREDISPOSING FACTORS: Patients who smoke both marijuana and tobacco may have larger increases in olanzapine clearance.(3)

PATIENT MANAGEMENT: Monitor olanzapine efficacy closely and observe the patient for a change in the therapeutic effects of olanzapine if the patient starts, alters, or discontinues marijuana use. Adjust olanzapine dose accordingly.

DISCUSSION: In a study in chronic marijuana users, users of both marijuana and tobacco, and control subjects, theophylline (a CYP1A2 substrate) clearance was 42% higher in marijuana users. Theophylline clearance was increased 79% in subjects who smoked both marijuana and tobacco.(3) Case reports have noted clinically significant changes in olanzapine levels in patient starting and stopping marijuana.(4,5)

Olanzapine/Selected Cyp1a2 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inducers of CYP1A2 may increase the metabolism of olanzapine.(1,2)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inducer may result in decreased levels and effectiveness of olanzapine.(1,2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with olanzapine and a CYP1A2 inducer may require increased dosages of olanzapine. The dosage of olanzapine may need to be adjusted if concurrent therapy with a CYP1A2 inducer is initiated or discontinued.(1,2) If a CYP1A2 inducer is initiated in a patient maintained on olanzapine, monitor for decreased effectiveness of olanzapine. If a CYP1A2 inducer is discontinued in a patient maintained on olanzapine, monitor for olanzapine toxicity.

DISCUSSION: Concurrent use of carbamazepine, a CYP1A2 inducer, increased olanzapine clearance by 50%.(1,2)

Olanzapine/Selected Strong Cyp1a2 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of olanzapine by CYP1A2.(1-5)

CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and toxicity from olanzapine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for olanzapine side effects. The dose of olanzapine may need to be adjusted if a strong CYP1A2 inhibitor is initiated or discontinued.

DISCUSSION: In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(2) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(3) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(4,5) Strong CYP1A2 inhibitors linked include: enasidenib, enoxacin, fluvoxamine, and rofecoxib.(6)

Selected Antipsychotics; Phenothiazines/Levomethadyl (Ir)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids such as levomethadyl and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids such as levomethadyl and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as levomethadyl with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Antipsychotics; Phenothiazines/Meperidine (Ir)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids such as meperidine and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids such as meperidine and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as meperidine with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Antipsychotics; Phenothiazines/Methadone (Non Mat)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids such as methadone and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids such as methadone and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as methadone with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Antipsychotics; Phenothiazines/Oliceridine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids such as oliceridine with antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids such as oliceridine with other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as oliceridine with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Antipsychotics; Phenothiazines/Tramadol (Ir)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids such as tramadol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids such as tramadol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as tramadol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Slt Antipsychotics; Phenothiazines/Codeine; Levorphanol (Ir)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids such as codeine and levorphanol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids such as codeine and levorphanol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as codeine and levorphanol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

*None.

• Neuroleptic malignant syndrome
• Parkinsonism

• Acute myocardial infarction
• Angle-closure glaucoma
• Benign prostatic hyperplasia
• Cardiac arrhythmia
• Cerebrovascular disorder
• Chronic heart failure
• Dehydration
• Diabetes mellitus
• Esophageal dysmotility
• Hypotension
• Leukopenia
• Lower seizure threshold
• Myocardial ischemia
• Neutropenic disorder
• Paralytic ileus
• Predisposition to aspiration
• Restless leg syndrome
• Seizure disorder
• Senile dementia
• Suicidal ideation
• Tardive dyskinesia
• Transient cerebral ischemia

• Disease of liver
• Hyperlipidemia
• Hyperprolactinemia
• Obesity
• Tobacco smoker

Adverse effects occurring in 5% or more of adult patients with schizophrenia receiving oral olanzapine monotherapy in clinical studies and with an incidence of at least twice that of placebo included postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia. In adolescents with schizophrenia, common adverse effects included sedation, increased weight, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, and dry mouth.

Adverse effects occurring in 5% or more of adult patients with manic or mixed episodes associated with bipolar I disorder receiving oral olanzapine monotherapy in clinical studies and with an incidence of at least twice that of placebo included asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, and tremor. In adolescents with manic or mixed episodes associated with bipolar I disorder, common adverse effects included sedation, increased weight, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, and pain in extremity.

When oral olanzapine was used in conjunction with lithium or valproate for treatment of manic or mixed episodes associated with bipolar I disorder in adults, adverse effects occurring in 5% or more of patients in clinical studies and with an incidence of at least twice that of placebo included dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, and paresthesia.

When short-acting IM olanzapine was used for the management of acute agitation in clinical studies in adults, somnolence was the only adverse effect that occurred in 5% or more of patients with schizophrenia or bipolar I mania and with an incidence at least twice that of placebo.

When extended-release olanzapine pamoate injection was used IM in adults with schizophrenia in a clinical study, adverse effects occurring in 5% or more of patients and more frequently than with placebo included headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

More Frequent

• Akathisia
• Parkinsonism
• Personality disorders

Less Frequent

• Altered mental status
• Chest pain
• Euphoria
• Extrapyramidal disease
• Fever
• Memory impairment
• Peripheral edema
• Tardive dyskinesia

Rare or Very Rare

• Accidental fall
• Accommodation disorder
• Acquired dystonia
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Bradycardia
• Cerebrovascular accident
• Cholestatic hepatitis
• Diabetes mellitus
• Diabetic ketoacidosis
• DRESS syndrome
• Dysphagia
• Dyspnea
• Eosinophilia
• Esophageal dysmotility
• Exfoliative dermatitis
• Facial edema
• Heat stroke
• Hepatic failure
• Hepatitis
• Hyperbilirubinemia
• Hyperglycemia
• Hyperlipidemia
• Hyperosmolar hyperglycemic state
• Ileus
• Jaundice
• Leukopenia
• Lymphadenopathy
• Menstrual disorder
• Neuroleptic malignant syndrome
• Neutropenic disorder
• Oculogyric crisis
• Osteoporosis
• Pancreatitis
• Priapism
• Rhabdomyolysis
• Seizure disorder
• SIADH syndrome
• Skin rash
• Sleep apnea
• Steatosis of liver
• Thrombocytopenic disorder
• Thromboembolic disorder
• Urinary retention
• Visual changes

More Frequent

• Back pain
• Constipation
• Disturbance of attention
• Dizziness
• Drowsy
• Fatigue
• General weakness
• Headache disorder
• Hyperprolactinemia
• Hypertriglyceridemia
• Increased appetite
• Orthostatic hypotension
• Rhinitis
• Sedation
• Toxic amblyopia
• Tremor
• Weight gain
• Xerostomia

Less Frequent

• Abdominal pain with cramps
• Abnormal hepatic function tests
• Arthralgia
• Chills
• Cough
• Dysarthria
• Dyspepsia
• Ecchymosis
• Edema
• Erectile dysfunction
• Gait abnormality
• Hypersomnia
• Hypertension
• Hypertonia
• Hypotension
• Insomnia
• Muscle rigidity
• Nausea
• Nervousness
• Pain in extremities
• Paresthesia
• Pharyngitis
• Polydipsia
• Sialorrhea
• Tachycardia
• Urinary incontinence
• Urinary tract infection
• Vomiting

Rare or Very Rare

• Acute cognitive impairment
• Alopecia
• Anticholinergic toxicity
• Epistaxis
• Fecal incontinence
• Galactorrhea not associated with childbirth
• Gynecomastia
• Increased urinary frequency
• Libido changes
• Mastalgia
• Pruritus of skin
• Restless leg syndrome
• Skin photosensitivity
• Sleep walking disorder
• Stuttering
• Urticaria
• Vasodilation of blood vessels

No enhanced messaging available.

The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term clinical trials in adolescents (13-17 years of age). Use of oral olanzapine in such adolescents is supported by evidence from adequate and well-controlled clinical trials in which 268 adolescents received olanzapine in a dosage range of 2.5-20 mg daily. The recommended initial dosage for adolescents is lower than that for adults. Compared with adults in clinical trials, adolescents treated with oral olanzapine were likely to gain more weight, experience increased sedation, and have greater increases in serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, prolactin, and hepatic transaminases.

Clinicians should consider the potential long-term risks (including weight gain and dyslipidemia) when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in such patients.

The manufacturer states that safety and efficacy of oral olanzapine for the treatment of schizophrenia or manic or mixed episodes associated with bipolar I disorder in children and adolescents younger than 13 years of age have not been established.

The safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder were established in a short-term clinical trial in pediatric patients 10-17 years of age. Use of oral olanzapine and fluoxetine in such children and adolescents is supported by evidence from a well-controlled clinical trial in which 255 pediatric patients received olanzapine in a dosage range of 3-12 mg daily. The recommended initial dosage of olanzapine in combination with fluoxetine for adolescents is lower than that for adults.

The manufacturer states that the safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of treatment-resistant depression have not been established in patients younger than 18 years of age.

The manufacturer states that the safety and efficacy of oral olanzapine in combination with fluoxetine have not been established in pediatric patients younger than 10 years of age.

The manufacturer states that the safety and efficacy of extended-release olanzapine pamoate IM injection in patients younger than 18 years of age have not been established.

A pregnancy exposure registry is available that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, 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/research/pregnancyregistry/. Currently available data from published epidemiologic studies of pregnant women exposed to olanzapine 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 olanzapine, during pregnancy. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.

In pregnant rats and rabbits receiving oral olanzapine at doses 9 to 30 times the maximum recommended human dose based on mg/m2 body surface area, no teratogenicity was observed; however, some fetal toxicities (e.g., increased or early resorptions, increased numbers of nonviable fetuses, and decreased fetal weight) were observed.

Neonates exposed to antipsychotic agents, including olanzapine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.

Olanzapine is distributed into milk. There are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk. There are no data on the effects of olanzapine on milk production.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for olanzapine and any potential adverse effects on the breast-fed child from the drug or from the mother's underlying condition.

Monitor infants exposed to olanzapine for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

The manufacturer suggests consideration of a lower starting dosage of oral olanzapine and extended-release IM olanzapine pamoate (e.g., Zyprexa(R) Relprevv) for any geriatric patient with factors present that could decrease pharmacokinetic clearance or increase pharmacodynamic response to olanzapine. When short-acting olanzapine for injection (e.g., Zyprexa(R) IntraMuscular) is used IM to treat agitation associated with schizophrenia and bipolar I mania in geriatric patients, a dose of 5 mg per injection should be considered when other clinical factors warrant.

In premarketing clinical studies with oral olanzapine, 11% (263 of 2500) of the patients were 65 years of age or older. Clinical experience in patients with schizophrenia generally has not revealed differences in tolerability of oral olanzapine in geriatric patients compared with younger adults.

Studies in patients with dementia-related psychosis have suggested that oral olanzapine may have a different tolerability profile in patients 65 years of age or older with this condition compared with younger patients with schizophrenia. Geriatric patients with dementia-related psychosis receiving antipsychotic agents, including olanzapine, are at an increased risk of death compared with that among patients receiving placebo. In addition, a significantly higher incidence of adverse cerebrovascular events (e.g., stroke, transient ischemic attack) was observed in patients receiving olanzapine compared with those receiving placebo in these trials. In 5 placebo-controlled studies of olanzapine in geriatric individuals with dementia-related psychosis, certain treatment-emergent adverse effects, including falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations, occurred in at least 2% of the patients and the incidence was significantly higher than in patients receiving placebo. Discontinuance of therapy because of adverse effects occurred in a significantly higher number of olanzapine-treated patients than in those receiving placebo (13% and 7%, respectively) in these studies.

The manufacturer states that olanzapine is not approved for the treatment of patients with dementia-related psychosis.

The manufacturer states that the presence of factors that might decrease the clearance of or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower initial dosage of the drug in geriatric patients.

Clinical studies of olanzapine in combination with fluoxetine did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.

Clinical studies of extended-release IM olanzapine pamoate did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.