comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.triazolamMonitor Closely (1)lurasidone, triazolam. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.trifluoperazineMonitor Closely (1)lurasidone, trifluoperazine. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.trimipramineMonitor Closely (2)lurasidone, trimipramine. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity. lurasidone, trimipramine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Potential for increased risk of hypotension with concurrent use. Monitor blood pressure and adjust dose of antihypertensive agent as needed.triprolidineMonitor Closely (1)lurasidone, triprolidine. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.tucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.valsartanMonitor Closely (1)lurasidone increases effects of valsartan by Other (see comment). Use Caution/Monitor. Comment: Potential for increased risk of hypotension with concurrent use. Monitor blood pressure and adjust dose of antihypertensive agent as needed.venlafaxineMonitor Closely (2)lurasidone, venlafaxine. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity. venlafaxine, lurasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).verapamilMonitor Closely (2)verapamil increases levels of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Manufacturer recommends decreasing starting dose of lurasidone to 20 mg/day and maximum daily dose of lurasidone 80 mg when coadministered with moderate CYP3A4 inhibitors. Concurrent use may increase risk of lurasidone-related adverse reactions. lurasidone increases effects of verapamil by Other (see comment). Use Caution/Monitor. Comment: Potential for increased risk of hypotension with concurrent use. Monitor blood pressure and adjust dose of antihypertensive agent as needed.vigabatrinMonitor Closely (1)lurasidone, vigabatrin. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.vilazodoneMonitor Closely (2)lurasidone, vilazodone. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity. vilazodone, lurasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).voriconazoleContraindicated (1)voriconazole increases levels of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of lurasidone and strong CYP3A4 inhibitors is contraindicated.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.zafirlukastMonitor Closely (1)zafirlukast increases levels of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Concurrent use of weak CYP3A4 inhibitors can theoretically lead to an increased risk of lurasidone-related adverse reactions.zaleplonMonitor Closely (1)lurasidone, zaleplon. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.ziconotideMonitor Closely (1)lurasidone, ziconotide. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.ziprasidoneMonitor Closely (1)lurasidone, ziprasidone. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.zolmitriptanMonitor Closely (1)zolmitriptan, lurasidone. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).zolpidemMonitor Closely (1)lurasidone, zolpidem. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.zonisamideMonitor Closely (1)lurasidone, zonisamide. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity. >10% Somnolence, dose related (15-26%) Akathisia, dose related (6-22%) Extrapyramidal disorder, dose related (6-22%) Parkinsonism, dose related (6-17%) Fasting glucose increased, dose related (10-14%) Nausea, dose related (9-13%) Insomnia, dose-related (7-11%) 1-10% Agitation, dose related (3-10%) Vomiting, dose related (6-8%) Dyspepsia, dose related (5-8%) Anxiety, dose related (3-8%) Elevated serum creatinine, dose related (1-7.2%) Dystonia (5%) Dizziness, dose related (4-6%) Fatigue (4%) Back pain, dose related (2-4%) Restlessness (3%) Salivary hypersecretion, dose related (1-4%) Hypertension Rash Pruritus CPK increased Abdominal pain Diarrhea Blurred vision Tachycardia <1% Anemia AV block 1st degree Angina pectoris Bradycardia Vertigo Gastritis Rhabdomyolysis Cerebrovascular accident Dysarthria Abnormal dreams Panic attack Sleep disorder Dysuria Renal failure Amenorrhea Dysmenorrhea Breast enlargement Breast pain Galactorrhea Erectile dysfunction Angioedema Postmarketing Reports Hypersensitivity (urticaria, throat swelling, tongue swelling, and dyspnea) Hyponatremia Black Box Warnings Increased mortality in elderly patients with dementia-related psychosis Not indicated for dementia-related psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; lurasidone is not approved for the treatment of patients with dementia-related psychosis; placebo-controlled trials with other atypical antipsychotics showed higher incidence of cerebrovascular adverse reactions (eg, CVA, TIA), including fatalities, compared with placebo Suicidal thoughts and behaviors Antidepressants increased the risk of suicidal thoughts and behavior in children and young adults in short-term studies; closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors Contraindications Hypersensitivity Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil) Coadministration with strong CYP3A4 inducers (eg, rifampin, St. John’s wort, phenytoin, carbamazepine) Cautions Possibility of suicide attempt inherent to psychotic illness; close supervision required when therapy is initiated, dosage is changed, or drug is discontinued; the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use (eg, >4 months) is unknown; there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder Patients with Parkinson’s disease or dementia with Lewy bodies are reported to have an increased sensitivity to antipsychotic medication Orthostatic hypotension and syncope reported, possibly due to its alpha-1receptor antagonism Risk of neuroleptic malignant syndrome (NMS) reported in association with administration of antipsychotic drugs, including lurasidone; clinical manifestations of NMS (eg, hyperpyrexia, muscle rigidity, altered mental status, evidence of autonomic instability); additional symptoms (eg, elevated creatine phosphokinase, myoglobinuria [rhabdomyolysis], acute renal failure); the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment; if NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring Hyperprolactinemia reported; galactorrhea, amenorrhea, gynecomastia, and impotence reported with prolactin-elevating compounds; long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients Exercise caution in patients with a history of seizures or with conditions that lower the seizure threshold (eg, Alzheimer’s dementia); conditions that lower the seizure threshold may be more prevalent in patients ≥65 years May cause leukopenia, neutropenia, and agranulocytosis; monitor patients with neutropenia should for fever or other signs of infection and treat promptly if symptoms occur; discontinue treatment in patients with severe neutropenia (ANC <1,000/mm³) and follow WBC until recovery May disrupt body temperature regulation May lead to cognitive and motor impairment; caution patients about operating hazardous machinery Incidence of cerebrovascular effects (eg, transient ischemic attacks, stroke) may increase Esophageal dysmotility or aspiration may occur May increase QT interval: In trials, increase in baseline adjusted QTc intervals did not exceed mean based on individual correction method (QTcI) was 7.5 ms (120-mg dose) and 4.6 ms (600-mg dose) observed at 2-4 hours after dosing; additionally, in separate trial, QTc did not increase by >60 msec from baseline or exceed 500 msec with supratherapeutic doses (ie, 120 mg/day, 600 mg/day) Acute overdose: If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry theoretical hazard of additive QT-prolonging effects when given to patient with acute lurasidone overdose Motor instability, somnolence, and orthostatic hypotension reported, which may lead to falls and, consequently, fractures or other fall-related injuries; assess risk of falls when initiating treatment and recurrently for patients receiving repeated doses, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects Metabolic changes with atypical antipsychotic use Hyperglycemia, some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, reported; monitor glucose control in patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics Monitor symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness) In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for lurasidone 20-80 mg/day Undesirable alterations in lipids observed Weight gain observed; clinically monitor weight Tardive dyskinesia Extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia may occur; risk of tardive dyskinesia may increase in the elderly; risk of dystonia may increase with high doses Risk of developing tardive dyskinesia and likelihood of it becoming irreversible may increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase Drug interactions overview Coadministration with strong (eg, ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil) and moderate CYP3A4 inhibitors increased exposure of lurasidone (see Dosage Modifications, Contraindications) Coadministration with strong (eg, rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine) and moderate CYP3A4 inducers decreased exposure of lurasidone (see Dosage Modifications, Contraindications) Pregnancy Neonates exposed to antipsychotic drugs during 3rd trimester of pregnancy are at risk for extrapyramidal symptoms (EPS) and/or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU support and prolonged hospitalization There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone during pregnancy National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-andresearchprograms/pregnancyregistry Lactation Unknown whether drug is distributed in breast milk Lurasidone is present in rat milk Consider development and health benefits of breastfeeding along with mother’s clinical need for drug and any potential adverse effects on breastfed infant from therapy or from underlying maternal conditionPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Atypical antipsychotic; precise mechanism is unknown; efficacy suggested to involve mediation of central dopamine type 2 and serotonin type 2 (5HT-2A) receptor antagonism Absorption Bioavailability: 9-19% Peak plasma time: 1-3 hr