New therapeutic agents marketed in 2020: Part 2

Abstract

Part 1 (Pharmacy Today, February 2021) of this series on new FDA-approved therapeutic agents marketed in 2020 reviewed five new therapeutic agents: lasmiditan hemisuccinate (Reyvow—Lilly), ubrogepant (Ubrelvy—Allergan), rimegepant sulfate (Nurtec ODT—Biohaven), eptinezumab-jjmr (Vyepti—Lundbeck), and lemborexant (Dayvigo—Eisai). This second part of the series reviews four additional agents (see table on page 49) marketed in 2020: bempedoic acid (Nexletol—Esperion), opicapone (Ongentys—Neurocrine), lumateperone tosylate (Caplyta—Intra-Cellular Therapeutics), and remdesivir (Veklury—Gilead). Following our review of each new therapeutic agent, we compare the new drug with the older medication(s) with which it is most similar in properties and uses and identify advantages and disadvantages of the new drug at the time it was first marketed. Advantages and disadvantages do not reflect approval of additional new drugs and/or changes that occur after the drug is initially marketed. Heart disease, the leading cause of death in the United States, is responsible for approximately 650,000 deaths each year. High blood pressure, high blood cholesterol, and smoking are key risk factors for heart disease, and almost one-half of Americans have at least one of these risk factors. Diabetes, overweight/obesity, physical inactivity, unhealthy diet, and excessive alcohol use can also put people at a higher risk for heart disease. Familial hypercholesterolemia is an inherited condition associated with high concentrations of LDL-C. The statins—atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin—have been widely prescribed as the standard of therapy for reducing elevated LDL-C concentrations and the related risks of cardiovascular disease. The statins inhibit HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol and other sterols, thereby reducing cholesterol synthesis in the liver. Although the statins are highly effective in reducing LDL-C concentrations, some patients do not tolerate them well, and many patients who are treated with a maximally tolerated dose of a statin still require additional lowering of LDL-C. Other medications used to regulate LDL-C and other blood lipid concentrations, sometimes in conjunction with a statin, include the fibric acid derivatives fenofibrate and gemfibrozil; niacin; the cholesterol absorption inhibitor ezetimibe; the bile acid sequestrants cholestyramine, colesevelam, and colestipol; icosapent (Vascepa); and the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors alirocumab (Praluent) and evolocumab (Repatha). The PCSK9 inhibitors are administered subcutaneously, whereas the other medications are administered orally. Bempedoic acid (Nexletol—Esperion) has a unique mechanism of action in reducing cholesterol synthesis in the liver and lowering LDL-C in blood via upregulation of LDL receptors. It acts by inhibiting adenosine triphosphate-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. Administered orally, bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C. Learning objectivesAt the conclusion of this knowledge-based activity, pharmacists will be able to▪Identify the new therapeutic agents and explain their appropriate use.▪Identify the indications and mechanisms of action of the new agents.▪Identify the most important adverse events and other risks of the new agents.▪State the route of administration for each new drug and the most important considerations for dosage and administration.▪Compare the new therapeutic agents with older medications to which they are most similar in properties and/or use, and identify the most important advantages and disadvantages of the new drugs. Preassessment questionsBefore participating in this activity, test your knowledge by answering the following questions. These questions will also be part of the CPE assessment.1.Which of the following drugs is most likely to be associated with dyskinesia?a.Bempedoic acidb.Opicaponec.Lumateperoned.Remdesivir2.In comparing bempedoic acid with atorvastatin, which of the following statements is correct?a.Bempedoic acid is less likely to cause skeletal muscle adverse events.b.Both agents have been demonstrated to decrease cardiovascular morbidity and mortality.c.The labeled indications for the two drugs are the same.d.When used concurrently, the dosage of atorvastatin should be reduced by one-half. At the conclusion of this knowledge-based activity, pharmacists will be able to ▪Identify the new therapeutic agents and explain their appropriate use.▪Identify the indications and mechanisms of action of the new agents.▪Identify the most important adverse events and other risks of the new agents.▪State the route of administration for each new drug and the most important considerations for dosage and administration.▪Compare the new therapeutic agents with older medications to which they are most similar in properties and/or use, and identify the most important advantages and disadvantages of the new drugs. Before participating in this activity, test your knowledge by answering the following questions. These questions will also be part of the CPE assessment. 1.Which of the following drugs is most likely to be associated with dyskinesia?a.Bempedoic acidb.Opicaponec.Lumateperoned.Remdesivir2.In comparing bempedoic acid with atorvastatin, which of the following statements is correct?a.Bempedoic acid is less likely to cause skeletal muscle adverse events.b.Both agents have been demonstrated to decrease cardiovascular morbidity and mortality.c.The labeled indications for the two drugs are the same.d.When used concurrently, the dosage of atorvastatin should be reduced by one-half. Bempedoic acid's effectiveness was evaluated in two placebo-controlled trials that enrolled more than 3,000 patients with HeFH and/or established ASCVD as add-on to a maximally tolerated dose of a statin alone or in combination with other lipid-lowering therapies. In the two trials, the primary efficacy outcome measure was the percentage change in LDL-C from baseline to week 12. The difference between the drug and placebo in mean percentage change was −18% and −17%, respectively, with the maximum LDL-C lowering effects occurring at week 4 in both studies. There were also reductions of at least 10% in total cholesterol (TC), non-HDL-C, and apolipoprotein B (apo B). HDL-C and triglycerides (TG) were examined as exploratory endpoints, but the changes in these parameters were small (−6% for HDL-C in both studies, and +3% and −2% for TG). The labeled indication for bempedoic acid is much more limited than the indications for the statins, with which long-term studies and use have demonstrated effectiveness in multiple dyslipidemias and in reducing the risk of myocardial infarction, stroke, and other complications in patients with multiple risk factors. Although bempedoic acid's effect on cardiovascular morbidity and mortality has not been demonstrated, its LDL-C lowering effect is additive to that of the statins, and it can be anticipated that the benefits identified for the statins will be extended. Bempedoic acid has not been compared directly with the statins, but the LDL-C lowering effect of the statins when given alone (30%–60% reduction depending on the particular statin and the dosage) is more pronounced than that provided with the new agent when added to statin treatment. Soon after approving bempedoic acid, FDA approved a fixed-dose combination product (Nexlizet) that also includes ezetimibe. In a study of patients with HeFH, established ASCVD, or multiple risk factors for cardiovascular disease already being treated with a statin, the addition of both bempedoic acid and ezetimibe provided a 36% reduction in LDL-C, which was significantly greater than that with either of these agents alone. Adverse events experienced most often in the clinical studies included upper respiratory tract infection (5%), muscle spasms (4%), back pain (3%), abdominal pain/discomfort (3%), bronchitis (3%), pain in extremity (3%), and anemia (3%). By inhibiting renal tubular organic anion transporter 2, the new drug may increase blood uric acid concentrations, and hyperuricemia was reported in 4% of the patients in the clinical trials. Gout was reported in 1.5% of patients, compared with 0.4% of patients receiving placebo, with the risk being higher in patients with a history of gout. Patients should be monitored for signs and symptoms, and uric acid concentrations should be assessed as clinically indicated. Tabled 1New therapeutic agents marketed in the United States in 2020: Part 2Generic nameTrade name (manufacturer)Therapeutic classificationRoute of administrationFDA classificationaFDA classification of new drugs: 1 = new molecular entity; P = priority review; S = standard review.Bempedoic acidNexletol (Esperion)Lipid-regulating agentOral1-SLumateperone tosylateCaplyta (Intra-Cellular Therapeutics)Antipsychotic agentOral1-SOpicaponeOngentys (Neurocrine)Antiparkinson agentOral1-SRemdesivirVeklury (Gilead)Antiviral agentI.V.1-Pa FDA classification of new drugs: 1 = new molecular entity; P = priority review; S = standard review. Open table in a new tab Bempedoic acid is associated with an increased risk of tendon rupture or injury, and its use should be avoided in patients with a history of tendon problems. Tendon rupture involving the rotator cuff, biceps tendon, or Achilles tendon occurred in 0.5% of patients in the clinical studies compared with 0% of the patients receiving placebo. The risk of tendon rupture is increased in patients older than 60, in those taking a fluoroquinolone or corticosteroid, and in those with renal failure. The drug should be immediately discontinued if a patient experiences a tendon rupture, and treatment discontinuation should be considered if a patient experiences joint pain, swelling, or inflammation. Bempedoic acid has been associated with an increased risk of benign prostatic hyperplasia; increases in liver enzymes, creatinine, blood urea nitrogen, and platelet counts; and decreases in hemoglobin and leukocytes. However, these changes are generally asymptomatic and do not require intervention. No data are available on use of bempedoic acid in pregnant or lactating women. However, its action to reduce the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol, as well as limited studies in animals, suggest the risk of adverse events in this population. Statin use is contraindicated during pregnancy and in nursing mothers, so use of bempedoic acid is precluded in patients already being treated with a statin. For statin-intolerant patients who are not being treated with any of the statins, use of bempedoic acid is best avoided during pregnancy or in nursing mothers. Consumption of food has no effect on oral bioavailability of bempedoic acid. It is converted, in part, to an active metabolite, and both compounds are converted to inactive glucuronide conjugates. Approximately 70% of a dose is recovered in the urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and approximately 30% is recovered in the feces. Less than 5% of a dose is excreted as unchanged bempedoic acid in feces and urine combined. Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment or mild or moderate renal impairment. Bempedoic acid has not been studied in patients with severe hepatic impairment, and data are very limited in patients with severe renal impairment. The combination of bempedoic acid and ezetimibe is not recommended in patients with moderate or severe hepatic impairment. Concurrent use of bempedoic acid increases the concentrations of pravastatin and simvastatin and may increase the risk of myopathy with the latter two agents. When the new drug is used concomitantly, the dosage of pravastatin should not exceed 40 mg daily, and the dosage of simvastatin should not exceed 20 mg daily. Bempedoic acid also increases the concentrations of atorvastatin and rosuvastatin, but to a lesser extent that is generally within the individual statin exposures, and dosage adjustment/restrictions are not necessary. The recommended dosage of bempedoic acid, in combination with maximally tolerated statin therapy, is 180 mg orally once a day, with or without food. Lipid concentrations should be assessed within 8 to 12 weeks following initiation of bempedoic acid treatment. Nexlizet tablets contain 180 mg of bempedoic acid and 10 mg of ezetimibe, and the recommended dosage is one tablet orally with or without food. When this combination product is used, the risks associated with use of ezetimibe should be considered in addition to those for bempedoic acid. Comparison of bempedoic acid with the statins; atorvastatin is used for comparisonAdvantages▪Has a unique mechanism of action (ACL inhibitor)▪Extends the LDL-C lowering effect of the statins▪Is not likely to cause skeletal muscle adverse events (e.g., myopathy)▪Is less likely to interact with other drugsDisadvantages▪Is not a first-line treatment for lowering LDL-C▪Effect on cardiovascular morbidity and mortality is not yet known▪May cause hyperuricemia, gout, and tendon rupture▪Has not been evaluated in pediatric patients, whereas atorvastatin is indicated for use in patients ages 10 years and older▪Labeled indications are more limited, whereas atorvastatin lowers other blood lipids (e.g., triglycerides), is indicated for several types of dyslipidemias, and has been demonstrated to reduce the risk of myocardial infarction, stroke, and other cardiovascular events Advantages ▪Has a unique mechanism of action (ACL inhibitor)▪Extends the LDL-C lowering effect of the statins▪Is not likely to cause skeletal muscle adverse events (e.g., myopathy)▪Is less likely to interact with other drugs Disadvantages ▪Is not a first-line treatment for lowering LDL-C▪Effect on cardiovascular morbidity and mortality is not yet known▪May cause hyperuricemia, gout, and tendon rupture▪Has not been evaluated in pediatric patients, whereas atorvastatin is indicated for use in patients ages 10 years and older▪Labeled indications are more limited, whereas atorvastatin lowers other blood lipids (e.g., triglycerides), is indicated for several types of dyslipidemias, and has been demonstrated to reduce the risk of myocardial infarction, stroke, and other cardiovascular events More than one million Americans have Parkinson's disease, the second most common neurodegenerative disorder after Alzheimer's disease. Parkinson's disease is associated with a reduction in dopamine activity in the brain, and most of the medications used in treatment increase this neurotransmitter's concentration and activity (i.e., a dopaminergic or dopamine agonist action). The combination of levodopa and carbidopa is the most effective treatment for the motor symptoms of Parkinson's disease, but its effectiveness diminishes with long-term use (i.e., 3–5 years). As the extent and duration of the benefit of levodopa/carbidopa decrease, patients experience more and/or longer “off” episodes—periods during treatment in which there is an increase in Parkinson symptoms such as tremor and difficulty walking. Because levodopa is metabolized extensively in the periphery by dopa decarboxylase (DDC), carbidopa is used concurrently as a DDC inhibitor. As a result, more levodopa reaches and crosses the blood–brain barrier into the central nervous system, thereby increasing its effectiveness. When the decarboxylation pathway is inhibited by carbidopa, the primary pathway for the metabolism of levodopa in the peripheral tissues is via catechol-O-methyltransferase (COMT). In 1998, tolcapone was marketed as the first COMT inhibitor to be used with levodopa to reduce its peripheral metabolism. Although tolcapone increases the effectiveness of levodopa/carbidopa, its use has been very limited because of concerns about hepatotoxicity and because entacapone (e.g., Comtan), a COMT inhibitor with less risk, was approved the following year. Entacapone is used with a levodopa/carbidopa formulation or in a combination product (e.g., Stalevo) that contains all three agents. Opicapone (Ongentys—Neurocrine), a peripherally acting reversible inhibitor of COMT, is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing “off” episodes. Administration of opicapone once a day at bedtime, with levodopa/carbidopa administered every 3 or 4 hours, increased peak and overall levodopa exposure compared with administration of levodopa/carbidopa alone. The new agent was evaluated in two placebo-controlled clinical trials in patients experiencing “off” episodes while being treated with levodopa/carbidopa, with or without other medications used for treatment of Parkinson's disease. The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed 3 days before each of the scheduled visits. Opicapone reduced OFF-time from a baseline of approximately 6.2 hours by about 2 hours in each study, compared with a reduction of about 1 hour in patients receiving placebo. A secondary efficacy endpoint was the change in ON-time without troublesome dyskinesia in patients with a baseline of approximately 9.5 hours. Patients treated with opicapone had increases in ON-time of 1.84 hours and 1.43 hours in the two studies, compared with increases of 0.75 hours and 0.8 hours, respectively, in those receiving placebo. In one of the studies in which one group of patients received entacapone, opicapone was determined to be noninferior to entacapone. The most commonly reported adverse events attributed to the addition of opicapone to levodopa/carbidopa and other antiparkinson agents in the clinical studies included dyskinesia (20%), constipation (6%), hypotension/syncope (5%), weight loss (4%), and increased blood creatine kinase (5%). Diarrhea was reported in less than 2% of patients, whereas it is one of the most common adverse events with entacapone. Unlike entacapone, the new agent does not cause discoloration of the urine. By potentiating the effects of levodopa, opicapone may cause dyskinesia or exacerbation of preexisting dyskinesia, and this was the most common reason for treatment discontinuation. A reduction in the daily dosage of levodopa or another dopaminergic drug may mitigate this response. Patients should be advised about the risk of hypotension and syncope, and if such events are experienced, discontinuing opicapone or adjusting the dosage of other medications that lower pressure should be considered. Other adverse experiences reported with treatment regimens containing opicapone included hallucinations (3%), impulse control/compulsive disorders (e.g., urges to gamble, spend money, binge eat; 1%), and sedation/somnolence. Patients should be cautioned about the potential for daytime sleepiness and the risks during activities (e.g., driving) that require full alertness and attention. There have been infrequent reports of withdrawal-emergent hyperpyrexia and confusion with rapid dosage reduction or withdrawal of other medications that increase central dopaminergic tone, but there were no reports of these events in the clinical trials with opicapone. There are no data on the safety of opicapone use during pregnancy or lactation, but results of animal studies suggest a risk of developmental effects if used during pregnancy and of adverse events in breastfed infants. The selective MAO-B inhibitors used to treat Parkinson's disease—selegiline, rasagiline (Azilect), and safinamide (Xadago)—may be used concomitantly with opicapone. However, both opicapone and nonselective MAO inhibitors (e.g., phenelzine, isocarboxazid, tranylcypromine) inhibit catecholamine metabolism, and their concurrent use is contraindicated because of the increased risk of arrhythmias, increased heart rate, and excessive changes in blood pressure. The new drug is also contraindicated in patients with pheochromocytoma, paraganglioma, and other catecholamine-secreting neoplasms. Cardiovascular risks also exist if opicapone is used concurrently with drugs that are metabolized by COMT (e.g., isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine), regardless of the route of administration. Patients being treated concomitantly with these medications should be closely monitored. Accreditation informationProvider: APhATarget audience: PharmacistsRelease date: April 1, 2021Expiration date: April 1, 2024Learning level: 1ACPE Universal Activity Number: 0202-0000-21-150-H01-PCPE credit: 1 hour (0.1 CEUs)Fee: There is no fee associated with this activity for APhA. There is a $25 fee for nonmembers. APhA is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity Number assigned to this activity by the accredited provider is 0202-0000-21-150-H01-P.Advisory board: Mark S. Johnson, PharmD, BCPS, professor, Department of Pharmacy Practice, and director of postgraduate education, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA.Disclosures: Mark S. Johnson, PharmD, BCPS, declares that he and his spouse hold stock in Merck & Co.; Daniel A. Hussar, PhD, FAPhA; Eric F. Hussar, MD; and APhA's editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see www.pharmacist.com/apha-disclosures.Development: This home-study CPE activity was developed by APhA. Provider: APhA Target audience: Pharmacists Release date: April 1, 2021 Expiration date: April 1, 2024 Learning level: 1 ACPE Universal Activity Number: 0202-0000-21-150-H01-P CPE credit: 1 hour (0.1 CEUs) Fee: There is no fee associated with this activity for APhA. There is a $25 fee for nonmembers. APhA is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity Number assigned to this activity by the accredited provider is 0202-0000-21-150-H01-P. Advisory board: Mark S. Johnson, PharmD, BCPS, professor, Department of Pharmacy Practice, and director of postgraduate education, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA. Disclosures: Mark S. Johnson, PharmD, BCPS, declares that he and his spouse hold stock in Merck & Co.; Daniel A. Hussar, PhD, FAPhA; Eric F. Hussar, MD; and APhA's editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see www.pharmacist.com/apha-disclosures. Development: This home-study CPE activity was developed by APhA. Because peak plasma concentration and bioavailability of opicapone are reduced by food, it should be administered apart from food. Opicapone is extensively metabolized, primarily via the sulphation pathway, and approximately 70% of a dose is recovered in the feces (mostly as metabolites), 20% in expired air, and 5% in urine. The plasma exposure of opicapone is increased in patients with hepatic impairment; therefore it should be used in a reduced dosage in patients with moderate hepatic impairment and avoided in patients with severe hepatic impairment. Dosage adjustment is not necessary in patients with mild or moderate renal impairment, but opicapone has not been studied in patients with severe renal impairment, and its use should be avoided in these patients. Opicapone has a longer duration of action than entacapone and is administered once a day, whereas entacapone is administered with each dose of levodopa/carbidopa or in the combination formulation that includes all three agents. The recommended dosage of opicapone is 50 mg orally once a day at bedtime. Patients should not eat food for 1 hour before and at least 1 hour after administration. In patients with moderate hepatic impairment, the dosage should be reduced to 25 mg once a day at bedtime apart from food. Comparison of opicapone with entacaponeAdvantages▪Has a longer duration of action and is administered once a day (although levodopa/carbidopa, with which it is used as adjunctive treatment, is administered multiple times a day)▪May be less likely to cause diarrhea▪Does not cause discoloration of urineDisadvantage▪Is not available in a combination formulation with levodopa/carbidopa Advantages ▪Has a longer duration of action and is administered once a day (although levodopa/carbidopa, with which it is used as adjunctive treatment, is administered multiple times a day)▪May be less likely to cause diarrhea▪Does not cause discoloration of urine Disadvantage ▪Is not available in a combination formulation with levodopa/carbidopa Opicapone capsules are supplied in 25-mg and 50-mg potencies. Schizophrenia affects more than two million individuals in the United States, is often initially diagnosed during adolescence or young adulthood, and is typically a lifelong challenge. It is usually characterized by a combination of “positive” symptoms (e.g., agitation, delusions, hallucinations) and “negative” symptoms (e.g., apathy, social withdrawal). Although the first-generation antipsychotic agents such as the phenothiazines and haloperidol are used to a limited extent, the atypical (second-generation) antipsychotic agents (e.g., aripiprazole, risperidone) are preferred for most patients, primarily because they may be better tolerated. Of the more than 25 antipsychotic drugs approved over the years, clozapine is the most effective. However, because of the risk of serious adverse events (e.g., severe neutropenia), its use is reserved for patients with treatment-resistant schizophrenia. The other atypical antipsychotic agents act primarily at certain dopamine receptors and certain serotonin receptors. They are generally similar in effectiveness, although many patients who do not experience an adequate response with one agent may respond to other agents. The risks of these agents are also generally similar, as are the types of adverse events; however, the incidence of the most common adverse events (e.g., extrapyramidal symptoms, diabetes, weight gain, sedation) may vary widely among the agents. Accordingly, selection of the particular agent with which to initiate treatment is based on a consideration of risk factors that predispose a patient to certain adverse events, avoidance of those adverse events with the drug selected, avoidance of interactions with other drugs the patient is taking, and treatment cost. Lumateperone tosylate (Caplyta—Intra-Cellular Therapeutics) is an atypical antipsychotic agent indicated for treatment of schizophrenia in adults. Although its specific mechanism of action is not known, its effectiveness may be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors. Lumateperone's effectiveness was evaluated in two 4-week, placebo-controlled clinical trials in which the primacy efficacy measure was the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS total score may range from 30 to 210, with higher scores reflecting greater overall symptom severity. In both studies, the recommended dosage of lumateperone (42 mg/d) showed a statistically significant reduction from baseline to day 28 in the PANSS total score. A dosage of lumateperone 84 mg daily was also evaluated in one of the studies. Surprisingly, with this dosage, the reduction in the PANSS total score was less than that of the 42-mg daily dosage and was not statistically different from the total score of those receiving placebo. Risperidone (4 mg/d) was used as an active comparator in a group of patients in this study, although the study was not designed to compare lumateperone and risperidone. Risperidone provided a reduction in the PANSS total score that was very similar to that attained with the 42-mg daily dosage of lumateperone. Another study conducted over 6 weeks raises additional questions about the predictability of lumateperone's effectiveness. The reduction in the PANSS total score was approximately the same for the new drug (42 mg/d) and placebo, whereas patients receiving risperidone experienced a statistically significant reduction in PANSS total scores compared with placebo. The labeled indication for lumateperone is more limited than the indications for risperidone and most other atypical antipsychotics. Risperidone is also indicated for use alone or in combination with lithium or valproate for short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and for treatment of irritability associated with autistic disorder in children and adolescents ages 5 to 16 years. As with other antipsychotic agents, the labeling for lumateperone includes a boxed warning that older adult patients with dementia-related psychosis are at an increased risk of death (e.g., heart failure) if treated with an antipsychotic agent. None of these agents have been approved for treatment of patients with dementia-related psychosis, who are also at risk of cerebrovascular events, including stroke. Numerous other risks associated with the atypical antipsychotic agents are applicable to lumateper