Kathryn Wheeler, PharmD, BCPS, is assistant clinical professor of pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.

Kathryn Wheeler, PharmD, BCPS

On February 27, 2020, the FDA approved an intravenous solution of amisulpride (Barhemsys; Acacia Pharma) to treat and prevent postoperative nausea and vomiting (PONV). For prevention, amisulpride can be used alone or with another antiemetic. For PONV treatment, it may be administered to patients who received no prophylactic therapy or received a different drug during prophylaxis. Amisulpride, a selective D2/D3 dopamine receptor antagonist, is the first of Acacia Pharma’s pipeline medications to be approved after showing positive results in 4 phase 3 clinical trials.

Data from 4 randomized double-blind, placebo-controlled, multicenter trials supported the approval of amisulpride for prevention and treatment of PONV.

Two studies evaluated the agent’s use for prevention of PONV in patients undergoing general anesthesia and elective surgery. In both studies, treatment groups were matched for PONV risk factors. In study 1, participants (n = 342) received 5 mg of amisulpride (n = 176) or placebo (n = 166). In study 2, participants (n = 1147) received amisulpride plus standard therapy of ondansetron, betamethasone, or dexamethasone (n = 572) or placebo plus a standard antiemetic (n = 575). The primary outcome in both studies was complete response (CR), defined as no emesis and no use of rescue medication in the 24-hour postoperative period. In both studies, groups receiving amisulpride demonstrated increased rates of CR: study 1, 44% in the amisulpride treatment group vs 33% in the placebo group (difference, 12%; 95% CI, 2%-22%); study 2, 58% in the amisulpride plus standard antiemetic group vs 47% in the placebo plus standard antiemetic group (difference, 11%; 95% CI, 5%-17%).

Amisulpride’s effectiveness for treating PONV was demonstrated in 2 studies using the agent as a 10-mg single dose. In study 3
(n = 369), participants did not receive prior prophylaxis. Participants in study 4 (n = 465) received prior prophylaxis therapy with a nondopaminergic antiemetic (77%, 5-HT3 receptor antagonist; 65%, dexamethasone; 10%, other medication). Both studies evaluated the CR rates within 24 hours after administration with amisulpride excluding emesis within the first 30 minutes. Groups receiving amisulpride demonstrated increased rates of CR: study 3, 31% in the amisulpride treatment group vs 22% in the placebo group (difference, 10%; 95% CI, 1%-19%); study 4, 42% in the amisulpride treatment group vs 29% in the placebo group (difference, 13%; 95% CI, 5%-22%).

Overall, participants given amisulpride experienced significantly lower incidence of emesis, nausea, and rescue medication use compared with placebo, as monotherapy, and combined with other antiemetics.

Among all the studies of amisulpride, the adverse event (AE) profile was similar to that of the placebo groups. The most common AEs include infusion-site pain (6%), increased serum prolactin (5%), hypokalemia (4%), chills (4%), procedural hypotension (3%), and abdominal distention (2%). QT prolongation is a dose- and concentration-dependent AE associated with amisulpride use. It is unlikely to contribute to a meaningful QT prolongation at approved doses, but monitoring is recommended in patients who are at higher risk; have preexisting arrhythmia or cardiac conduction disorders, congestive heart failure, hypokalemia, hypomagnesemia; or receive concurrent medications that can prolong the QT interval (such as ondansetron). Amisulpride is extensively renally eliminated; its use should be avoided in patients who have severe renal dysfunction, with an estimated glomerular filtration rate less than 30 mL/min/1.73m2, because these patients may be at increased risk of AEs.

For prevention of PONV, amisulpride is given as a 5-mg, single-dose infusion over 1 to 2 minutes at the induction of anesthesia. This may be administered as monotherapy

or with another antiemetic medication. For treatment of PONV, amisulpride is infused as a 10-mg dose over 1 to 2 minutes in the event of nausea or vomiting after surgery.

Barhemsys. Acacia Pharma; 2020. Accessed May 19, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2020/209510s000lbl.pdf

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On February 27, 2020, the FDA approved an intravenous solution of amisulpride (Barhemsys; Acacia Pharma) to treat and prevent postoperative nausea and vomiting. 

Barhemsys (Amisulpride) for Postoperative Nausea and Vomiting

On December 20, 2019, the FDA approved lumateperone tosylate (Caplyta™, Intra-Cellular Therapies) for treatment of schizophrenia in adult patients. Lumateperone is an atypical antipsychotic. The exact mechanism of action is unknown. However, lumateperone demonstrates binding affinity and antagonistic activity at central serotonin 5-HT2A receptors and postsynaptic central dopamine D2 receptors.

The efficacy of lumateperone was studied in 2 randomized, double-blind placebo-controlled multicenter trials (study 1 and study 2). The primary efficacy measure in both studies is the Positive and Negative Syndrome Scale (PANSS) total score. This scale scores patients’ symptoms associated with schizophrenia on a scale of 1 (absent) to 7 (severe).

In study 1, a total of 335 patients participated, with an age range of 20 to 55 years old. All participants met diagnosis criteria of schizophrenia, according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV). Patients were randomized to receive lumateperone 42 mg, lumateperone 84 mg (double the recommended dose), an active comparator, or a placebo. Compared with the placebo group, participants randomly assigned lumateperone 42 mg demonstrated a statistically significant reduction from baseline to day 28 in the PANSS total score, compared with participants who were administered the placebo.

Participants administered lumateperone 84 mg did not demonstrate a statistically significant difference in PANSS total score compared with those taking the placebo. A total of 450 participants, ranging from 19 to 60 years old, are included in study 2. All participants met diagnosis criteria of schizophrenia, according to the DSM-IV. Participants were randomized to receive lumateperone 28 mg, lumateperone 42 mg, or a placebo. Participants randomized to lumateperone 42 mg demonstrated a statistically significant reduction from baseline to day 28 in total PANSS score, compared with participants administered the placebo. The group receiving treatment with lumateperone 28 mg was not statistically significant compared with those receiving the placebo.

In studies, the most common adverse reactions occurring with greater frequency than placebo are: somnolence/sedation (24%), nausea (9%), dry mouth (6%), dizziness (5%), an increase in creatinine phosphokinase (4%), fatigue (3%), vomiting (3%), decreased appetite (2%), and an increase in hepatic transaminases (2%). In studies, extrapyramidal symptoms occurred at rates of 6.7% for lumateperone and 6.3% for placebo. Metabolic changes, such as hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain, have been associated with antipsychotic drugs. A patient’s fasting plasma glucose, weight, and fasting lipid profile should be monitored before or soon after starting therapy and throughout treatment. Leukopenia, neutropenia, and agranulocytosis have been associated with antipsychotic medications. Patients demonstrating clinically significant

neutropenia must be monitored for signs of infection. Discontinue lumateperone in patients with an absolute neutrophil count <1000/mm3 and monitor the patient’s white blood cell count until recovery. Patients with hypotension, with cardiovascular disease, or with cerebrovascular disease should be monitored for orthostatic hypotension.

The use of lumateperone is not recommended in patients with moderate (Child-Pugh class B) to severe hepatic impairment (Child-Pugh class C). No dose adjustment is recommended in patients with mild hepatic impairment (Child-Pugh A). Concomitant use of lumateperone with a moderate or strong CYP3A4 inhibitor or a UGT inhibitor increases lumateperone exposure, which may increase the risk of adverse effects. Concomitant use of lumateperone with a CYP3A4 inducer should be avoided.

In adult patients with schizophrenia, lumateperone should be administered 42 mg orally once daily. Lumateperone does not require any dose titration. Lumateperone should be given with food. Lumateperone is available only in 42-mg strength capsules.

1. Caplyta [package insert]. Hamilton, Bermuda: Intra-Cellular Therapies, Inc; 2019.

The FDA has approved lumateperone tosylate (Caplyta™, Intra-Cellular Therapies) for treatment of schizophrenia in adults.

Lumateprone Tosylate Approved for Schizophrenia

On December 23, 2019, the FDA approved ubrogepant for the acute treatment of migraine with and without aura in adult patients.

 Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist. CGRP is a protein released when the trigeminal nerve is activated. Binding of CGRP to its receptor is associated with blood vessel dilation, inflammatory mediator release, and transmission of pain stimulus to the central nervous system–mechanisms involved with migraine pathology. Blocking CGRP from binding to its receptor is a novel mechanism for migraine treatment.

Ubrogepant was approved based on the results of 2 randomized, double-blind, placebo-controlled trials. In these trials,
		1439 participants were randomized to placebo, or 50mg of ubrogepant in both trials. Some patients (23%) were taking preventive migraine therapies, but none were on medications affecting CGRP. In study 1, participants were randomized
		to an additional 100-mg arm. In both trials, participants were instructed to treat a migraine of moderate-to-severe intensity with the study drug. A second dose of study drug or the participant’s usual acute migraine therapy could be administered 2 to 48 hours after the initial dose as needed. 

In both studies, a comparison of pain and most bothersome symptom (MBS) at 2 hours post-dose for ubrogepant versus placebo serves as the primary outcome.Both studies showed that participants taking ubrogepant demonstrated greater rates of absence of pain or MBS at 2 hours post dose compared with placebo. In study 1, both doses of ubrogepant were associated with reduced occurrence of photophobia or phonophobia compared with placebo.

The most common adverse effects seen in studies with ubrogepant are nausea and somnolence. Ubrogepant is primarily eliminated via metabolism by cytochrome P450 3A4 (CYP3A4). Administration of ubrogepant is contraindicated in patients taking a concomitant strong CYP3A4 inhibitor, as this will significantly increase exposure to ubrogepant. Patients taking concomitant moderate 3A4 inhibitors should administer a lower dose (50 mg) and avoid a second dose within 24 hours of the first dose.

Ubrogepant is also a substrate for BCRP and P-gp transporters. Based on the findings of clinical interaction studies, patients taking concomitant BCRP and/or P-gp inhibitors should utilize a lower dose of ubrogepant to limit exposure. Patients with severe hepatic impairment (Child- Pugh class C) should administer the reduced dose. Patients taking strong CYP3A4 inducers, or who have end stage renal disease (CrCl <15 mL/min) should avoid taking ubrogepant. There are no data regarding the safety of treating more than 8 migraines in a 30-day period or on the effect of ubrogepant on a breastfed infant.

Ubrogepant is approved for use in adult patients as both 50-mg and 100-mg tablets to be administered as a single dose as needed for migraine symptoms. It can be administered with or without food. A second dose may be administered no sooner than 2 hours after the initial dose, with a maximum dose of 200 mg per 24 hours. Administration of ubrogepant with a high-fat meal may reduce peak drug concentration by 22% and delay the peak drug concentrations by 2 hours without an overall change in the AUC.

1. Ubrelvy [package insert]. Madison, NJ: Allergan USA, Inc., December 2019

2. Durham PL. Calcitonin Gene-Regulated Peptide (CGRP) and Migraine.Headache. 2006;46(1):S3-S8.

On December 23, 2019, the FDA approved ubrogepant for the acute treatment of migraine with and without aura in adult patients.

Ubrogepant: A Novel Drug Mechanism for Migraine Treatment

In March, the FDA approved brexanolone (Zulresso, Sage therapeutics, Inc.) for treatment of postpartum depression in adult women. Brexanolone exerts its effect by modulation of GABAA receptors. It is the first medication approved specifically to treat postpartum depression.

The efficacy of brexanolone was studied in two randomized double-blind placebo-controlled multicenter trials (study 1 and study 2) in 247 adult women (age 18 to 45 years). Eligible participants had been diagnosed with moderate (study 2) to severe (study 1) postpartum depression and met DSM-IV criteria for a major depressive episode with onset within the third trimester (24%) or within four weeks after delivery (76%). Oral antidepressant use was not an exclusion criterion; 23% of women reported taking oral antidepressants at baseline.

Participants in the study received a continuous infusion of brexanolone or placebo for 60 hours. In both studies, brexanolone was titrated to a target dose of 90 mcg/kg/hour. Study 1 also evaluated a target dosage of 60 mcg/kg/hour. The mean change from baseline depressive symptoms as measured by HAM-D total score at hour 60 of the infusion serves as the primary endpoint. An additional measurement and comparison to baseline scores at day 30 serves as the secondary endpoint.

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For both studies and dosages, brexanolone was superior to placebo for improving depressive symptoms by the end of the infusion and at 30 days after drug administration. Subgroup analysis demonstrated no differences in response by race.

In studies, brexanolone was associated with a loss of or altered consciousness. This adverse effect was not associated with the placebo. Adverse effects related to consciousness were not associated with pattern or timing of dose or preceded by sedation or somnolence in all patients.  The manufacturer includes a warning about excessive sedation and sudden loss of consciousness. It has restricted availability through the Zulresso Risk Evaluation and Mitigation Strategy program.

Patients must have continuous pulse oximetry monitoring and be observed for excessive sedation and loss of consciousness every two hours during nonsleep times when the infusion is administered. In the event of excessive sedation, stop the infusion immediately. The infusion may be restarted at the same or lower dose after symptoms resolve. Participants returned to baseline within 15 to 60 minutes of dose reduction or interruption. If hypoxia occurs, stop the infusion and do not restart. Patients must also be accompanied during interactions with their children. Other adverse effects seen in trials include dry mouth and hot flashes. 

Brexanolone should be avoided in patients with end stage renal disease due to the inability to clear the solubilizing agent used in the product. Coadministration of mediations with CNS depressant effects may increase the risk of sedation-related adverse effects. 

Brexanolone was approved for use as a 60-hour continuous infusion to be administered in a setting with continuous monitoring by a healthcare provider who is available on site. The infusion titration begins at 30 mcg/kg/hour for the first 4 hours and then increases to 60 mcg/kg/hour for 20 hours, then increases a second time to 90 mcg/kg/hour for the next 28 hours. At hour 52, the dosage decreases to 60 mcg/kg/hour for 4 hours before reducing to 30 mcg/kg/hour for the final 4 hours of administration. An alternative titration schedule maintains a maximum of 60 mcg/kg/hour for patients who do not tolerate 90 mcg/kg/min.

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Data on brexanolone use in breastfeeding women is limited. Infant exposure is expected to be low, as the drug has a low oral bioavailability. There is no data on brexanolone effect on milk production.

. Cambridge, MA: Sage Therapeutics, Inc., March 2019.

The first drug approved to specifically treat post-partum depression.