Summary Basis of Decision for Vraylar

As described above, the clinical review of the New Drug Submission for Vraylar was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Vraylar contains the medicinal ingredient cariprazine. The mechanism of action of cariprazine in schizophrenia and bipolar I disorder is unknown. Its therapeutic effect may be mediated through a combination of partial agonist activity at central dopamine D₃, D₂ and serotonin 1A (5-HT_1A) receptors and antagonist activity at serotonin 2A (5‑HT_2A) receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding and functional activity profiles similar to the parent drug.

The submitted clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies which support the use of Vraylar for the recommended indications.

Cariprazine is primarily metabolized to its active metabolites DCAR and DDCAR by cytochrome P450 (CYP)3A4, while CYP2D6 plays a minor role in the biotransformation of cariprazine. A two-fold increase in total cariprazine exposure was observed in subjects who received cariprazine and ketoconazole, a strong CYP3A4 inhibitor, compared to subjects who received cariprazine only. However, the study had several limitations and may have underestimated the effect of strong CYP3A4 inhibitors on cariprazine pharmacokinetics. Considering the key role of CYP3A4 in cariprazine metabolism, the co-administration of CYP3A4 inducers with cariprazine may lead to a significant reduction of cariprazine exposure, therefore the concomitant use of cariprazine with moderate and strong CYP3A4 inducers is contraindicated. As it remains unknown how weak CYP3A4 inhibitors could influence cariprazine pharmacokinetics, statements have been added to the Vraylar Product Monograph indicating that caution should be exercised when cariprazine is co-administered with a weak CYP3A4 inhibitor.

The results from a food effect study demonstrated that food had no significant effect on the maximum concentration (C_max) of Vraylar nor on the area under the concentration time curve (AUC). However, administration of 1.5 mg Vraylar with a high-fat, high-calorie meal delayed the mean time to C_max (T_max) by approximately 5 hours relative to the administration of 1.5 mg Vraylar under fasting conditions.

For further details, please refer to the Vraylar Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Schizophrenia

The efficacy of Vraylar for the treatment of the symptoms of schizophrenia was demonstrated in four pivotal studies. These included three short-term (6-week) studies (Study RGH-MD-16 [Phase IIb] and Studies RGH-MD-04 and RGH-MD-05 [both Phase III]) and Study RGH-MD-06, a longer-term Phase III study in which patients were treated for up to 92 weeks. Study RGH-MD-03, an additional 6-week Phase II study, provided supportive efficacy data.

The three pivotal 6-week studies were multinational, randomized, double-blind, placebo-controlled, parallel-group studies that evaluated 1.5 mg/day to 9 mg/day doses of Vraylar in adult patients experiencing acute exacerbations of schizophrenia (no first episode patients included). All patients were markedly ill as indicated by the baseline efficacy assessments. The studies were each 6 weeks in duration and had a two-week safety follow-up period.

The primary endpoint for all studies was the change from baseline to endpoint in the Positive and Negative Symptom Scale (PANSS) total score. The secondary endpoint was the change from baseline to endpoint in the Clinical Global Impression-Severity (CGI-S) score. In all three pivotal studies, the statistical analyses for the primary and secondary endpoints controlled for multiplicity (multiple doses being tested and two endpoints). The main differences between the studies were the doses that were evaluated and whether the treatment regimen was fixed-dose (Studies RGH-MD-16 and RGH-MD-04) or fixed-flexible dose ranges (Study RGH-MD-05). Active control arms (risperidone or aripiprazole) were included in two studies for assay sensitivity.

The results of these studies demonstrated that there were statistically significant and clinically relevant improvements in the symptoms of schizophrenia with all proposed doses (1.5 mg/day to 6 mg/day). Statistically significant treatment differences for the primary endpoint were observed starting at the end of Week 1 with doses of 3 mg/day to 9 mg/day or at the end of Week 2 with doses of 1.5 mg/day. Treatment differences remained statistically significant in favor of Vraylar through Week 6. The 1.5 mg/day dose was shown to be an effective dose and was not associated with higher rates of discontinuation due to treatment-emergent adverse effects related to the underlying condition (e.g., exacerbation of schizophrenia or psychotic disorder) when compared to higher doses. Therefore, dosing recommendations for the treatment of schizophrenia were revised to clarify that 1.5 mg/day is included in the recommended target dose range and to emphasize the use of gradual dose increases (1.5 mg increments only), based on clinical response and tolerability.

The efficacy of cariprazine was also demonstrated in the longer-term Phase III Study RGH-MD-06, a multinational, randomized, placebo-controlled study that used a randomized withdrawal design. The study population was consistent with the population included in the 6-week pivotal studies. Patients received open-label Vraylar for the first 20 weeks of the study. Those who were optimized on a stable dose for the last 14 weeks of the open-label period and who met protocol-defined criteria for a stable response at Week 20 could be randomized 1:1 to double-blind treatment with placebo or Vraylar for observation of relapse for up to 72 weeks.

The primary endpoint was the time to first protocol-defined relapse event. Patients randomized to receive Vraylar had a statistically significant delay in the time to a protocol-defined relapse event, compared to patients randomized to placebo. By the end of the double-blind period 47.5% of patients in the placebo group compared to 24.8% in the Vraylar group had a relapse event.

Bipolar I disorder

Bipolar Depression

The efficacy of Vraylar for the treatment of bipolar depression was primarily supported by three pivotal multicenter, randomized, double-blind, placebo-controlled studies (Study RGH-MD-56 [Phase IIb], and Studies RGH-MD-53 and Study RGH-MD-54 [both Phase III]). These studies evaluated fixed doses of 0.75, 1.5, and 3.0 mg/day in bipolar I disorder patients undergoing a depressive episode. The evaluation of efficacy was based on the primary and secondary efficacy endpoints, which consisted of the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score and Clinical Global Impressions – Severity (CGI-S) score at Week 6, respectively.

The 0.75 mg dose was only included in one of the studies and it did not exhibit efficacy for any of the evaluated endpoints. The 1.5 mg dose met the primary endpoint in the three pivotal studies demonstrating statistical superiority to placebo in reducing depressive symptoms as measured by the change from baseline to Week 6 in MADRS total score. The difference from placebo was also clinically meaningful as a difference of ≥2 points on the MADRS total score was noted. The secondary endpoint, change in CGI-S at Week 6, was in line with the primary endpoint and reached statistical significance in Studies RGH-MD-56 and RGH-MD-53 but not in Study RGH-MD-54. The 3 mg dose only met the primary endpoint in Study RGH‑MD‑54 and this observation was not supported by the secondary endpoint. Although the 3 mg dose reached statistical significance for the primary endpoint in only one of the three pivotal studies, the difference from placebo was greater than the clinical meaningfulness threshold of a two‑point difference with placebo (except in Study RGH‑MD‑53 where it was -1.8).

Bipolar Mania

The efficacy of Vraylar for the treatment of bipolar mania was demonstrated in three double-blind, randomized, placebo-controlled studies pivotal studies. These included one Phase IIb study (RGH-MD-31) and two Phase III studies (RGH-MD-32 and RGH-MD-33). The design of the studies was similar and patients were administered an initial dose of 1.5 mg Vraylar, followed by a flexible-fixed dosing regimen of 3 to 12 mg once daily. Study RGH-MD-33 differed from the other two in that it had two treatment arms that compared 3 to 6 mg Vraylar to 6 to 12 mg Vraylar.

The primary endpoint for all three studies was the change from baseline to Week 3 in the total Young Mania Rating Scale (YMRS) score. There was no distinction made between statistical significance and clinical meaningfulness. The results from the three studies were consistent and supported the overall, although modest, efficacy of Vraylar in reducing the severity of the mania (or mixed mania) episode, in terms of YMRS score. One of the studies demonstrated that the most effective range of Vraylar daily doses was 3.0 to 4.5 mg/day, while remaining efficacious at 6.0 mg. However, at daily doses ≥6.0 mg/day, there is no therapeutic benefit, and more importantly, the incidence and severity of adverse events increase markedly.

Considering the population pharmacokinetic recommendations regarding exposure-efficacy relationship, and the increase in adverse events at higher doses (and their time to resolution), the dosing regimen favors slow titration of dose by 1.5 mg increments to reach efficacy, with an ideal daily dose of 3.0 to 4.5 mg, up to a maximum of 6 mg/day.

The lack of long-term maintenance or sustained efficacy of Vraylar as well as absence of data on concomitant administration of Vraylar with other pharmacotherapies to manage bipolar mania supported a periodical reassessment to confirm the effectiveness of Vraylar treatment and the need for other supplemental treatment.

Indication

The design of the longer-term study in patients with schizophrenia (Study RGH-MD-06) was not considered to be supportive of a specific indication for maintenance treatment in schizophrenia. Therefore, as for several of the other atypical antipsychotics approved in Canada, the positive longer-term study and short-term studies were considered to support an indication for Vraylar for the treatment of schizophrenia, which does not specify acute or maintenance treatment.

The sponsor's proposed indication was also modified to indicate that the efficacy of Vraylar for long-term use has not been systematically evaluated in controlled studies for bipolar mania and depression.

Sponsor's proposed indication

Health Canada-approved indication

Schizophrenia Vraylar (cariprazine capsules) is indicated for: the acute and long-term maintenance treatment of schizophrenia in adults. In controlled clinical trials, Vraylar was found to improve both positive and negative symptoms. In a clinical trial of up to 92 weeks in adult patients with schizophrenia, Vraylar has been shown to be more effective than placebo in maintaining clinical improvement and prolonging time to relapse. Bipolar disorder Vraylar is indicated as monotherapy for: Bipolar Mania: acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and Bipolar Depression: acute treatment of depressive episodes associated with bipolar I disorder in adults. Pediatrics Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. Geriatrics Geriatrics: Vraylar is not indicated in elderly patients with dementia. The safety and efficacy of Vraylar have not been systematically evaluated in patients 65 years of age or older. Caution should be used when treating geriatric patients.

Schizophrenia Vraylar (cariprazine) is indicated for: the treatment of schizophrenia in adults. In controlled clinical trials, Vraylar was found to improve both positive and negative symptoms. Bipolar I disorder Vraylar is indicated as monotherapy for: Bipolar Mania: acute management of manic or mixed episodes associated with bipolar I disorder in adults, and Bipolar Depression: acute management of depressive episodes associated with bipolar I disorder in adults. The efficacy of Vraylar for long-term use has not been systematically evaluated in controlled studies for bipolar mania and depression. The physician who elects to use Vraylar for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Pediatrics Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. Geriatrics Geriatrics: Vraylar is not indicated in elderly patients with dementia. The safety and efficacy of Vraylar have not been systematically evaluated in patients 65 years of age or older. Caution should be used when treating geriatric patients.

Overall Analysis of Efficacy

Overall, the efficacy of Vraylar for the treatment of schizophrenia in adults was demonstrated at doses of 1.5 to 6.0 mg/day and within this dose range Vraylar was generally well-tolerated. The efficacy of Vraylar was also demonstrated for the management of depressive or mania/mixed-mania episodes associated with bipolar I disorder in adult patients. At the recommended doses up to 3.0 mg/day and 6.0 mg/day, Vraylar was generally well-tolerated in patients with bipolar depression and bipolar mania, respectively. The long-term efficacy of Vraylar was not evaluated for bipolar mania or bipolar depression.

For more information, refer to the Vraylar Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Schizophrenia

The safety of Vraylar was assessed based on data collected in the four 6-week placebo-controlled studies (Group 1A Safety Population: three pivotal 6-week studies [Studies RGH-MD-16, RGH-MD-04 and RGH-MD-05] and one supportive 6-week study [RGH-MD-03]) and data from the pivotal longer-term randomized withdrawal study (Study RGH-MD-06). A description of these studies is found in the Clinical Efficacy section above.

In Group 1A, 1,317 patients received at least one dose of Vraylar (1.5 to 12 mg/day). Completion rates (6 weeks) were similar for patients treated with Vraylar (61.7%) or placebo (57.2%). In the longer-term study, 765 patients received at least one dose of Vraylar in the 20-week open-label phase (3 to 9 mg/day, fixed-dose after the first 6 weeks for the remainder of study); 216 patients completed 20 weeks of open-label treatment; and 200 patients were randomized 1:1 to receive Vraylar or placebo in the double-blind phase.

At least one treatment-emergent adverse event (TEAE) was reported in 74.7% of patients receiving Vraylar (1.5 to 12 mg/day) and 69% of patients receiving placebo in Group 1A. In Study RGH-MD-06, at least one TEAE was reported in 80% of patients during the 20-week open-label phase. In the double-blind phase, 74% of patients on Vraylar experienced a TEAE compared to 65% on placebo. Many of the reported adverse effects were TEAEs known to occur with other atypical antipsychotics and they were also reported with Vraylar in the bipolar patient populations.

Class-related TEAEs were reported in Group 1A at higher frequencies in patients treated with Vraylar as compared to placebo. These included akathisia, restlessness, extrapyramidal symptoms (EPS; e.g., tremor, dystonias, parkinsonism, bradykinesia, dyskinesia, hypokinesia, and tardive dyskinesia), increased blood creatine phosphokinase (CPK), gastrointestinal adverse events (e.g., constipation, dry mouth, diarrhea, nausea, and vomiting), somnolence and sedation, insomnia, and dizziness.

Most TEAEs were dose-related, with the highest incidences occurring in patients that received doses above the maximum recommended dose of 6 mg/day. Among the commonly reported class-related TEAEs, akathisia and restlessness were reported more frequently with Vraylar at doses from 1.5 to 6 mg/day (recommended range) than with either active control treatment (aripiprazole and risperidone). Akathisia was reported in 9.1% to 12.5% of patients on Vraylar 1.5 to 6 mg/day; 3.6% on placebo; 8.6% on risperidone; and 7.2% on aripiprazole. Restlessness was reported in 3.9% to 5.7% of patients on 1.5 to 6 mg/day; 3.1% on placebo; 2.9% on risperidone; and 3.3% on aripiprazole. Extrapyramidal disorder was also reported more frequently with Vraylar (6.9% to 7.5%) than with aripiprazole (3.9%), but less frequently than with risperidone (12.9%). Metabolic disturbances (e.g., clinically significant increases in fasting glucose and lipids, and weight gain) are also a known adverse effect of atypical antipsychotics, but there were no meaningful differences between patients on Vraylar or placebo in Group 1A.

Other TEAEs that were reported more frequently with Vraylar than with placebo in the schizophrenia clinical studies, which are not reported consistently with other drugs in the atypical antipsychotic drug class, included hypertension/increases in blood pressure (2% to 3% with Vraylar 1.5 to 6 mg/day vs. 1% with placebo), increases in heart rate (2% with Vraylar 1.5 to 6 mg/day vs. 1% with placebo), and transaminase elevations (1% to 2% with Vraylar 1.5 to 6 mg/day vs. <1% with placebo). 

The first onset of many of the adverse effects associated with Vraylar occurred within the first 2 to 3 weeks of treatment for the majority of patients who experienced them. This is consistent with the time when total Vraylar plasma concentrations would be approaching steady state.

The safety profile in Study RGH-MD-06, longer-term randomized withdrawal study, was generally consistent with what was observed in Group 1A. During longer-term treatment, increased incidences of clinically significant changes were observed for some metabolic parameters.

Cataracts and ocular toxicity were observed with Vraylar in the nonclinical studies, but with the 6-week duration of the short-term schizophrenia studies, a strong signal for treatment emergent cataracts or other lenticular changes did not emerge. Blurred vision was the most common ocular TEAE reported in Group 1A (1% to 2% with Vraylar 1.5 to 6 mg/day vs. <1% with placebo). Because there were treatment emergent lenticular changes reported in a small number of patients in Study RGH-MD-06 and in Group 1B (long-term, open label studies in patients with schizophrenia), the data suggested that the potential for lenticular changes during long-term treatment with Vraylar could not be excluded at this time. As such, a warning with a recommendation for ophthalmologic examinations has been incorporated in the Vraylar Product Monograph.

Vraylar caused teratogenicity in rats at exposures between 0.2 and 3.5 times the exposure at the maximum recommended dose of 6 mg/day. There are no data available from the use of Vraylar in pregnant women. As it is not known whether Vraylar will cause human fetal harm if used during pregnancy, the use of Vraylar in pregnancy is not recommended. The Vraylar Product Monograph was revised to include appropriate warnings to reflect potential harm and to include information for enrollment in a United States-based national pregnancy registry, which exists to collect data on pregnancy outcomes when there has been fetal exposure to antipsychotics.

Long-Term Studies

Two long-term (48 weeks), open-label, extension studies in patients with schizophrenia (from lead-in studies RGH-MD-04, -05 and -16) were conducted to evaluate the safety, tolerability, and pharmacokinetics of long-term treatment with Vraylar. The two studies had comparable study designs, but RGH-MD-11 (number of patients [n] = 585) evaluated a flexible dosing regimen of 3 to 9 mg/day while RGH-MD-17 (n = 93) used a flexible dosing regimen of 1.5 to 4.5 mg/day.

Despite the high dropout rates that ranged between 50% to 60% in the open-label extension studies, over 300 patients were exposed to Vraylar for more than 24 weeks and over 100 patients were exposed for longer than 48 weeks, which is an acceptable exposure based on the International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E1 guidelines. Of note, most subjects were treated with the 6 mg dose in RGH-MD-11, which is the maximum recommended dose in the Product Monograph.

Overall, the long-term safety profile of Vraylar was generally consistent with what was observed in short-term studies. The most common AEs were akathisia (15.5%), insomnia (13.3%), headache (12.8%), increased weight (10.5%), anxiety (8.5%), tremor (6.9%), EPS (6.6%), schizophrenia (5.7%), nausea (5.6%), restlessness (5.6%), and dyspepsia (5.4%). No clear dose-relationships were established for most of the AEs reported in ≥2% of the patients.

Weight gain, metabolic-related AEs and changes in laboratory data were noted in the long-term extension studies. Over the 48-week exposure, a mean increase in weight of 2.09 kg, relative to baseline was observed. Approximately 25% of the subjects had an increase in weight of 7% or more.

Overall, mean changes from baseline for liver biochemistry parameters were not clinically relevant and were within the same range as that observed in the short-term schizophrenia studies. Shifts from normal classification to potentially clinically significant high levels were observed in a limited number of patients for both studies (for RGH-MD-11, 0.4% for alanine transaminase [ALT] and bilirubin, 0.2% for aspartate transaminase [AST] and 0% for alkaline phosphatase). Increases greater than or equal to three-times the upper limit of normal (ULN) for ALT or AST were seen in 2.6% of patients and in 0.5% for bilirubin. No patient met the biochemical criteria for potential drug-induced liver injury/Hy’s Law criteria.

Increases in insulin and fasting glucose levels were observed, and 7% of patients had a significant shift in hemoglobin A1C (HbA1c) ≥6.1%. Increases in total cholesterol, low density cholesterol (LDL), high density cholesterol (HDL) and triglycerides were more prominent in the long-term extension studies compared to the short-term placebo-controlled studies. Creatine phosphokinase (CPK) elevations (>1,000 U/L) were also observed more frequently in the long-term open-label studies (8.7% for all doses) than in the short-term studies (ranged of 4% to 6% in the Vraylar group vs. 4% in the placebo group) reflecting the longer exposure and observation period. Vital signs and electrocardiogram were evaluated as part of long-term extension studies and limited changes were observed.

An in-depth ophthalmologic evaluation was conducted as part of the two long-term extension studies and minimal or no changes were noted for visual acuity, intraocular pressure, slit-lamp examinations, and ocular coherence tomography scans. The most common ocular TEAEs was blurred vision, reported in 1.8% of Vraylar-treated patients in the long-term studies. There was one case of cataract that resolved spontaneously (uncertain if related to the drug).

Bipolar I disorder

Bipolar Depression

The safety of Vraylar was assessed based on data collected in the by three pivotal studies (Studies RGH-MD-56, RGH-MD-53, and Study RGH-MD-54) described in the Clinical Efficacy section above. In addition to these studies, the Phase II Study RGH-MD-52 was considered as a supportive study that contributed safety data.

Across the four clinical studies, 1,230 patients were exposed to Vraylar. Overall, study completion rates were similar for Vraylar-treated patients, relative to placebo-treated patients (77.9% and 79.8%, respectively). Treatment-emergent adverse events were reported in 732 (59.5%) Vraylar-treated patients and in 298 (54.7%) placebo-treated patients during the double-blind treatment period. The most common TEAEs were reported for the following systems: nervous system disorders (headache [8.1%], akathisia [7.3%], somnolence [4.0%], and dizziness [3.3%]), psychiatric disorders (insomnia [8.8%], restlessness [4.2%], anxiety [3.1%], and agitation [2.2%]) and gastrointestinal disorders (nausea [7.8%], diarrhea [3.7%], and dry mouth [3.4%]).

Severe AEs were reported more frequently in placebo‑treated patients (5.1%) as compared to the Vraylar-treated patients (4.4%). One death, a completed suicide, was reported in one of the four studies. Adverse events that led to discontinuation were higher for Vraylar-treated patients (6.7%) compared to placebo-treated patients (4.8%), with the most common being akathisia.

Several AEs were of interest given the known safety profile of antipsychotic drugs and the pharmacological treatment context of bipolar disorder. Extrapyramidal symptoms (EPS), including akathisia and restlessness, occurred in a dose-dependent manner in the pooled analysis of the four clinical studies. Most cases of EPS were mild or moderate in severity. Akathisia accounted for most of the reported EPS AEs, with most of these events reported within the first three weeks of treatment. Weight gain was limited overall, ranging from -0.1 kg in placebo to +0.6 kg overall in Vraylar-treated patients, however, weight increases >7% were reported in more Vraylar-treated patients (3.2%) than placebo subjects (0.9%).

Bipolar Mania

A total of 1,025 bipolar mania patients received Vraylar at doses ranging from 3.0 to 12.0 mg/day in the three pivotal studies described in the Clinical Efficacy section as well as in Study RGH-MD-36, an open-label, multicentre, 16-week flexible dose safety and tolerability study. In the three pivotal studies, TEAEs were reported in 79.6% of Vraylar-treated patients and 67.0% or placebo-treated patients. In the open-label supportive study, 83.3% of Vraylar-treated patients reported a TEAE. The most common TEAEs for the pivotal studies and supportive study, respectively, were reported as follows: gastrointestinal disorders (nausea [11.4% and 10.4%], constipation [9.1% and 10.7%]), eye disorders (blurred vision [3.5% and 2.5%]), nervous system and psychiatric disorders (akathisia [20.2% and 32.6%], extrapyramidal disorder [13.2% and 6.7%], restlessness [6.4% and 6.5%], insomnia [8.3% and 7%] and dizziness [6.4% and 0.2%]), and vascular disorders (hypertension [2.1% and 4.2%]). Severe TEAEs were reported by 7.4% of Vraylar-treated patients in the pivotal studies versus 4.5% for the placebo group and 6.0% for the Vraylar-treated patients in the open-label study. Across the four studies, there was one death and three suicide attempts.

Generally, the administration of Vraylar for a 3‑week period, or at most 16-week period, was well tolerated, especially at doses ≤6 mg/kg/day. Based on the safety review of the studies supporting the bipolar mania indication, the following safety concerns of interest were identified: akathisia, restlessness, and extrapyramidal symptoms; hypertension, tachycardia, and other cardiovascular effects; ophthalmologic effects including cataract and blurred vision; metabolic effects, including increased appetite, weight gain, and blood glucose increases; and suicidal ideation/behaviour. These safety concerns were mitigated with changes to the dosing regimen, as well as appropriate warnings and recommendations in the Vraylar Product Monograph.

Overall Analysis of Safety

Overall, Vraylar was generally well tolerated at doses within the recommended dose range of 1.5 to 6 mg/day. Some patients received doses >6 mg/day in the schizophrenia clinical studies, but these doses did not confer meaningful additional benefit and were associated with the highest incidences of most AEs. The known antipsychotic class AEs are typically managed or mitigated via warnings and recommendations in the product monograph, including: close monitoring (e.g., akathisia, EPS, suicidal ideation/suicidal behaviour, periodic monitoring of weight, glucose and lipid profiles); dose reductions; treatment discontinuation; or, introducing concomitant medications when appropriate, if the patient will remain on the antipsychotic. The less consistently reported AEs in this class that were reported with Vraylar, such as hypertension, asymptomatic transaminase elevations, and ocular changes can also be managed in this way at this time. Because the Vraylar safety profile shares many similarities with the safety profiles of other atypical antipsychotics a similar level of patient monitoring is recommended to manage these harms and uncertainties.

Appropriate warnings and precautions are in place in the approved Vraylar Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box describing increased mortality in elderly patients with dementia has been included in the Product Monograph for Vraylar. Vraylar is not approved for the treatment of patients with dementia-related psychosis. For more information, refer to the Vraylar Product Monograph, approved by Health Canada and available through the Drug Product Database.