ADJUNCTIVE ATYPICAL ANTIPSYCHOTICS IN MDD
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OVER 3 MILLION TOTAL PRESCRIPTIONS IN THE US1
ADJUNCTIVE ATYPICAL
ANTIPSYCHOTICS IN MDD:
WHY NOT EARLIER?
INDICATION
REXULTI® (brexpiprazole) is indicated for:
• Use as an adjunctive therapy to antidepressants in adults with major
depressive disorder
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increase the risk of suicidal thoughts and behaviors
in patients aged 24 years and younger. Monitor for clinical worsening
and emergence of suicidal thoughts and behaviors. The safety and
effectiveness of REXULTI have not been established in pediatric patients.
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at increased risk of death. REXULTI is not
approved for the treatment of patients with dementia-related psychosis.
MDD, major depressive disorder.
Please see IMPORTANT SAFETY INFORMATION on pages 8 and 9.
© 2021 Otsuka America Pharmaceutical, Inc. All rights reserved. February 2021 11US21EBP0021Many patients with MDD experience partial
response on an antidepressant
In the STAR*D study, >4 OUT OF 5 patients continued to have a
partial response after their second antidepressant treatment2,a
a
As demonstrated in almost 3700 adult patients with MDD who were prescribed antidepressants. In the STAR*D study, partial
response was defined as a less-than-50% reduction from treatment step entry in Quick Inventory of Depressive Symptomatology
Self-Report score at 12-14 weeks. The patient sample received successive acute treatment steps: 3671 patients entered at Step
1; 1439 patients continued at Step 2; 390 patients proceeded to Step 3; 123 patients advanced through all 4 steps. After SSRI
monotherapy in Step 1, treatment options included switching medications or augmentation with either medication or cognitive
therapy. Adjunctive atypical antipsychotics were not included at any step. Patients who either did not achieve response with a
treatment or were unable to tolerate a treatment were encouraged to move to the next step.2
SSRI, selective serotonin reuptake inhibitor; STAR*D, Sequenced Treatment Alternatives to Relieve Depression.
2Despite evidence supporting appropriate
use, adjunctive atypical antipsychotics
were prescribed late in the MDD
treatment journey3,4
~2x
greater chance of response (odds ratio=1.68) was seen in
a meta-analysis of those treated with adjunctive atypical
antipsychotics vs antidepressant treatments alone3,a
A chart review study showed that a patient may undergo ~5
TREATMENT CHANGES before being prescribed an adjunctive
atypical antipsychotic4
a
In a meta-analysis, response was defined as a 50% improvement from baseline to endpoint on either the MÅDRS or HAM-D17.
Meta-analysis included 17 randomized trials with 3807 patients (duration range: 4-12 weeks) comparing adjunctive antipsychotic
treatment to SSRI/SNRI treatment in adult patients (age range: 18-65 years) with MDD. There was a 68% greater chance of
response from the antidepressant + adjunctive antipsychotic group vs the antidepressant + placebo group.3
HAM-D17, 17-item Hamilton Depression Rating Scale; MÅDRS, Montgomery-Åsberg Depression Rating Scale; SNRI, serotonin and
norepinephrine reuptake inhibitor.
3For patients with MDD experiencing partial response on an antidepressant,
Add REXULTI® (brexpiprazole): Amplify antidepressant
symptom response
BETTER TOGETHER: REXULTI + antidepressants
ANTIDEPRESSANTS REXULTI
SSRI OR SNRI
MDD STUDY DESIGN
REXULTI was studied in two 6-week, double-blind, placebo-controlled, fixed-dose pivotal trials of adult patients
meeting DSM-IV-TR criteria for MDD. After a screening phase of 1-4 weeks, patients who met inclusion criteriaa
were treated with an SSRI or SNRI for 8 weeks. Patients who met criteria for persistent partial responseb to an
8-week prospective treatment with an antidepressant were randomized to receive adjunctive REXULTI.5,6,c
Both studies enrolled patients with and without symptoms of anxietyd
• At randomization, 49% of patients had symptoms of anxiety, and 51% of patients had no symptoms of anxiety7
Primary endpoint was the mean change from baseline to Week 6 in the MÅDRS total score in the
randomization phase5,6
a
Screening: Patients with partial response to ADT entered the trial with partial response to 1 to 3 courses of ADT in current episode,
MDD >8 weeks’ duration, HAM-D17 score of ≥18, andWhen taken with an antidepressant,
REXULTI® (brexpiprazole) amplified antidepressant
symptom response in patients with MDD experiencing
partial response
Prospective Phase5,9 Randomization Phase5
(n=379)
a
Randomization
30
-3.9 (mean change from baseline)
(n=178)
Antidepressant
Mean MÅDRS total score
+ REXULTI
25
2 mg/day
62 %
(n=175) -5.2
20
greater reduction
in MÅDRS total score
-8.4 vs antidepressant
+ placebo (p=0.0002)10
0.5 1 2 mg
mg mg
15
0 2 4 6 8/0 1 2 3 4 5 6
Treatment week
Antidepressant + Placebo Antidepressant + REXULTI 2 mg/day
n=379 patients with confirmed partial response to ADT + single-blind placebo. Persistent partial response criteria (prospective phase)
a
included:REXULTI® (brexpiprazole) + ADT: safety profile in
patients with MDD
Adverse reactions that occurred in ≥2% of patients and with greater
incidence than placebo from two 6-week pivotal trials across all doses
Rates for ADT + REXULTI (all doses; n=643) vs ADT + placebo (n=411)
• Akathisia: 9% vs 2% • Increased appetite: 3% vs 2%
• Headache: 7% vs 6% • Anxiety: 3% vs 1%
• Weight increase: 7% vs 2% • Dizziness: 3% vs 1%
• Somnolence: 5% vs 0.5% • Restlessness: 3% vs 0%
• Nasopharyngitis: 4% vs 2% • Blood cortisol decrease: 2% vs 1%
• Tremor: 4% vs 2% • Constipation: 2% vs 1%
• Fatigue: 3% vs 2%
Most common adverse reactions occurred in ≥5% of patients and at least
twice the rate of placebo from two 6-week pivotal trials
9% 7%
2 %
2%
Akathisia Weight increase
ADTa + REXULTI (all doses) (n=643) ADTa + Placebo (n=411)
Dose-dependent adverse reactions
ADT + REXULTI ADT + Placebo
(n=643) (n=411)
1 mg 2 mg 3 mg
n=226 n=188 n=229
Akathisia 4% 7% 14% 2%
Restlessness 2% 3% 4% 0%
A majority of the akathisia cases reported were mild or moderate11
The antidepressants studied included SSRIs or SNRIs.
a
The safety population included patients randomized between 1 mg/day and 3 mg/day of ADT + REXULTI.
Important Warning and Precaution for Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs
including REXULTI. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence
of autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria
(rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, intensive
symptomatic treatment, and monitoring.
6 Please see IMPORTANT SAFETY INFORMATION on pages 8 and 9.REXULTI® (brexpiprazole) + ADT: few discontinuations
due to adverse reactions over 6 weeks across all doses
Discontinuation rates for antidepressant treatment + REXULTI
vs antidepressant treatment + placebo
3% 1%
ADT + REXULTI ADT + Placebo
(n=643) (n=411)
In patients taking ADT + REXULTI (n=643, all doses) vs ADT + placebo (n=411), the rate of
discontinuation due to akathisia wasADT 0.9% vs 0% and the
+ REXULTI
(n=643)
rate of discontinuation due to weight
ADT + Placebo
(all doses)
(n=411)
gain was 0% vs 0%,Duerespectively
to akathisia
12,13
12
0.9% 0%
Due to weight increased13 0% 0%
Once-daily dosing and titration schedule with target dose of 2 mg
/day Option 1: Starting dose 0.5 mg/day (1 week) 1 mg/day (1 week) 2 mg/day
Option 2: Starting dose 1 mg/day (1 week) 2 mg/day
Maximum dose: 3 mg/day
Now, the REXULTI Savings Card offers TWO separate benefits:
REXULTI as well as a Generic ANTIDEPRESSANTb
REXULTI
Two Months of REXULTI $0
REXULTI Refills as little as $15
90-day Prescription as little as $15
Generic ANTIDEPRESSANT
Generic ANTIDEPRESSANT $0
For eligible commercial patients who are prescribed REXULTI. Benefits apply to copays, co-insurance, and pharmacy deductibles.
b
Further conditions apply. Please see REXULTIsavings.com for additional details.
Important Warning and Precaution for Tardive Dyskinesia (TD)
Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total
cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or
after discontinuation of treatment. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed
to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.
7 Please see IMPORTANT SAFETY INFORMATION on pages 8 and 9.IMPORTANT SAFETY INFORMATION for
REXULTI® (brexpiprazole)
WARNING: SUICIDAL THOUGHTS AND of TD appear, drug discontinuation should
BEHAVIORS be considered.
Antidepressants increase the risk of suicidal Metabolic Changes: Atypical antipsychotic drugs
thoughts and behaviors in patients aged have caused metabolic changes including:
24 years and younger. Monitor for clinical • Hyperglycemia/Diabetes Mellitus:
worsening and emergence of suicidal thoughts Hyperglycemia, in some cases extreme and
and behaviors. The safety and effectiveness associated with ketoacidosis or hyperosmolar
of REXULTI have not been established in coma or death, has been reported in patients
pediatric patients. treated with atypical antipsychotics. Assess
fasting plasma glucose before or soon after
WARNING: INCREASED MORTALITY initiation of antipsychotic medication, and
IN ELDERLY PATIENTS WITH monitor periodically during long-term treatment.
DEMENTIA-RELATED PSYCHOSIS • Dyslipidemia: Atypical antipsychotics cause
Elderly patients with dementia-related adverse alterations in lipids. Before or soon after
psychosis treated with antipsychotic drugs initiation of antipsychotic medication, obtain
are at increased risk of death. REXULTI is not a fasting lipid profile at baseline and monitor
approved for the treatment of patients with periodically during treatment.
dementia-related psychosis. • Weight Gain: Weight gain has been observed in
Contraindication: In patients with known patients treated with REXULTI. Monitor weight at
hypersensitivity reaction to brexpiprazole or any baseline and frequently thereafter.
of its components. Reactions have included: rash, Pathological Gambling and Other Compulsive
facial swelling, urticaria and anaphylaxis. Behaviors: Intense urges, particularly for
Cerebrovascular Adverse Events, Including gambling, and the inability to control these
Stroke: In clinical trials, elderly patients with urges have been reported while taking REXULTI.
dementia randomized to risperidone, aripiprazole, Other compulsive urges have been reported less
and olanzapine had a higher incidence of stroke frequently. Prescribers should ask patients or
and transient ischemic attack, including fatal their caregivers about the development of new or
stroke. REXULTI is not approved for the treatment intense compulsive urges. Consider dose reduction
of patients with dementia-related psychosis. or stopping REXULTI if such urges develop.
Neuroleptic Malignant Syndrome (NMS): NMS is Leukopenia, Neutropenia, and Agranulocytosis:
a potentially fatal symptom complex reported in Leukopenia and neutropenia have been reported
association with administration of antipsychotic with antipsychotics. Agranulocytosis (including
drugs including REXULTI. Clinical signs of NMS fatal cases) has been reported with other agents
are hyperpyrexia, muscle rigidity, altered mental in this class. Monitor complete blood count in
status and evidence of autonomic instability. patients with pre-existing low white blood cell
Additional signs may include elevated creatinine count (WBC)/absolute neutrophil count or
phosphokinase, myoglobinuria (rhabdomyolysis), history of drug-induced leukopenia/neutropenia.
and acute renal failure. Manage NMS with Discontinue REXULTI at the first sign of a clinically
immediate discontinuation of REXULTI, intensive significant decline in WBC and in severely
symptomatic treatment, and monitoring. neutropenic patients.
Tardive Dyskinesia (TD): Risk of TD, and the Orthostatic Hypotension and Syncope: Atypical
potential to become irreversible, are believed antipsychotics cause orthostatic hypotension
to increase with duration of treatment and total and syncope. Generally, the risk is greatest
cumulative dose of antipsychotic drugs. TD can during initial dose titration and when increasing
develop after a relatively brief treatment period, the dose. Monitor in patients vulnerable to
even at low doses, or after discontinuation of hypotension, and those with cardiovascular
treatment. For chronic treatment, use the lowest and cerebrovascular diseases.
dose and shortest duration of REXULTI needed to
produce a clinical response. If signs and symptoms (continued)
8 Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.IMPORTANT SAFETY INFORMATION for
REXULTI® (brexpiprazole) (continued)
Falls: Antipsychotics may cause somnolence, Most commonly observed adverse reactions:
postural hypotension, motor and sensory In clinical trials, the most common adverse
instability, which may lead to falls causing reactions were:
fractures or other injuries. For patients with • Major Depressive Disorder (MDD) (adjunctive
diseases, conditions, or medications that could treatment to antidepressant therapy; ≥5%
exacerbate these effects, complete fall risk incidence and at least twice the rate of placebo
assessments when initiating treatment and for REXULTI vs. placebo): akathisia and
recurrently during therapy. weight increase
Seizures: REXULTI may cause seizures and Dystonia: Symptoms of dystonia may occur in
should be used with caution in patients with a susceptible individuals during the first days of
history of seizures or with conditions that lower treatment and at low doses.
the seizure threshold.
Pregnancy: Adequate and well-controlled studies
Body Temperature Dysregulation: Use REXULTI to assess the risks of REXULTI during pregnancy
with caution in patients who may experience have not been conducted. REXULTI should be used
conditions that increase body temperature (e.g., during pregnancy only if the benefit justifies the
strenuous exercise, extreme heat, dehydration, risk to the fetus.
or concomitant use with anticholinergics).
Lactation: It is not known if REXULTI is excreted
Dysphagia: Esophageal dysmotility and aspiration in human breast milk. A decision should be made
have been associated with antipsychotics, whether to discontinue nursing or to discontinue
including REXULTI, and should be used with the drug, taking into account the importance of the
caution in patients at risk for aspiration. drug to the mother.
Potential for Cognitive and Motor Impairment: To report SUSPECTED ADVERSE REACTIONS,
REXULTI has the potential to impair judgment, contact Otsuka America Pharmaceutical, Inc.
thinking, or motor skills. Patients should not drive at 1-800-438-9927 or FDA at 1-800-FDA-1088
or operate hazardous machinery until they are (www.fda.gov/medwatch).
reasonably certain REXULTI does not affect
them adversely.
Concomitant Medication: Dosage adjustments
are recommended in patients who are known
cytochrome P450 (CYP) 2D6 poor metabolizers
and in patients taking concomitant CYP3A4
inhibitors or CYP2D6 inhibitors or strong
CYP3A4 inducers.
Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.
References: 1. IMS Xponent Data on File. October 2020. 2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term
outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):
1905-1917. 3. Wen XJ, Wang LM, Liu ZL, Huang A, Liu YY, Hu JY. Meta-analysis on the efficacy and tolerability of the augmentation of
antidepressants with atypical antipsychotics in patients with major depressive disorder. Braz J Med Biol Res. 2014;47(7):605-616.
4. McIntyre RS, Weiller E. Real-world determinants of adjunctive antipsychotic prescribing for patients with major depressive disorder
and inadequate response to antidepressants: a case study review. Adv Ther. 2015;32(5):429-444. 5. Thase ME, Youakim JM, Skuban
A, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled
study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76(9):1224-1231. 6. Thase ME, Youakim JM,
Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to
antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015;76(9):1232-1240. 7. Data on file (REX-291).
8. Kostic D, Weiller E, Zhang P, et al. Adjunctive brexpiprazole (OPC-34712) in patients with MDD and anxiety symptoms:
results from post-hoc analyses of two pivotal studies. Poster presented at: 54th Annual Meeting of the American College of
Neuropsychopharmacology; December 6-10, 2015; Hollywood, FL. 9. Data on file (REX-284). 10. Data on file (REX-014).
11. Weiss C, Skuban A, Hobart M, Zhang P, Weiller E. Incidence, onset, duration and severity of akathisia with adjunctive brexpiprazole
(OPC-34712) in major depressive disorder: analysis of two pivotal studies. Poster presented at: American Society of Clinical
Psychopharmacology Annual Meeting; June 22-25, 2015; Miami, FL. 12. Data on file (REX-022). 13. Data on file (REX-034).
9When partial response isn’t enough for your patients with MDD,
Add REXULTI® (brexpiprazole): Amplify
antidepressant symptom response
BETTER TOGETHER: REXULTI + antidepressants
ADT + REXULTI
(all doses)
ADT + Placebo
Akathisia 9% 2%
ANTIDEPRESSANTS R E X U LT I Weight increase 7% 2%
Most common adverse reactions that occurred
in ≥5% of patients and at least twice the rate of
placebo were akathisia and weight increase
Antidepressant vs Antidepressant
alone (+ Placebo) + REXULTI 2 mg/day
Consider adding REXULTI earlier
62 % greater reduction in MÅDRS
total score with ADT + REXULTI10
for appropriate patients
Visit REXULTIHCP.com to learn more
2-mg/day recommended dose (SE): -5.2 (0.6) for ADT
+ placebo vs -8.4 (0.6) for ADT + REXULTI, p=0.00025,a
3-mg/day maximum dose (SE): -6.3 (0.5) for ADT
+ placebo vs -8.3 (0.5) for ADT + REXULTI, p=0.00796,a
LS mean change from baseline in MÅDRS total score.
a
REXULTI was studied in two 6-week, double-blind, placebo-controlled, fixed-dose pivotal trials of adult patients meeting DSM-IV-TR
criteria for MDD, who met criteria for persistent partial response to an 8-week prospective treatment with antidepressants. Primary
endpoint was the mean change from baseline in the MÅDRS total score at 6 weeks. The efficacy and safety of REXULTI were also
studied in patients randomized to receive 1 mg/day in Study 2 (n=211). Results for the antidepressant + REXULTI 1 mg group for the
primary efficacy parameter were not statistically significant when compared with antidepressant + placebo, p =0.0737.5,6
INDICATION
REXULTI is indicated for:
• Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increase the risk of suicidal thoughts and behaviors in patients aged 24 years and younger.
Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of
REXULTI have not been established in pediatric patients.
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of
death. REXULTI is not approved for the treatment of patients with dementia-related psychosis.
Please see IMPORTANT SAFETY INFORMATION on pages 8 and 9.
© 2021 Otsuka America Pharmaceutical, Inc. All rights reserved. February 2021 11US21EBP0021You can also read
