For US Healthcare Professionals

Indications: LYBALVI® is indicated for the treatment of adults with schizophrenia or bipolar I disorder for acute treatment of manic or mixed episodes as monotherapy and as an adjunct to lithium or valproate, or as a maintenance monotherapy treatment.

Schizophrenia

ENLIGHTEN-1
Efficacy & Safety

Woman in a bookstore smiling and holding a sign that shows the components of LYBALVI® (olanzapine and samidorphan)
Not an actual patient.
ENLIGHTEN-1 SAFETY EXTENSION STUDY

LYBALVI (olanzapine and samidorphan) demonstrated proven efficacy vs placebo

In ENLIGHTEN-1, LYBALVI demonstrated a statistically significant improvement in the change from baseline in PANSS total score vs placebo at Week 4 in adults with schizophrenia1

STUDY DESIGN1-3

  • Antipsychotic efficacy and safety of LYBALVI were evaluated in a 4-week, randomized, double-blind, placebo- and active-controlled, phase 3 study. The study was designed to compare LYBALVI with placebo, not with olanzapine
  • Adult patients who met DSM-5 criteria were randomized to LYBALVI, olanzapine, or placebo. Dosing was flexible for the first 2 weeks of the study and fixed thereafter. Patients assigned to LYBALVI could receive either 10 mg/10 mg or 20 mg/10 mg, and patients assigned to olanzapine could receive either 10 mg or 20 mg. Olanzapine was an active control. Patients took one tablet by mouth each day, preferably at bedtime
  • Patients were 18 to 70 years of age, with a body mass index (BMI) of 18.0–40.0 kg/m2, Positive and Negative Syndrome Scale (PANSS) total score of ≥80 with a score of ≥4 on at least 3 of the selected Positive Scale items, and Clinical Global Impression-Severity (CGI-S) score of ≥4
  • Key exclusion criteria: History of diabetes and previous exposure to olanzapine within 6 months prior to screening. Patients taking opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) within 14 days, or opioid antagonists within 60 days prior to screening were not allowed to participate

The inclusion of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic efficacy of olanzapine.1

PRIMARY ENDPOINT

Change From Baseline in PANSS Total Score at Week 4, Shown by Time (Week)1,2
Number showing the change from baseline in PANSS total score in a 4-week ENLIGHTEN-1 pivotal study in schizophrenia
Blue trendline showing the change from baseline in PANSS total score in a 4-week ENLIGHTEN-1 pivotal study in schizophrenia
Dotted gray trendline showing the change from baseline in PANSS total score in a 4-week ENLIGHTEN-1 pivotal study in schizophrenia
Solid gray trendline showing the change from baseline in PANSS total score in a 4-week ENLIGHTEN-1 pivotal study in schizophrenia
Chart canvas containing a graph of the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in a 4-week pivotal study in schizophrenia
  • The placebo-subtracted difference in change from baseline PANSS total score at Week 4 (95% CI) was -6.4 (-10.0, -2.8) for LYBALVI and -5.3 (-8.9, -1.7) for olanzapine1‡; the LS mean SE was 1.3 for all 3 groups2

‡Difference (drug minus placebo) in least squares mean change from baseline. A negative value for the placebo-subtracted difference represents improvement.1

ENLIGHTEN-1 was not a head-to-head study between LYBALVI and olanzapine, and was not designed to compare the efficacy of LYBALVI to the efficacy of olanzapine. Comparative conclusions of efficacy between LYBALVI and olanzapine cannot be drawn from these data.2

  • Early discontinuation rates: 9.0% (n=12) in the LYBALVI group, 10.5% (n=14) in the olanzapine group, and 17.2% (n=23) in the placebo group2
 

SECONDARY ENDPOINT

Change from baseline in CGI-S at Week 4

  • The LS mean difference ± SE versus placebo in change from baseline at Week 4 in CGI-S score was -0.38 ± 0.12 (P=0.002) for the LYBALVI group1,2
 

Adverse reactions observed in ENLIGHTEN-1

Most Common Adverse Reactions Observed With the Use of LYBALVI (Incidence of ≥5% and ≥2x Placebo)1

Adverse Reaction
LYBALVI

10 mg/10 mg and
20 mg/10 mg
(N=134)

Placebo

(N=134)

Weight increased
19%
3%
Somnolence
9%
2%
Dry mouth
7%
1%
Headache
6%
3%
  • No patient treated with LYBALVI discontinued the study due to these common adverse reactions1
  • The reasons for discontinuation for patients taking LYBALVI vs placebo, respectively: patient withdrawal (6% [n=8] vs 6% [n=8]), adverse reaction (1.5% [n=2] vs 5.2% [n=7]), lack of efficacy (0.7% [n=1] vs 6% [n=8]), and loss to follow-up (0.7% [n=1] vs 0% [n=0])2
  • Adverse reactions that led to discontinuation in patients treated with LYBALVI included schizophrenia (1%) and abnormal liver function tests (1%)1
  • The frequency of reported adverse reactions related to extrapyramidal symptoms, including akathisia, restlessness, muscle spasms, bradykinesia, tremor, extrapyramidal disorder, and parkinsonism was 2% both in patients treated with LYBALVI and placebo-treated patients1

For a complete list of adverse reactions, please refer to the full Prescribing Information for LYBALVI.

ENLIGHTEN-1 safety extension study:
52-week, open-label safety study assessed safety and tolerability

In adult patients with schizophrenia

STUDY DESIGN1,2,4

  • Eligible participants in this phase 3, multicenter, open-label safety extension study were adults with schizophrenia who completed the ENLIGHTEN-1 pivotal study. A total of 352 patients completed ENLIGHTEN‑1 and a total of 281 patients enrolled in this safety extension study. Of these, 277 received ≥1 dose of study drug (safety population) and 248 had ≥1 postbaseline PANSS assessment (efficacy population)
  • The first study visit occurred within 7 days of the last visit in ENLIGHTEN-1. Study visits occurred weekly for the first 2 weeks, then every other week thereafter to Week 52
  • All patients started the safety extension study on LYBALVI 10 mg/10 mg. The LYBALVI dose could be increased to 15 mg/10 mg or 20 mg/10 mg
  • Key exclusion criteria from the ENLIGHTEN‑1 pivotal trial were also applied to this study, including patients with diabetes mellitus, or olanzapine use 6 months prior to enrolling in ENLIGHTEN‑1
  • Exclusion criteria for the safety extension study included: Findings compromising the safety of patients or affecting their ability to meet study requirements, use of medications contraindicated with olanzapine or that had drug-interaction potential with olanzapine, use of prohibited drugs, and women who were pregnant or nursing

Adverse Events Observed With the Use of LYBALVI (Incidence of ≥2%)4

Adverse Event
Patients
(N=277)
Increased weight
13%
Somnolence
8%
Headache
4%
Nasopharyngitis
4%
Extra dose administered
3%
Schizophrenia
3%
Anxiety
3%
Dry mouth
3%
Social stay hospitalization
3%
Decreased weight
2%
Increased blood prolactin
2%
Increased blood insulin
2%
Insomnia
2%

Based on observed data without imputation.

Numbers rounded to the nearest percentage.

  • Adverse events were reported by 49% of patients4
  • 3% of patients reported serious adverse events4
  • 33.9% (n=94) of patients discontinued before completing the safety extension study4
  • Reasons for discontinuation included patient withdrawal (15.5% [n=43]), patient lost to follow-up (6.9% [n=19]), adverse events (5.4% [n=15]), and lack of efficacy (1.8% [n=5])4
    • The only adverse event leading to discontinuation that occurred in more than 1 patient was worsening/exacerbation of schizophrenia (2.2% [n=6])4
 

In addition to the primary objective of safety and tolerability, durability of treatment effect was evaluated in the 52-week, open-label safety extension study

In adult patients with schizophrenia

The ENLIGHTEN-1 safety extension study was an open-label safety study in which all participants received LYBALVI. The study was not designed to compare efficacy based on prior treatment group from ENLIGHTEN-1, nor was it designed to prospectively assess or evaluate the effect of LYBALVI on PANSS total score or CGI-S. No conclusions of efficacy can be drawn from these data.4

Mean PANSS Total Score for Patients Treated With LYBALVI in Safety Extension Study By Visit, Grouped by ENLIGHTEN-1 Treatment4

The secondary assessment of observed mean change in PANSS total score in a 52-week open-label ENLIGHTEN-1 safety extension study
  • Mean change from baseline for PANSS total score (95% CI) was -16.2 (-18.5 to -14.0) at 52 weeks4

Change From Baseline in CGI-S

  • Mean change from baseline for CGI-S (95% CI) was -0.9 (-1.0 to -0.8) at 52 weeks4

Change from baseline in PANSS total score and CGI-S was summarized using last observation carried forward for missing data and was based on observed data without imputation4

The ENLIGHTEN-1 safety extension study was an open-label safety study in which all participants received LYBALVI. The study was not designed to compare efficacy based on prior treatment group from ENLIGHTEN-1, nor was it designed to prospectively assess or evaluate the effect of LYBALVI on PANSS total score or CGI-S. No conclusions of efficacy can be drawn from these data.4

Mean PANSS Total Score for Patients Treated With LYBALVI In Safety Extension Study By Visit, Grouped by ENLIGHTEN-1 Treatment4

The secondary assessment of observed mean change in PANSS total score in a 52-week open-label ENLIGHTEN-1 safety extension study
  • Mean change from baseline for PANSS total score (95% CI) was -16.2 (-18.5 to -14.0) at 52 weeks4

Change From Baseline in CGI-S

  • Mean change from baseline for CGI-S (95% CI) was -0.9 (-1.0 to -0.8) at 52 weeks4

Change from baseline in PANSS total score and CGI-S was summarized using last observations carried forward for missing data and was based on observed data without imputation4

PANSS was assessed in all patients who received ≥1 dose of study drug and had ≥1 postbaseline PANSS measurement.4

STUDY LIMITATIONS4

  • Open-label study design with loss of randomization, potential differential dropout of patients, and no comparator arm limits interpretation of efficacy and safety
  • Missing data may have impacted the findings as approximately one-third of patients discontinued before 52 weeks
  • In this study, patients’ baseline characteristics were affected by prior treatment with LYBALVI, olanzapine, or placebo in the antecedent study
ENLIGHTEN-2 Efficacy & Safety

References: 1. LYBALVI [prescribing information]. Waltham, MA: Alkermes, Inc.; 2021. 2. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. J Clin Psychiatry. 2020;81(2):19m12769. 3. Data on file. Alkermes, Inc. 4. Yagoda S, Graham C, Simmons A, Arevalo C, Jiang Y, McDonnell D. Long-term safety and durability of effect with a combination of olanzapine and samidorphan in patients with schizophrenia: results from a 1-year open-label extension study. CNS Spectr. 2020;12:1-31.

Important Safety Information

Boxed Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI is not approved for the treatment of patients with dementia-related psychosis.

Contraindications:

LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products.

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis,

including stroke, transient ischemia attack, and fatalities. See Boxed Warning above.

Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids:

LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers.

Vulnerability to Life-Threatening Opioid Overdose:

Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life-threatening or fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes. Inform patients of the potential consequences of trying to overcome the opioid blockade and the serious risks of taking opioids concurrently with LYBALVI or while transitioning off LYBALVI. In emergency situations, if a LYBALVI-treated patient requires opioid treatment as part of anesthesia or analgesia, discontinue LYBALVI. Opioids should be administered by properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. Patients with a history of chronic opioid use prior to treatment with LYBALVI may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Advise patients that this decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage.

Neuroleptic Malignant Syndrome,

a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatinine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),

a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue if DRESS is suspected.

Metabolic Changes,

including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required anti-diabetic treatment despite discontinuation of the suspect drug. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically.

Tardive Dyskinesia (TD):

Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered.

Orthostatic Hypotension and Syncope:

Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease.

Falls:

LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI.

Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases):

Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors.

Dysphagia:

Use LYBALVI with caution in patients at risk for aspiration.

Seizures:

Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment:

Because LYBALVI may cause somnolence, impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely.

Body Temperature Dysregulation:

Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Anticholinergic (Antimuscarinic) Effects:

Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications.

Hyperprolactinemia:

LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Risks Associated with Combination Treatment with Lithium or Valproate:

If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for a description of the risks for these products.

Most common adverse reactions observed in clinical trials were:

  • Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache
  • Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor
  • Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine): dry mouth, dyspepsia, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia

Concomitant Medication:

LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling.

Pregnancy:

May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy.

Renal Impairment:

LYBALVI is not recommended for patients with end-stage renal disease (eGFR of <15 mL/minute/1.73 m²).

To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indications

LYBALVI is indicated for the treatment of:

  • Schizophrenia in adults
  • Bipolar I disorder in adults
    • Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
    • Maintenance monotherapy treatment

Please see full Prescribing Information, including Boxed Warning, for LYBALVI.