LYBALVI
Generic: OLANZAPINE AND SAMIDORPHAN L-MALATE
Basic Information
Manufacturer
Alkermes, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
32ffddd1-4e2b-45d9-9b36-bb730167ec80
Indications & Usage
1 INDICATIONS AND USAGE 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 LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, indicated for the treatment of: Schizophrenia in adults ( 1 ) Bipolar I disorder in adults ( 1 ) Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate Maintenance monotherapy treatment
Adverse Reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-related Psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] Precipitation of Opioid Withdrawal in Patients Who Are Dependent on Opioids [see Warnings and Precautions ( 5.3 ) ] Vulnerability to Life-Threatening Opioid Overdose [see Warnings and Precautions ( 5.4 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.5 )] Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions ( 5.6 )] Metabolic Changes [see Warnings and Precautions ( 5.7 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.14 )] Body Temperature Regulation [see Warnings and Precautions ( 5.15 )] Anticholinergic (Antimuscarinic) Effects [see Warnings and Precautions ( 5.16 )] Hyperprolactinemia [see Warnings and Precautions ( 5.17 )] Risks Associated with Combination Treatment with Lithium or Valproate [see Warnings and Precautions ( 5.18 )] Most common adverse reactions (incidence ≥5% and at least twice placebo): Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache.
( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, tremor.
( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine): dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions in Patients with Schizophrenia Patient Exposure The safety of LYBALVI was evaluated in 1262 patients (18 to 67 years of age) diagnosed with schizophrenia in four double-blind, controlled studies and three long-term safety extension studies of up to 3 years of duration.
This experience corresponds to approximately 910 person-years.
In these studies, there were a total of 663 patients exposed to LYBALVI for at least 6 months, and 386 patients for at least one year.
Adverse Reactions in the Short-Term (4 week) Placebo-Controlled Trial in Adults with Schizophrenia The most common adverse reactions (incidence of at least 5% of patients exposed to LYBALVI and greater than twice the rate of placebo) are weight increased, somnolence, dry mouth, and headache.
Adverse reactions associated with the use of LYBALVI (incidence of 2% or greater and greater than in placebo-treated patients) are shown in Table 2 .
Table 2: Adverse Reactions Reported in ≥2% of LYBALVI-Treated Patients and Greater than Placebo in a 4-Week Schizophrenia Trial Adverse Reaction Placebo (N=134) % LYBALVI (10 mg/10 mg, 20 mg/10 mg) (N=134) % Weight increased 3 19 Somnolence 2 9 Dry mouth 1 7 Headache 3 6 Blood insulin increased 1 3 Sedation 0 2 Dizziness 1 2 Neutrophil count decreased 0 2 Adverse reactions that led to discontinuation in LYBALVI-treated patients in the short-term placebo-controlled trial in adults with schizophrenia include schizophrenia (1%) and abnormal liver function tests (1%).
Adverse Reactions in the Long-Term (24-week), Active-Controlled Trial in Adults with Schizophrenia In the 24-week, olanzapine-controlled trial in patients with stable schizophrenia, adverse reactions associated with the use of LYBALVI (incidence of 2% or greater) include: weight increased (25%), somnolence (21%), dry mouth (13%), increased appetite (11%), waist circumference increased (6%), blood creatine phosphokinase increased (5%), headache (4%), lethargy (4%), sedation (4%), akathisia (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), constipation (3%), dizziness (3%), fatigue (3%), nausea (3%), blood pressure increased (3%), neutrophil count decreased (3%), blood insulin increased (2%), weight decreased (2%), and dyslipidemia (2%).
Adverse reactions that led to LYBALVI treatment discontinuation in more than one patient include somnolence (2%), weight increased (2%), neutropenia (2%), glycosylated hemoglobin increased (1%), schizophrenia (1%), and liver function test abnormal (1%).
Hyperglycemia Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).
The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.
Hyperglycemia, as defined by fasting glucose ≥126 mg/dL, has been observed in patients treated with LYBALVI.
In the 4-week placebo-controlled trial in adult patients with schizophrenia, shifts in fasting glucose from normal to high occurred in 4% of patients treated with LYBALVI, 1% of patients treated with olanzapine, and no patients treated with placebo.
In the 24-week olanzapine-controlled trial, patients treated with LYBALVI were more likely to experience abnormal shifts in glycemic parameters than patients treated with olanzapine ( Table 3 ) Table 3: Changes in Glycemic Parameters in a 24-Week Trial of Patients with Schizophrenia * n: number of patients with reported abnormal shifts; N: number of patients who had assessments at both baseline and endpoint for mean change, or normal at baseline and at least 1 post-baseline assessment for shift.
LYBALVI Olanzapine Proportion of Patients with Shifts, % (n/N)* Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) 12 (26/223) 8 (18/219) Impaired (≥100 mg/dL and <126 mg/dL) to High (≥126 mg/dL) 24 (9/38) 11 (5/47) Increase ≥10 mg/dL 66 (174/265) 57 (154/270) Hemoglobin A1c Normal (<5.7%) to Impaired (≥5.7% and <6.5%) 42 (86/204) 35 (68/197) Normal to High (<5.7% to ≥6.5%) 0.5 (1/204) 1.5 (3/197) Impaired (≥5.7% and <6.5%) to High (≥6.5%) 9.5 (6/63) 9.2 (7/76) Dyslipidemia In the 4-week, placebo-controlled trial in adult patients with schizophrenia, shifts in fasting triglycerides from normal to high occurred in 14% of patients treated with LYBALVI and 4% of patients treated with placebo.
In the 24-week olanzapine-controlled study, mean changes in fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were similar in patients treated with LYBALVI and in patients treated with olanzapine.
Weight Gain In the 4-week placebo-controlled study in adult patients with schizophrenia, mean changes in weight, and proportion of patients with ≥7% weight increase, were greater in patients treated with LYBALVI and olanzapine than in patients on placebo.
In that study, mean weight gain was 3.0 kg in patients treated with LYBALVI, 2.4 kg in patients treated with olanzapine, and 0.2 kg in patients treated with placebo.
The proportion of patients with ≥7% weight increase was 26% in patients treated with LYBALVI, 20% in patients treated with olanzapine, and 5% in patients treated with placebo.
In the 24-week trial, LYBALVI-treated patients gained on average 4.2% of baseline body weight.
The proportion of patients treated with LYBALVI with ≥10% body weight gain was 17.8% [see Clinical Studies ( 14 )] .
Extrapyramidal Symptoms In the 4-week placebo-controlled trial in adult patients with schizophrenia, patients were assessed using the Simpson-Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS) (total score ranges from 1 to 14), the Barnes Akathisia Rating Scale (BARS) for akathisia (total score ranges from 0 to 14), and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias (total score ranges from 0 to 28).
The mean changes from baseline to last study visit for the SAS, BARS, and AIMS was similar in LYBALVI-treated patients and in placebo-treated patients.
The mean changes for LYBALVI- vs placebo-treated patients were 0.00 vs -0.2 for AIMS, 0.0 vs -0.1 for BARS, and 0.0 vs -0.3 for SAS, respectively.
The rate of parkinsonism (SAS total score >3) was lower in patients treated with LYBALVI (4%) compared to those on placebo (10%).
The rates of akathisia (BARS global clinical assessment score ≥2) and dyskinesia (AIMS score ≥3 on any of the first 7 items, or a score ≥2 on two or more of any of the first 7 items) were similar in patients treated with LYBALVI and in those on placebo.
Rates of akathisia were 6.0% and 8.2% in patients treated with LYBALVI and placebo, respectively, and the rate of dyskinesia was 1.5% both in LYBALVI-treated and in placebo-treated patients.
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 LYBALVI-treated and in placebo-treated patients.
In the 24-week active-controlled trial, the mean change from baseline to the last visit for the SAS, BARS, and AIMS was similar in LYBALVI-treated patients and in those treated with the active control.
Extrapyramidal adverse reactions, including parkinsonism, akathisia, and dyskinesia, had a similar incidence in LYBALVI-treated patients and in those treated with the active control: any extrapyramidal symptom was 8%, akathisia was 3%.
Dystonia Symptoms of dystonia, (prolonged abnormal contractions of muscle groups) may occur in susceptible individuals during the first few days of treatment.
Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.
Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs.
An elevated risk of acute dystonia is observed in males and younger age groups.
Adverse Reactions in Patients with Bipolar Disorder The safety of LYBALVI for the treatment of bipolar I disorder (mixed or manic) monotherapy and adjunct to lithium or valproate relies on information from adequate and well-controlled studies of olanzapine tablets in bipolar I disorder.
The most common adverse reactions (incidence of at least 5% of patients exposed to olanzapine and greater than or equal to twice the rate of placebo) from short-term trials of olanzapine (manic or mixed episodes) are somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor.
The most common adverse reactions (incidence of at least 5% of patients exposed to olanzapine and greater than or equal to twice the rate of placebo) from short-term trials of olanzapine as adjunct to lithium or valproate (manic or mixed episodes) are dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of olanzapine.
Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.
allergic reactions (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria) cholestatic or mixed liver injury, hepatitis, jaundice diabetic coma, diabetic ketoacidosis discontinuation reaction (diaphoresis, nausea or vomiting) Drug reaction with eosinophilia and systemic symptoms (DRESS) fecal incontinence hyperlipidemia (random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported) neutropenia pancreatitis priapism rash restless legs syndrome rhabdomyolysis salivary hypersecretion syndrome of inappropriate antidiuretic hormone secretion (SIADH) somnambulism stuttering Stuttering was only studied in oral and long acting injection (LAI) formulations.
venous thromboembolic events (including pulmonary embolism and deep venous thrombosis)
( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, tremor.
( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine): dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions in Patients with Schizophrenia Patient Exposure The safety of LYBALVI was evaluated in 1262 patients (18 to 67 years of age) diagnosed with schizophrenia in four double-blind, controlled studies and three long-term safety extension studies of up to 3 years of duration.
This experience corresponds to approximately 910 person-years.
In these studies, there were a total of 663 patients exposed to LYBALVI for at least 6 months, and 386 patients for at least one year.
Adverse Reactions in the Short-Term (4 week) Placebo-Controlled Trial in Adults with Schizophrenia The most common adverse reactions (incidence of at least 5% of patients exposed to LYBALVI and greater than twice the rate of placebo) are weight increased, somnolence, dry mouth, and headache.
Adverse reactions associated with the use of LYBALVI (incidence of 2% or greater and greater than in placebo-treated patients) are shown in Table 2 .
Table 2: Adverse Reactions Reported in ≥2% of LYBALVI-Treated Patients and Greater than Placebo in a 4-Week Schizophrenia Trial Adverse Reaction Placebo (N=134) % LYBALVI (10 mg/10 mg, 20 mg/10 mg) (N=134) % Weight increased 3 19 Somnolence 2 9 Dry mouth 1 7 Headache 3 6 Blood insulin increased 1 3 Sedation 0 2 Dizziness 1 2 Neutrophil count decreased 0 2 Adverse reactions that led to discontinuation in LYBALVI-treated patients in the short-term placebo-controlled trial in adults with schizophrenia include schizophrenia (1%) and abnormal liver function tests (1%).
Adverse Reactions in the Long-Term (24-week), Active-Controlled Trial in Adults with Schizophrenia In the 24-week, olanzapine-controlled trial in patients with stable schizophrenia, adverse reactions associated with the use of LYBALVI (incidence of 2% or greater) include: weight increased (25%), somnolence (21%), dry mouth (13%), increased appetite (11%), waist circumference increased (6%), blood creatine phosphokinase increased (5%), headache (4%), lethargy (4%), sedation (4%), akathisia (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), constipation (3%), dizziness (3%), fatigue (3%), nausea (3%), blood pressure increased (3%), neutrophil count decreased (3%), blood insulin increased (2%), weight decreased (2%), and dyslipidemia (2%).
Adverse reactions that led to LYBALVI treatment discontinuation in more than one patient include somnolence (2%), weight increased (2%), neutropenia (2%), glycosylated hemoglobin increased (1%), schizophrenia (1%), and liver function test abnormal (1%).
Hyperglycemia Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).
The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.
Hyperglycemia, as defined by fasting glucose ≥126 mg/dL, has been observed in patients treated with LYBALVI.
In the 4-week placebo-controlled trial in adult patients with schizophrenia, shifts in fasting glucose from normal to high occurred in 4% of patients treated with LYBALVI, 1% of patients treated with olanzapine, and no patients treated with placebo.
In the 24-week olanzapine-controlled trial, patients treated with LYBALVI were more likely to experience abnormal shifts in glycemic parameters than patients treated with olanzapine ( Table 3 ) Table 3: Changes in Glycemic Parameters in a 24-Week Trial of Patients with Schizophrenia * n: number of patients with reported abnormal shifts; N: number of patients who had assessments at both baseline and endpoint for mean change, or normal at baseline and at least 1 post-baseline assessment for shift.
LYBALVI Olanzapine Proportion of Patients with Shifts, % (n/N)* Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) 12 (26/223) 8 (18/219) Impaired (≥100 mg/dL and <126 mg/dL) to High (≥126 mg/dL) 24 (9/38) 11 (5/47) Increase ≥10 mg/dL 66 (174/265) 57 (154/270) Hemoglobin A1c Normal (<5.7%) to Impaired (≥5.7% and <6.5%) 42 (86/204) 35 (68/197) Normal to High (<5.7% to ≥6.5%) 0.5 (1/204) 1.5 (3/197) Impaired (≥5.7% and <6.5%) to High (≥6.5%) 9.5 (6/63) 9.2 (7/76) Dyslipidemia In the 4-week, placebo-controlled trial in adult patients with schizophrenia, shifts in fasting triglycerides from normal to high occurred in 14% of patients treated with LYBALVI and 4% of patients treated with placebo.
In the 24-week olanzapine-controlled study, mean changes in fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were similar in patients treated with LYBALVI and in patients treated with olanzapine.
Weight Gain In the 4-week placebo-controlled study in adult patients with schizophrenia, mean changes in weight, and proportion of patients with ≥7% weight increase, were greater in patients treated with LYBALVI and olanzapine than in patients on placebo.
In that study, mean weight gain was 3.0 kg in patients treated with LYBALVI, 2.4 kg in patients treated with olanzapine, and 0.2 kg in patients treated with placebo.
The proportion of patients with ≥7% weight increase was 26% in patients treated with LYBALVI, 20% in patients treated with olanzapine, and 5% in patients treated with placebo.
In the 24-week trial, LYBALVI-treated patients gained on average 4.2% of baseline body weight.
The proportion of patients treated with LYBALVI with ≥10% body weight gain was 17.8% [see Clinical Studies ( 14 )] .
Extrapyramidal Symptoms In the 4-week placebo-controlled trial in adult patients with schizophrenia, patients were assessed using the Simpson-Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS) (total score ranges from 1 to 14), the Barnes Akathisia Rating Scale (BARS) for akathisia (total score ranges from 0 to 14), and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias (total score ranges from 0 to 28).
The mean changes from baseline to last study visit for the SAS, BARS, and AIMS was similar in LYBALVI-treated patients and in placebo-treated patients.
The mean changes for LYBALVI- vs placebo-treated patients were 0.00 vs -0.2 for AIMS, 0.0 vs -0.1 for BARS, and 0.0 vs -0.3 for SAS, respectively.
The rate of parkinsonism (SAS total score >3) was lower in patients treated with LYBALVI (4%) compared to those on placebo (10%).
The rates of akathisia (BARS global clinical assessment score ≥2) and dyskinesia (AIMS score ≥3 on any of the first 7 items, or a score ≥2 on two or more of any of the first 7 items) were similar in patients treated with LYBALVI and in those on placebo.
Rates of akathisia were 6.0% and 8.2% in patients treated with LYBALVI and placebo, respectively, and the rate of dyskinesia was 1.5% both in LYBALVI-treated and in placebo-treated patients.
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 LYBALVI-treated and in placebo-treated patients.
In the 24-week active-controlled trial, the mean change from baseline to the last visit for the SAS, BARS, and AIMS was similar in LYBALVI-treated patients and in those treated with the active control.
Extrapyramidal adverse reactions, including parkinsonism, akathisia, and dyskinesia, had a similar incidence in LYBALVI-treated patients and in those treated with the active control: any extrapyramidal symptom was 8%, akathisia was 3%.
Dystonia Symptoms of dystonia, (prolonged abnormal contractions of muscle groups) may occur in susceptible individuals during the first few days of treatment.
Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.
Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs.
An elevated risk of acute dystonia is observed in males and younger age groups.
Adverse Reactions in Patients with Bipolar Disorder The safety of LYBALVI for the treatment of bipolar I disorder (mixed or manic) monotherapy and adjunct to lithium or valproate relies on information from adequate and well-controlled studies of olanzapine tablets in bipolar I disorder.
The most common adverse reactions (incidence of at least 5% of patients exposed to olanzapine and greater than or equal to twice the rate of placebo) from short-term trials of olanzapine (manic or mixed episodes) are somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor.
The most common adverse reactions (incidence of at least 5% of patients exposed to olanzapine and greater than or equal to twice the rate of placebo) from short-term trials of olanzapine as adjunct to lithium or valproate (manic or mixed episodes) are dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of olanzapine.
Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.
allergic reactions (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria) cholestatic or mixed liver injury, hepatitis, jaundice diabetic coma, diabetic ketoacidosis discontinuation reaction (diaphoresis, nausea or vomiting) Drug reaction with eosinophilia and systemic symptoms (DRESS) fecal incontinence hyperlipidemia (random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported) neutropenia pancreatitis priapism rash restless legs syndrome rhabdomyolysis salivary hypersecretion syndrome of inappropriate antidiuretic hormone secretion (SIADH) somnambulism stuttering Stuttering was only studied in oral and long acting injection (LAI) formulations.
venous thromboembolic events (including pulmonary embolism and deep venous thrombosis)