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.

Bipolar I Disorder

Efficacy & Safety

Woman in home looking down
Actor portrayal.

LYBALVI (olanzapine and samidorphan) is the ONLY branded oral atypical antipsychotic with a maintenance indication for bipolar I disorder1-6

LYBALVI is proven to treat manic or mixed episodes of bipolar I in adults1

The efficacy of LYBALVI in the treatment of adult patients with bipolar I disorder has been established based on adequate and well-controlled studies of orally administered olanzapine. The information below describes the results of adequate and well-controlled studies of olanzapine in patients with bipolar I disorder.
In adults with bipolar I disorder with manic or mixed episodes

Olanzapine monotherapy was superior in reduction of mania as measured by the Y-MRS total score1*

Y-MRS
total score
In a 3-week trial (N=67) and a 4-week trial (N=115)†

Olanzapine demonstrated superiority vs placebo

†Dose range of olanzapine was 5 mg/day to 20 mg/day, once daily, starting at 10 mg/day in the 3-week study and starting at 15 mg/day in the 4-week study.

Study participants were adults who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes, including patients with or without psychotic features and with or without a rapid-cycling course.

In an identically designed 3-week study

  • In an identically designed 3-week study conducted simultaneously with the first study, olanzapine demonstrated a similar treatment difference but, possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome1

Olanzapine, in combination with lithium or valproate, was superior in reduction of mania as measured by the Y-MRS total score1*

Y-MRS
total score
Across two 6-week, placebo-controlled combination studies (N=175 and N=169)‡

Olanzapine demonstrated superiority in combination with lithium or valproate vs lithium or valproate with placebo

In outpatients on lithium or valproate therapy:
  • With inadequately controlled manic or mixed symptoms (Y-MRS ≥16)
  • With or without psychotic symptoms
  • With or without rapid cycling course

‡Olanzapine was administered (in a dose range of 5 mg/day to 20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 µg/mL to 125 µg/mL, respectively).

Study participants were outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16).

*The primary outcome in these studies was change from baseline in the Y-MRS total score. The Y-MRS is an 11-item clinician‑rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score).1

Patients taking olanzapine maintenance monotherapy had a significantly longer time to relapse§ vs placebo1

  • Patients meeting DSM-IV criteria with manic or mixed episodes who had responded during an initial open-label, 2-week treatment phase to olanzapine 5 mg/day to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136) for observation of relapse1
  • In the randomized phase, approximately 50% of the patients had discontinued from the olanzapine group by Day 59, and 50% of the placebo group had discontinued by Day 23 of double-blind treatment1
Patients taking olanzapine stayed on treatment longer vs placebo
Days to discontinuation

Olanzapine

Day 59

Placebo

Day 23

§Relapse was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression.1

Adverse reactions with olanzapine in bipolar I disorder1

The safety of LYBALVI for the treatment of bipolar I disorder (manic or mixed) monotherapy and adjunct to lithium or valproate is based on adequate and well-controlled studies of olanzapine tablets in bipolar I disorder.1

Most common adverse reactions from short-term trials of olanzapine in patients with manic or mixed episodes1

  • Incidence of ≥5% of patients exposed to olanzapine and ≥2X the rate of placebo
As monotherapy
  • Somnolence
  • Dry mouth
  • Dizziness
  • Asthenia
  • Constipation
  • Dyspepsia
  • Increased appetite
  • Tremor
As adjunct to lithium or valproate
  • Dry mouth
  • Weight gain
  • Increased appetite
  • Dizziness
  • Back pain
  • Constipation
  • Speech disorder
  • Increased salivation
  • Amnesia
  • Paresthesia
ENLIGHTEN-1 Efficacy & Safety
References: 1. LYBALVI [prescribing information]. Alkermes, Inc.; 2021. 2. Caplyta® (lumateperone) [prescribing information]. Intra-Cellular Therapies, Inc.; 2022. 3. Latuda® (lurasidone hydrochloride) [prescribing information]. Sunovion Pharmaceuticals, Inc.; 2022. 4. Vraylar® (cariprazine) [prescribing information]. Allergan USA, Inc.; 2022. 5. Rexulti® (brexpiprazole) [prescribing information]. Otsuka Pharmaceutical Co., Ltd.; 2021. 6. Fanapt® (iloperidone) [prescribing information]. Vanda Pharmaceuticals Inc.; 2017.

Important Safety Information

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.

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