Lybalvi (olanzapine and samidorphan) - 2 indications

Scroll down for information on each indication:

• adults with schizophrenia
• adults with bipolar 1 disorder, manic or mixed episodes

General Information

Lybalvi is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist.

Lybalvi is specifically indicated for the treatment of the following conditions:

• Schizophrenia in adults
• Bipolar I disorder in adults: 1) Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate; 2) maintenance monotherapy treatment

Lybalvi is supplied as a tablet for oral administration. Scroll down to see recommended dosing for each therapeutic condition.

Mechanism of Action

Lybalvi is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist. The mechanism of action of olanzapine is unclear; however, its efficacy in the treatment of schizophrenia or bipolar I disorder could be mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.

Side Effects

Adverse effects associated with the use of Lybalvi may include, but are not limited to, the following:

Schizophrenia:

• weight increased
• somnolence
• dry mouth
• headache

Bipolar I Disorder, Manic or Mixed Episodes:

• 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

The Lybalvi drug label comes with the following Black Box 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.

Indication 1 - adults with schizophrenia

approved June of 2021

Dosing/Administration

Initiate Lybalvi at 5 mg/10 mg (contains 5 mg of olanzapine and 10 mg of samidorphan) or 10 mg/10 mg (contains 10 mg of olanzapine and 10 mg of samidorphan) orally once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg (contains 15 mg of olanzapine and 10 mg of samidorphan), or 20 mg/10 mg (contains 20 mg of olanzapine and 10 mg of samidorphan) once daily. Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of Lybalvi) depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily.

Clinical Trial Results

The FDA approval of Lybalvi for schizophrenia was based on the ENLIGHTEN clinical program.

ENLIGHTEN-1 evaluated the antipsychotic efficacy, safety and tolerability of Lybalvi compared to placebo over four weeks in 403 patients experiencing an acute exacerbation of schizophrenia. This study met its prespecified primary endpoint, with Lybalvi demonstrating statistically significant reductions from baseline in Positive and Negative Syndrome Scale (PANSS) scores compared to placebo. An olanzapine comparator arm was also included, which achieved similar improvements from baseline PANSS scores compared to placebo. 

ENLIGHTEN-2 evaluated the weight gain profile of Lybalvi compared to olanzapine over six months in 561 patients with stable schizophrenia. This study met its prespecified co-primary endpoints, demonstrating both a lower mean percent weight gain from baseline at six months compared to the olanzapine group and a lower proportion of patients who gained 10% or more of their baseline body weight at six months compared to the olanzapine group.

Indication 2 - Bipolar 1 disorder, manic or mixed episodes

approved June of 2021

Dosing/Administration

Monotherapy:

• Initiate Lybalvi at 10 mg/10 mg or 15 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily. The maximum recommended dosage is 20 mg/10 mg once daily. Dosage adjustments should occur at intervals of not less than 24 hours. When dosage adjustments are necessary, dose increments/decrements of 5 mg (based on the olanzapine component of Lybalvi) are recommended.

Maintenance Monotherapy:

• Administer Lybalvi at 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily.

Adjunctive to lithium or valproate:

• Initiate Lybalvi at 10 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg or 20 mg/10 mg, once daily.

Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of Lybalvi), depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily.

Clinical Trial Results

The FDA approval of Lybalvi was based on the following trials:

Monotherapy

The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled studies in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and with or without a rapid-cycling course. The primary rating instrument used for assessing manic symptoms in these studies was the Young Mania Rating Scale (Y-MRS), 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). The primary outcome in these studies was change from baseline in the Y-MRS total score. The results of the studies follow:

In one 3-week placebo-controlled study (n=67) which involved a dose range of olanzapine (5 mg/day to 20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed 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 outcome.

In a 4-week placebo-controlled study (n=115) which involved a dose range of olanzapine (5 mg/day to 20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.

In another study, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, 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 relapse. 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 treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase 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. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse.

Adjunct to Lithium or Valproate

The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled studies in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and with or without a rapid-cycling course. The results of the studies follow:

In one 6-week placebo-controlled combination study, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (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) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

In a second 6-week placebo-controlled combination study, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (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) was superior to lithium or valproate alone in the reduction of Y-MRS total score.