2.1 LYBALVI Initiation In Patients Using Opioids

LYBALVI is contraindicated in patients using opioids or undergoing acute opioid withdrawal.

In patients who use opioids, delay initiation of LYBALVI for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids [see Warnings and Precautions (5.3)].

2.2 Recommended Dosage in Schizophrenia

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.

2.3 Recommended Dosage in Bipolar I Disorder (Manic or Mixed Episodes)

2.4 Administration Information

Administer LYBALVI orally once daily with or without food as a single tablet.

Do not divide tablets or combine strengths.

2.5 Dosage Recommendations in Specific Populations

The recommended starting dosage of LYBALVI is 5 mg/10 mg once daily in patients who have a higher risk of hypotensive reactions, are at risk of slower olanzapine metabolism, or may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.9), Drug Interactions (7.2), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)]. If dose escalation is necessary, increase the dosage slowly in these patients.

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than in placebo-treated patients (3.5% vs 1.5%, respectively). Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. LYBALVI is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.2)].

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

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with olanzapine compared to patients treated with placebo. LYBALVI is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

5.3 Precipitation of Severe Opioid Withdrawal in Patients Who Are Physiologically Dependent on Opioids

Samidorphan, an opioid antagonist that is a component of LYBALVI, can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. Therefore, 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 [see Dosage and Administration (2.1), Drug Interactions (7.3)].

5.4 Vulnerability to Life-Threatening Opioid Overdose

5.5 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue LYBALVI and provide intensive symptomatic treatment and monitoring.

5.6 Drug Reaction with Eosinophilia and Systemic Symptoms

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with exposure to olanzapine, a component of LYBALVI [see Adverse Reactions (6.2)]. DRESS may present with 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. DRESS is sometimes fatal. Discontinue LYBALVI if DRESS is suspected.

5.7 Metabolic Changes

Atypical antipsychotic drugs, including LYBALVI, have been associated with metabolic changes that include hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain [see Adverse Reactions (6.1)]. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

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. Patients who develop symptoms of hyperglycemia during treatment with LYBALVI should undergo fasting blood glucose testing. 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. Patients starting treatment with LYBALVI should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Antipsychotics have caused adverse alterations in lipids. Patients starting treatment with LYBALVI should undergo fasting lipid profile testing at the beginning of treatment and periodically during treatment.

Weight gain has been observed with use of antipsychotics. Monitor weight prior to initiating LYBALVI and frequently thereafter.

5.8 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that 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. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on LYBALVI, drug discontinuation should be considered. However, some patients may require treatment with LYBALVI despite the presence of the syndrome.

5.9 Orthostatic Hypotension and Syncope

Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the 4-week, placebo-controlled study, from analysis of the vital signs data, rates of orthostatic hypotension were less than 2% in LYBALVI- and placebo-, and olanzapine-treated patients. In the 24-week, olanzapine-controlled study, from analysis of the vital signs data, rates of orthostatic hypotension in LYBALVI-treated patients were 3.7%, compared to 0.4% in olanzapine-treated patients.

Monitor orthostatic vital signs in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medications or CNS depressants [see Drug Interactions (7.1, 7.2)], patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. LYBALVI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from the premarketing clinical trials.

5.10 Falls

Antipsychotics, including LYBALVI, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.11 Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including LYBALVI [see Adverse Reactions (6)]. Agranulocytosis (including fatal cases) has been reported with other agents in this class.

Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of LYBALVI at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue LYBALVI in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

5.12 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including LYBALVI, should be used cautiously in patients at risk for aspiration.

5.13 Seizures

Like other antipsychotic drugs, LYBALVI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.

5.14 Potential for Cognitive and Motor Impairment

LYBALVI, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, or motor skills. In a LYBALVI placebo-controlled study, somnolence occurred in 9% of LYBALVI-treated patients compared to 2.2% in patients treated with placebo.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that LYBALVI therapy does not affect them adversely.

5.15 Body Temperature Dysregulation

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use LYBALVI with caution in patients who may experience these conditions.

5.16 Anticholinergic (Antimuscarinic) Effects

Olanzapine, a component of LYBALVI, exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology (12.2)]. In premarketing clinical trials with oral olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations, but LYBALVI should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1)].

5.17 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, olanzapine, a component of LYBALVI, elevates prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

In the 4-week placebo-controlled trial, shifts from normal to high prolactin values (>30 ng/mL for females; >20 ng/mL for males) occurred in 41.4% of females and 32.9% of males treated with LYBALVI, in 56.1% of females and 37.1% of males treated with olanzapine, and in 10% of females and 4.8% of males treated with placebo [see Use in Specific Populations (8.3)].

In the 24-week, olanzapine-controlled study, shifts from normal to high prolactin values occurred in 32.9% of females and 22.5% of males treated with LYBALVI, and in 41.7% of females and 28.5% of males treated with olanzapine.

5.18 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 including, but not limited to, the warnings and precautions for lithium or valproate [see Contraindications (4)].

5.19 Interference with Laboratory Tests for Opioid Detection

LYBALVI may cause false positive results with urinary immunoassay methods used for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results [see Contraindications (4) and Drug Interactions (7.4)].

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.

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)
• 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
• stuttering1
• venous thromboembolic events (including pulmonary embolism and deep venous thrombosis)

1

Stuttering was only studied in oral and long acting injection (LAI) formulations.

7.1 Effects of Other Drugs on LYBALVI

Table 4 describes clinically significant drug interactions where the concomitant use of other drugs affects LYBALVI.

7.2 Effects of LYBALVI on Other Drugs

Table 5 describes clinically significant drug interactions where concomitant use of LYBALVI affects other drugs.

7.3 Opioids

LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal [see Contraindications (4)].

LYBALVI increases the risk of precipitating acute opioid withdrawal in patients who are dependent on opioids. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids [see Dosage and Administration (2.1), Warnings and Precautions (5.3)].

In emergency situations, if a LYBALVI-treated patient requires opioid treatment for anesthesia or analgesia, discontinue LYBALVI. The opioid should be administered by properly trained individual(s), and the patient should be properly monitored in a setting equipped and staffed for cardiopulmonary resuscitation [see Warnings and Precautions (5.4)].

In non-emergency situations, if a LYBALVI-treated patient is expected to require opioid treatment (e.g., for analgesia during or after an elective surgical procedure) discontinue LYBALVI at least 5 days before opioid treatment and start olanzapine or another antipsychotic, if needed.

Given that LYBALVI contains samidorphan, an opioid antagonist, opioid treatment may be less effective or ineffective shortly after LYBALVI discontinuation because of the presence of samidorphan.

7.4 Interference with Laboratory Tests

Interference with Laboratory Tests for Opioid Detection

Because LYBALVI contains samidorphan, an opioid antagonist, LYBALVI may be cross-reactive with urinary immunoassay methods used for detecting opioids, resulting in false positive results. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results [see Contraindications (4) and Warnings and Precautions (5.19)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of LYBALVI have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of LYBALVI did not include sufficient numbers of patients 65 years of age and older to determine whether they responded differently than younger adult patients.

8.6 Hepatic Impairment

Olanzapine and samidorphan plasma exposures were found to be higher in subjects with moderate hepatic impairment than in subjects with normal hepatic function. The effect of severe hepatic impairment was not studied. The higher plasma exposure in patients with moderate hepatic impairment was not expected to be clinically relevant. No dose adjustment of LYBALVI is needed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Plasma exposure to olanzapine and samidorphan was higher in patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2) compared to those with normal renal function [see Clinical Pharmacology (12.3)]. No dose adjustment of LYBALVI is needed in patients with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2), or severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2).

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

Human Experience

There is limited clinical experience with overdose with LYBALVI. In premarketing clinical trials of LYBALVI involving 861 patients, overdose of LYBALVI was identified in 7 patients. This included 4 patients with accidental overdose, 2 with intentional overdose, and 1 due to a medication administration error. None of the reported overdoses was associated with a fatal outcome. There was a reported ingestion of 11 tablets of LYBALVI 10 mg/10 mg (5.5 times and 11 times the maximum recommended daily dosage of the olanzapine and samidorphan components of LYBALVI, respectively). The patient was found unresponsive and admitted to the hospital. Medical treatment included fluids, electrolytes, a diuretic, and a detoxicant; the patient stabilized within 2 days.

In postmarketing reports of overdose with olanzapine, a component of LYBALVI, symptoms included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Less commonly reported symptoms include: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2,000 mg.

Management of Overdose

No specific antidotes for LYBALVI are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a certified Poison Control Center (1-800-222-1222) for additional overdosage management recommendations.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of both olanzapine and samidorphan are linear over the clinical dose range and there is no PK interaction between olanzapine and samidorphan after oral administration of LYBALVI. Steady-state concentrations of olanzapine and samidorphan are reached within 7 days of commencement of once-daily administration of LYBALVI. The primary pharmacological activities of LYBALVI are due to the parent drugs, olanzapine and samidorphan.

Following a single dose administration of LYBALVI (10 mg olanzapine/10 mg samidorphan), the mean AUC0-inf and Cmax of olanzapine was 628 ng·h/mL and 16 ng/mL, respectively. The mean AUC0-inf and Cmax of olanzapine after 10 mg single dose administration of olanzapine tablet was 610 ng·h/mL and 16 ng/mL, respectively.

Pharmacokinetic properties of the components of LYBALVI are provided in Table 6.

Specific Populations

Geriatric Patients

The pharmacokinetics of olanzapine may be altered in geriatric patients [see Dosage and Administration (2.5), Use in Specific Populations (8.5)]. In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly subjects (≥65 years) than in non-elderly subjects (<65 years).

No effect of age on samidorphan pharmacokinetics was found in a study involving 12 elderly [aged 66-80 years old (6 male, 6 female)] and 24 young [aged 18-39 years old (12 male, 12 female)] healthy subjects administered a single oral dose of 10 mg samidorphan.

Male and Female Patients

Clearance of olanzapine is approximately 30% lower in females than males. In clinical trials, however, there were no apparent differences between males and females in efficacy or adverse reactions. In clinical studies and population pharmacokinetic analysis, LYBALVI pharmacokinetics were consistent with that of olanzapine (as monotherapy) with no apparent effect of sex on samidorphan pharmacokinetics.

Racial or Ethnic Groups

In vivo studies of olanzapine as monotherapy have shown that olanzapine exposures are similar among Japanese, Chinese, and Caucasians, especially after normalization for body weight difference. A population pharmacokinetic analysis found that the clearance of olanzapine is greater in Black subjects (N=255) than non-Black subjects (N=329 White and N=17 other races), and that samidorphan pharmacokinetics are not affected by race.

Patients with Hepatic and Renal Impairment

Effects of hepatic and renal impairment on the exposure of olanzapine and samidorphan are summarized in Figure 1.

Figure 1: Effects of Hepatic Impairment and Renal Impairment on Olanzapine and Samidorphan Pharmacokinetics

* Based on PBPK simulations, the predicted Cmax and AUC ratios for samidorphan in subjects with severe hepatic impairment relative to healthy subjects were 2.1 and 2.3, respectively.

Smoking Status

Olanzapine clearance was approximately 40% higher in smokers than in non-smokers. Samidorphan pharmacokinetics were not affected by smoking.

Combined Effects

The combined effects of age, smoking, and sex could lead to substantial difference in olanzapine pharmacokinetics. The clearance of olanzapine in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Population pharmacokinetic analysis indicated that samidorphan pharmacokinetics was not affected by age, sex, race, and smoking status.

Drug Interaction Studies

Effect of Other Drugs on LYBALVI

Coadministration of LYBALVI with rifampin, a strong CYP3A4 inducer, decreased the total systemic exposure (based on area under the concentration-time curve from time 0 extrapolated to infinity [AUCinf]) of olanzapine and samidorphan by 48% and 73%, respectively (Figure 2).

Fluvoxamine, a strong CYP1A2 inhibitor, decreases clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC in female nonsmokers and male smokers is 52% and 108%, respectively.

Carbamazepine therapy (200 mg bid) causes an approximately 50% increased clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a CYP1A2 inducer.

Based on PBPK simulations, Itraconazole, a strong CYP3A inhibitor, is predicted to increase samidorphan Cmax by 25% and AUC by 56%.

Figure 2: Effect of Other Drugs on LYBALVI

Effect of LYBALVI on Other Drugs

Coadministration of LYBALVI and lithium or valproate did not have a clinically significant effect on the PK of lithium or valproate (Figure 3). Based on these results, no dosage adjustment of lithium or valproate is necessary when coadministered with LYBALVI.

Figure 3: Effect of LYBALVI on Other Drugs

In vitro Studies

Cytochrome P450 (CYP) Enzymes: Olanzapine does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Samidorphan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Samidorphan does not induce CYP1A2, CYP2B6, or CYP3A4/5.

Transporter Systems: Samidorphan is not a substrate of P-glycoprotein (P-gp; multidrug resistance protein 1), organic anion transporter (OATP) 1B1, or OATP1B3. Samidorphan does not inhibit these transporters or breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, or organic cation transporter (OCT)2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 Schizophrenia

The efficacy of LYBALVI in the treatment of schizophrenia in adults is based, in part, upon adequate and well-controlled studies of orally administered olanzapine. Efficacy of LYBALVI was also evaluated in a 4-week, randomized, double-blind, placebo- and active-controlled study (Study 1).

In Study 1 (NCT02634346), adult patients who met DSM-5 criteria for schizophrenia were randomized in a 1:1:1 ratio to LYBALVI, olanzapine, or placebo for 4 weeks of daily dosing. Dosing was flexible based on clinical response and tolerability for the first 2 weeks of the study; doses thereafter were fixed. 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. The study was designed to compare LYBALVI with placebo, not with olanzapine.

Eligible 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, and a score of ≥4 on at least 3 of the selected Positive Scale items. Patients were also required to have a Clinical Global Impression-Severity (CGI-S) score ≥4.

The primary efficacy endpoint was change from baseline in PANSS total score at Week 4. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210, with a higher score reflecting greater symptom severity. The secondary efficacy endpoint was defined as the change from baseline in CGI-S score at Week 4. The CGI-S is a validated scale that requires clinicians to rate a patient's current illness severity and overall clinical state based on experience with the illness population. Scores range from 1 (normal, not at all ill) to 7 (extremely ill).

Compared with patients on placebo, a statistically significant improvement in the change from baseline in PANSS total score at Week 4 was observed in patients treated with LYBALVI (Table 7). The inclusion of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic efficacy of olanzapine.

The change from baseline in PANSS total score in Study 1 is displayed in Figure 4.

Figure 4: Change from Baseline in PANSS Total Score by Time (Week) in Patients with Schizophrenia (Study 1)

Error bars represent standard error. The numbers under the figure indicate the number of patients at each timepoint.

Compared with patients on placebo, a statistically significant improvement in CGI-S score at Week 4 was observed in patients treated with LYBALVI.

Evaluation of Weight Changes in Patients with Schizophrenia

In Study 2 (NCT02694328), adult patients who met DSM-5 criteria for schizophrenia were randomized in a 1:1 ratio to LYBALVI or olanzapine for 24 weeks of daily dosing. Dosing was flexible for the first 4 weeks of the study, and doses were fixed thereafter. Patients were treated with doses of LYBALVI of 10 mg/10 mg or 20 mg/10 mg, or with doses of olanzapine of 10 mg or 20 mg.

Eligible patients were 18 to 55 years of age with a body mass index (BMI) of 18 to 30 kg/m2, PANSS total score of 50 to 90, CGI-S score of ≤4, and symptoms suitable for outpatient treatment; patients with diabetes mellitus were excluded.

The proportions of patients who discontinued study drug in the 24-week trial was 36% for both the LYBALVI and olanzapine-treated groups.

Weight Gain

The co-primary endpoints were percent change from baseline in body weight and the proportion of patients who gained ≥10% body weight at Week 24. LYBALVI was compared to olanzapine for each co-primary endpoint [see Adverse Reactions (6)]. Patients on stable, chronic olanzapine therapy were not specifically studied, so the weight effect of switching from olanzapine to LYBALVI is unknown.

Treatment with LYBALVI was associated with statistically significantly less weight gain than treatment with olanzapine, and with a smaller proportion of patients who gained ≥10% body weight (Table 8). Figure 5 displays the percent change in body weight over time.

Table 8: Primary Efficacy Results for Change from Baseline in Weight at Week 24 in Patients with Schizophrenia (Study 2)

Treatment Group	% Change From Baseline in Body Weight			≥10% Body Weight Gain
	Abbreviations: CI: confidence interval; LS: least squares; SD: standard deviation; SE: standard error.
	Baseline Mean, kg (SD)	LS Mean % Change From Baseline (SE)	Olanzapine-subtracted Difference (95% CI)	Percentage of Patients	Olanzapine-subtracted Risk Difference (95% CI)
LYBALVI (10 mg/10 mg, 20 mg/10 mg) (N=266)	77.0 (13.7)	4.2 (0.7)	-2.4 (-3.9, -0.9)	17.8	-13.7 (-22.8, -4.6)
Olanzapine (10 mg, 20 mg) (N=272)	77.5 (13.5)	6.6 (0.7)	__	29.8	__

Figure 5: Percent Change from Baseline in Body Weight by Time (Week) in Patients with Schizophrenia (Study 2)

Error bars represent standard error. The numbers under the figure indicate the number of patients at each timepoint.

14.2 Bipolar I Disorder

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.

How Supplied

LYBALVI (olanzapine and samidorphan) tablets have markings on both sides and are available as described in Table 9.

Storage and Handling

Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Keep tightly closed and protect from moisture.

Concomitant Use with Opioids is Contraindicated

Advise patients to inform their healthcare provider if they are taking, or plan to take any opioids for any reason, as LYBALVI is contraindicated with use of opioids or those undergoing acute opioid withdrawal [see Dosage and Administration (2.1), Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7.3)].

Precipitation of Opioid Withdrawal

Advise patients not to take LYBALVI when using opioids because of the risks of opioid withdrawal syndrome, sometimes requiring hospitalization. Advise patients that they should have an opioid-free period of a minimum of 7 days after last use of short-acting opioids and 14 days from last use of long-acting opioids before initiating LYBALVI [see Contraindications (4), Warnings and Precautions (5.3)].

Risk of Opioid Overdosage

Advise patients that they may be at increased risk of opioid overdosage if they attempt to use high or repeated opioid doses. 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 [see Warnings and Precautions (5.4)].

Risk of Resuming Opioids in Patients with Prior Opioid Use

Advise patients that if they used opioids prior to LYBALVI treatment, they may have decreased opioid tolerance if they use opioids after LYBALVI discontinuation or interruption [see Warnings and Precautions (5.4)].

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.5)].

Drug Reaction with Eosinophilia and Systemic Symptoms

Advise patients to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.7)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.8)].

Orthostatic Hypotension and Syncope

Educate patients about the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment [see Warnings and Precautions (5.9), Drug Interactions (7.2)].

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/ neutropenia that they should have their CBC monitored while taking LYBALVI [see Warnings and Precautions (5.11)].

Potential for Cognitive and Motor Impairment

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that LYBALVI therapy does not affect them adversely [see Warnings and Precautions (5.14)].

Concomitant Medication

Advise patients to inform their healthcare providers if they are taking, or plan to take any other olanzapine containing medication. Advise patients to inform their healthcare providers of any changes to their current prescription or over-the-counter medications because there is a potential for interactions [see Drug Interactions (7.1, 7.2, 7.3)].

Body Temperature Dysregulation

Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.15)].

Alcohol

Advise patients to use caution consuming alcohol while taking LYBALVI [see Drug Interactions (7.1)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Advise patients that LYBALVI used during the third trimester may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women using LYBALVI to monitor infants for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that LYBALVI may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

Administration Information

Advise patients to take LYBALVI once daily and not split or combine tablets [see Dosage and Administration (2.4)].

Distributed by:
Alkermes, Inc.
Waltham, MA 02451

©2024 Alkermes, Inc. All rights reserved.

ALKERMES® is a registered trademark of Alkermes, Inc. LYBALVI® is a registered trademark of Alkermes Pharma Ireland Limited, used by Alkermes, Inc., under license.

Printed in U.S.A.