Lybalvi (Olanzapine and Samidorphan)

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# Black Box Warning

# Overview
Lybalvi (Olanzapine and Samidorphan) is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist that is FDA approved for the treatment of schizophrenia and certain aspects of bipolar I disorder. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include somnolence, headache, dry mouth, and weight increase for patients with schizophrenia. Dizziness, asthenia, constipation, tremor, dry mouth, somnolence, and increase appetite for patients with Bipolar I Disorder, Manic or Mixed Episodes (Olanzapine). Weight gain, back pain, constipation, increased salivation, dry mouth, paresthesia, dyspepsia, increased appetite, and speech disorder for patients with Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (Olanzapine).

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Recommended Dosage in Schizophrenia
- Start Lybalvi orally, once daily 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).
- Recommended dosage of Lybalvi is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily.
- 5 mg is how much the dosage can be adjusted at weekly intervals.
Recommended Dosage in Bipolar I Disorder (Manic or Mixed Episodes) 
Monotherapy:
- Start Lybalvi once daily at either 10 mg/10 mg or 15 mg/10 mg.
- Recommended dosage of Lybalvi is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily.
- 5 mg is how much the dosage can be adjusted up or down at intervals of not less than 24 hours.
Maintenance Monotherapy:
- Recommended dosage of Lybalvi is 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily.
Adjunctive to lithium or valproate:
- Start Lybalvi orally, once daily at 10 mg/10 mg.
- Recommended dosage of Lybalvi is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily.
- 5 mg is how much the dosage can be adjusted at weekly intervals.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lybalvi (Olanzapine and Samidorphan) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Lybalvi (Olanzapine and Samidorphan) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lybalvi (Olanzapine and Samidorphan) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Lybalvi (Olanzapine and Samidorphan) in pediatric patients.

# Contraindications
- Lybalvi is contraindicated when patients are using opioids.
- Lybalvi is contraindicated when patients are undergoing acute opioid withdrawal.

# Warnings
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Patients at an increased risk of death include elderly patients who are treated with antipsychotic drugs for their dementia-related psychosis.
- 3.5% was the incidence of death in patients treated with Olanzapine who are part of the placebo-controlled clinical trials of elderly patients with dementia-related psychosis.
- 1.5% was the incidence of death in patients treated with the placebo who are part of the placebo-controlled clinical trials of elderly patients with dementia-related psychosis.
- Based on multiple placebo-controlled trials, there is a 1.6 to 1.7 high risk of death in olanzapine-treated patients than placebo-treated patients.
- Most deaths were infectious or cardiovascular related.
- Lybalvi is not approved for patients with dementia-related psychosis.
Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis
- Elderly patients with dementia-related psychosis treated with Olanzapine reported higher cases of cerebrovascular adverse reactions than patients treated with a placebo.
- Lybalvi is not approved for patients with dementia-related psychosis.
Precipitation of Severe Opioid Withdrawal in Patients Who Are Physiologically Dependent on Opioids
- Patients who are dependent on opioids experienced opioid withdrawal due to Samidorphan.
- Lybalvi is contraindicated undergoing acute opioid withdrawal or patients who are using opioids.
- For patients who use short-acting opioids, patients should be opioid free for at least 7 days before starting Lybalvi.
- For patients who use long-acting opioids, patients should be opioid free for at least 14 days before starting Lybalvi.
Vulnerability to Life-Threatening Opioid Overdose 
Risk of Opioid Overdose from Attempts to Overcome Samidorphan Blockade
- Samidorphan is an opioid antagonist which is part of Lybalvi.
- Fatal or life-threatening opioid intoxication may occur if Lybalvi interrupted or discontinued.
- Advise patients about the risks of potentially overcoming opioid blockade.
For patients who require opioid treatment while taking Lybalvi:
- Advise patients to discontinue Lybalvi use.
- Manage respiratory effects, patent airways, and assisted ventilation of patients caused by opioids.
- Advise patients to be monitored by trained personal in a setting that is staffed for cardiopulmonary resuscitation.
Risk of Resuming Opioids in Patients with Prior Opioid Use:
- Decreased opioid tolerance may occur in patients with a history of chronic opioid if Lybalvi is interrupted/discontinued.
- Advise patients that opioid overdose risk may increase if tolerance is decreased.
Neuroleptic Malignant Syndrome
- There is an association between antipsychotic drugs and Neuroleptic Malignant Syndrome.
- Delirium, hyperpyrexia, autonomic instability, and muscle rigidity are clinical manifestations that occur with NMS.
- Advise patients to stop Lybalvi treatment and seek immediate medical attention if they experience signs or symptoms of NMS.
Drug Reaction with Eosinophilia and Systemic Symptoms
- Exposure to Olanzapine has led to drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
- A cutaneous reaction such as a rash and/or lymphadenopathy with systemic complications such as hepatitis are associated with DRESS.
- Discontinue Lybalvi if patient experiences signs or symptoms of DRESS.
Metabolic Changes
- Dyslipidemia, hyperglycemia, body weight gain, and diabetes mellitus are some metabolic changes associated with taking Lybalvi.
- Monitor patients taking Lybalvi for polyuria, weakness, polydipsia, and polyphagia which are symptoms associated with hyperglycemia.
- Advise patients taking Lybalvi to undergo fasting blood glucose testing if they experience symptoms of hyperglycemia and perioidically during Lybalvi treatment.
- Advise patinets taking Lybalvi to undergo fasting lipid profile testing at the start and periodicially during the treatment.
Tardive Dyskinesia
- Tardive Dyskinesia is higher in elderly patients.
- The irreversibility of tardive dyskinesia increases as Lybalvi treatment continues.
- There may be partial or complete remit of Tardive Dyskinesia if antipsychotic treatment is stopped.
- Lowest doses possible of Lybalvi for the shortest duration of time should be given to patients to reduce chances of Tardive Dyskinesia.
- Based on the patient, Lybalvi treatment may continue or be stopped if the patient displays syndromes of Tardive Dyskinesia.
Orthostatic Hypotension and Syncope
- The risk of orthostatic hypotension and syncope is greater during the initial dose titration and when increasing dosage.
- 3.7% of patients taking Lybalvi in a 24-week, olanzapine-controlled study experienced orthostatic hypotension while only 0.4% of olanzapine-treated patients experienced orthostatic hypotension in the study.
- Orthostatic vital signs should be monitored in patients who have cerebrovascular disease or are vulnerable to hypotension.
Falls
- Advise patients that postural hypotension, motor and sensory instability, and somnolence may occur in patients taking Lybalvi.
- Advise patients to take a fall risk assessments if they are prone to falls before initiating Lybalvi.
Leukopenia, Neutropenia, and Agranulocytosis
- Lybalvi may cause neutropenia and leukopenia in patinets.
- Low absolute neutrophil count and low white blood cell count are risks factors associated with leukopenia and neutropenia.
- Discontinuation of Lybalvi treatment may be considered when low white blood cell count is detected in a patient.
- Lybalvi should be discontinued in patients with severe neutropenia.
Dysphagia
- Antipsychotic drug use can lead to aspiration and esophageal dysmotility.
- Monitor patients for risk of aspiration when taking Lybalvi.
Seizures
- Seizures may occur in patients taking Lybalvi.
- Patients that have a condition which lowers the seizure threshold or has a history of seizures are at the greatest risk of Lybalvi.
Potential for Cognitive and Motor Impairment
- Thinking, judgement, and thinking may be impaired in patients when taking Lybalvi.
- 9% of patients treated with Lybalvi experienced somnolence in a placebo-controlled study while only 2.2% of patients treated with placebo experienced it.
Body Temperature Dysregulation
- Lybalvi may affect the ability of the body to reduce its core body temperature.
Anticholinergic (Antimuscarinic) Effects
- In vitro muscarinic receptor affinity is displayed in Olanzapine.
- Dry mouth, constipation, and tachycardia are associated with Olanzapine.
- Monitor patients taking Lybalvi with a current diagnosis or prior history of urinary retention.
Hyperprolactinemia
- There are elevations of prolactin levels seen in patients due to Olanzapine.
- Hyperprolactinemia may suppress hypothalamic GnRH leading to a reduced gonadotropin secretion in the pitutary.
- Patients receiving prolactin-elevating compounds have experienced amenorrhea,  impotence, galactorrhea, and gynecomastia.
- Decreased bone density may occur in patients with long-standing hyperprolactinemia.
- 41.4% of females and 32.9% of males treated with Lybalvi had shifts from normal to high prolactin values in a 4-week placebo-controlled trial.
- 56.1% of females and 37.1% of males treated with Olanzapine had shifts from normal to high prolactin values in a 4-week placebo-controlled trial.
- 10% of females and 4.8% of males treated with placebo had shifts from normal to high prolactin values in a 4-week placebo-controlled trial.
Risks Associated with Combination Treatment with Lithium or Valproate
- Advise patients to review lithium or valproate prescribing information if Lybalvi is administered with lithium or valproate.

# Adverse Reactions

## Clinical Trials Experience
Clinical Studies Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the 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 practice.
Adverse Reactions in Patients with Schizophrenia
Patient Exposure:
- 1262 patients diagnosed with schizophrenia were looked at to test the safety of Lybalvi.
- There are four double-blind, controlled studies which were used on the patient pool.
- 636 patients received Lybalvi in the clinical studies for 6 months.
- 386 patients received Lybalvi in the clinical studies for at least one year.
Adverse Reactions in the Short-Term (4 week) Placebo-Controlled Trial in Adults with Schizophrenia:
- Somnolence, headache, weight increase, and dry mouth are the most common adverse reactions in the clinical studies.
Table 2 summarizes Adverse reactions associated with the use of Lybalvi.
Insert Table 2
Adverse Reactions in the Long-Term (24-week), Active-Controlled Trial in Adults with Schizophrenia:
- Increased appetite, lethargy, aspartate aminotransferase increase, somnolence, waist circumference increase, dry mouth, weight increase, dry mouth, blood creatine phosphokinase increase, headache, lethargy, sedation, akathisia, alanine aminotransferase increase, constipation, dizziness, fatigue, nausea, blood pressure increase, neutrophil count decrease, blood insulin increase, and dyslipidemia are the adverse reactions associated in patients with stable schizophrenia who are part of the the 24-week, Olanzapine-controlled trial.
- Weight increase, glycosylated hemoglobin increase, liver function test abnormalities, schizophrenia, somnolence, and neutropenia are adverse reactions reported in patients taking Lybalvi that led to discontinuation of treatment.
Hyperglycemia:
- Patients treated with Olanzapine in clinical trials had increases in mean blood glucose.
- Patients taking Lybalvi have had signs/symptoms of hyperglycemia.
- 4% patients who had schizophrenia treated with Lybalvi had shifts in fasting glucose from normal to high in a 4-week placebo-controlled trial.
- 1% patients who had schizophrenia treated with Olanzapine had shifts in fasting glucose from normal to high in a 4-week placebo-controlled trial.
- 0% patients who had schizophrenia treated with a placebo had shifts in fasting glucose from normal to high in a 4-week placebo-controlled trial.
Table 3 summarizes changes in Glycemic Parameters in a 24-Week Trial of Patients with Schizophrenia:
Insert Table 3
Dyslipidemia:
- 14% of patients treated with Lybalvi had shifts in fasting triglycerides from normal to high.
- 4% of patients treated with placebo had shifts in fasting triglycerides from normal to high.
- When comparing patients treated with Lybalvi vs. patients treated with Olanzapine, both groups displayed similar data when looking at mean changes in fasting LDL cholesterol, triglycerides, total cholesterol, and HDL cholesterol in a 24-week Olanzapine-controlled study.
Weight Gain:
- Patients treated with Lybalvi or Olanzapine had greater mean changes in weight when compared to patients treated with a placebo in the 4-week placebo-controlled study.
- An average 4.2% of baseline body weight increase was experienced by patients taking Lybalvi in a 24-week trial.
- 10% body weight gain was seen in 17.8% patients who experienced weight gain from Lyblavi in the 24-week trial.
Extrapyramidal Symptoms:
- Patients that received Lybalvi vs. patients that received a placebo displayed similar scores when it came to the Simpson-Angus Rating Scale, Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale.
- Parkinsonism rates were lower in patients receiving Lyblavi when compared to patients receiving a placebo.
- Rates of akathisia and dyskinesia were similar in patients receiving either Lybalvi or the placebo.
- Bradykinesia, akathisia, extrapyramidal disorder, restlessness, tremor, parkinsonism, and muscle spasms were the adverse reactions  related to extrapyramidal symptoms reported by patients in both the Lybalvi group and the placebo group.
- Mean changes in SAS, AIMS, and BARS were similar in patients either receiving Lybalvi or the placebo in the 24-week active-controlled trial.
Dystonia:
- Tightness of the throat, difficulty breathing, protrusion of the tongue, spasm of the neck, and swallowing difficulty are signs/symptoms associated with dystonia.
- Males and younger age groups have an elevated risk of acute dystonia.
Adverse Reactions in Patients with Bipolar Disorder
- Dry mouth, dyspepsia, tremor, somnolence, dizziness, constipation, and increased appetite are common adverse reactions found in the short-term trials of Olanzapine.
- Speech disorder, paresthesia, dry mouth, increased salivation, constipation, weight gain, back pain, and amnesia are the common adverse reactions found in the short-term trials of Olanzapine as adjunct to lithium or valproate.

## Postmarketing Experience
Post-approval use of Olanzapine Adverse Reactions
- Allergic reactions (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria)
- Cholestatic or mixed liver injury, hepatitis, jaundice
- Diabetic coma and 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 hyper-secretion
- Stuttering1
- Venous thromboembolic events (including pulmonary embolism and deep venous thrombosis)

# Drug Interactions
Effects of Other Drugs on Lybalvi 
Table 4 summarizes the Effects of Other Drugs on Lybalvi.
Insert Table 4
Effects of Lybalvi on Other Drugs 
Table 5 summarizes the  Effects of Lybalvi on Other Drugs.
Insert Table 5
Opioids
- Lybalvi is contraindicated in patients who either undergo acute opioid withdrawal or use opioids.
- Rrecipitating acute opioid withdrawal rate increases in patients who are treated with Lybalvi.
- Advise patients that they must be 7-day opioid-free from the last use of short-acting opioids before starting Lybalvi treatment.
- Advise patients that they must be 14-day opioid-free from the last use of long-acting opioids before starting Lybalvi treatment.
- Advise patients to discontinue Lybalvi if opioid treatment for anesthesia or analgesia is required.
- The presence of Samidorphan can cause opioid treatments to become less effective.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Exposure Registry
- Pregnancies are monitored by a registry in patients exposed to atypical antipsychotics such as Lybalvi.
- Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388.
Risk Summary
- Extrapyramidal and/or withdrawal symptoms following delivery of neonates are at higher rates when they are exposed to antipsychotic drugs in the third trimester of pregnancy.
- Data on pregnant humans is insufficient when looking into Lybalvi, Olanzapine, and Samidorphan effects on any drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
- Exposure to Lybalvi can put mothers with untreated schizophrenia or bipolar I disorder at certain risks.
Lybalvi:
- In pregnant rat studies, there were signs of adverse effects on fetal toxicity and embryofetal development based on AUC when doses that are 6 times and >400 times the maximum recommended human dose of 20 mg/10 mg Olanzapine/Samidorphan in Lybalvi.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lybalvi (Olanzapine and Samidorphan) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Lybalvi (Olanzapine and Samidorphan) during labor and delivery.

### Nursing Mothers
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) in women who are nursing.

### Pediatric Use
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) in pediatric settings.

### Geriatic Use
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) in geriatric settings.

### Gender
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lybalvi (Olanzapine and Samidorphan) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Lybalvi (Olanzapine and Samidorphan) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Administration in the drug label.

### Monitoring
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Lybalvi (Olanzapine and Samidorphan) and IV administrations.

# Overdosage
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Pharmacology in the drug label.

## Mechanism of Action
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Mechanism of Action in the drug label.

## Structure
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Structure in the drug label.

## Pharmacodynamics
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Pharmacodynamics in the drug label.

## Pharmacokinetics
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Pharmacokinetics in the drug label.

## Nonclinical Toxicology
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Nonclinical Toxicology in the drug label.

# Clinical Studies
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Clinical Studies in the drug label.

# How Supplied
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) How Supplied in the drug label.

## Storage
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Patient Counseling Information in the drug label.

# Precautions with Alcohol
Alcohol-Lybalvi (Olanzapine and Samidorphan) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Brand Names in the drug label.

# Look-Alike Drug Names
There is limited information regarding Lybalvi (Olanzapine and Samidorphan) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price