DRUG INTERACTIONS- (summary)

 • Strong CYP3A4 Inducers: Not recommended.

 • Strong CYP1A2 Inhibitors: Consider dosage reduction of olanzapine component of LYBALVI.

 • CYP1A2 Inducer: Consider dosage increase of the olanzapine component of LYBALVI.

 • CNS Acting Drugs: May potentiate orthostatic hypotension

 • Anticholinergic Drugs: Can increase risk for severe gastrointestinal adverse reactions.

 • Antihypertensive Agents: Monitor blood pressure.

 • Levodopa and Dopamine Agonists: Not recommended.

BRIEF SUMMARY

OLANZAPINE/SAMIDORPHAN- (May 2021)

Indn-  to treat schizophrenia in adult and certain aspects of bipolar 1 disorder in adults     

Comp-  Tablets (olanzapine/samidorphan): 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg and 20 mg/10 mg.                                                                                             

  Recommended Dose- (olanzapine/samidorphan) Schizophrenia (2.2) 5 mg/10 mg or 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg                                                  Bipolar I disorder (manic or mixed episodes) (2.3) 10 mg/10 mg or 15 mg/10 mg 5 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg                                                               Bipolar I disorder adjunct to lithium or valproate (2.3) 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg 

ADR-  Most common adverse reactions (incidence =5% and at least twice placebo):           • Schizophrenia : weight increased, somnolence, dry mouth, and headache.

 • Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor.

Pat Inform-

Advise patients to inform their healthcare provider if they are taking, or plan to take any opioids for any reason, as  is contraindicated with use of opioids or those undergoing acute opioid withdrawal

Precipitation of Opioid Withdrawal                                                                                   -Advise patients not to take  when using opioids because of the risks of opioid withdrawal syndrome, sometimes requiring hospitalization.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 25

Name of the Drug-    LYBALVI

Active Ingredient -   Olanzapine /samidophan

Pharmacological Classification-   To treat schizophrenia in adult and certain                                                                      aspects of bipolar 1 disorder in adults                                                                                                          

                                                                                                                                                  Date of Approval-          5/28/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                LYBALVI™ safely and effectively. See full prescribing information for LYBALVI™. LYBALVI™ (olanzapine and samidorphan) tablets, for oral use

Initial U.S. Approval: 2021

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS -                                                                                                  See full prescribing information for complete boxed 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.

INDICATIONS AND USAGE- 

 LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, indicated for the treatment of:

• Schizophrenia in adults  • Bipolar I disorder in adults  o Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate o Maintenance monotherapy treatment

DOSAGE AND ADMINISTRATION-

Indication- Recommended Starting Dose (olanzapine/samidorphan)

Recommended Dose- (olanzapine/samidorphan) Schizophrenia (2.2) 5 mg/10 mg or 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder (manic or mixed episodes) (2.3) 10 mg/10 mg or 15 mg/10 mg 5 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder adjunct to lithium or valproate (2.3) 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg • See the full prescribing information for the recommended titration and maximum recommended dosage.

 • Administer LYBALVI once daily with or without food. Do not divide tablets or combine strengths.

 • Recommended starting dosage is 5 mg/10 mg once daily in patients who have a predisposition to hypotensive reactions, have potential for slower metabolism of olanzapine, or may be more pharmacodynamically sensitive to olanzapine.

 DOSAGE FORMS AND STRENGTHS-

 Tablets (olanzapine/samidorphan): 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg and 20 mg/10 mg.

(3) ----------------------------------CONTRAINDICATIONS -------------------------------- • Patients using opioids. (4) • Patients undergoing acute opioid withdrawal. (4) • If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for those products. (4) -------------------------- WARNINGS AND PRECAUTIONS -------------------------- • Cerebrovascular Adverse Reactions in Elderly Patients with DementiaRelated Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities). (5.2) • Precipitation of Opioid Withdrawal in Patients Who are Dependent on Opioids: LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids. Prior to initiating LYBALVI, there should be at least

ADVERSE REACTIONS-

 Most common adverse reactions (incidence =5% and at least twice placebo):                  • 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.

CONTRAINDICATIONS-

 • Patients using opioids.

 • Patients undergoing acute opioid withdrawal

 • If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for those products.

 WARNINGS AND PRECAUTIONS-

 • Cerebrovascular Adverse Reactions in Elderly Patients with DementiaRelated Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities).

 • Precipitation of Opioid Withdrawal in Patients Who are Dependent on Opioids: LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids. Prior to initiating LYBALVI, there should be at least least a 14-day opioid-free interval from the last use of long-acting opioids to avoid precipitation of opioid withdrawal.

 • Vulnerability to Life-Threatening Opioid Overdose: o Risk of Opioid Overdose from Attempts to Overcome LYBALVI Opioid Blockade: Attempts to overcome LYBALVI opioid blockade with high or repeated doses of opioids may lead to fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued

 o Risk of Resuming Opioids in Patients with Prior Opioid Use: Patients with a history of chronic opioid use prior to LYBALVI treatment may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued.

 • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring.

 • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected.

 • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain.

 • Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope.

 • Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors.

 • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.

 • Potential for Cognitive and Motor Impairment: Use caution when operating machinery.

 • Anticholinergic (Antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions.

 • Hyperprolactinemia: May elevate prolactin levels.

DOSAGE AND ADMINISTRATION-

Indication- Recommended Starting Dose (olanzapine/samidorphan)

Recommended Dose- (olanzapine/samidorphan) Schizophrenia (2.2) 5 mg/10 mg or 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder (manic or mixed episodes) (2.3) 10 mg/10 mg or 15 mg/10 mg 5 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder adjunct to lithium or valproate (2.3) 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg • See the full prescribing information for the recommended titration and maximum recommended dosage.

 • Administer LYBALVI once daily with or without food. Do not divide tablets or combine strengths.

 • Recommended starting dosage is 5 mg/10 mg once daily in patients who have a predisposition to hypotensive reactions, have potential for slower metabolism of olanzapine, or may be more pharmacodynamically sensitive to olanzapine.

 DOSAGE FORMS AND STRENGTHS-

 Tablets (olanzapine/samidorphan): 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg and 20 mg/10 mg.

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Concomitant Use with Opioids is Contraindicate

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

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

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

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

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 Precautions 

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) .

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

Tardive Dyskinesia-                                                                                                 Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare adviser

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

Leukopenia/Neutropenia-                                                                                              Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/ neutropenia that they sho

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.

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 

Body Temperature Dysregulation-                                                                                Educate patients regarding appropriate care in avoiding overheating and dehydration 

Alcohol Advise patients to use caution consuming alcohol while taking LYBALVI [see Drug Interactions )

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

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

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 .

Administration Information-                                                                                             Advise patients to take LYBALVI once daily and not split or combine tablets

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Distributed by: Alkermes, Inc. 852 Winter Street Waltham, MA 02451-1420 ©2021 Alkermes, Inc. All rights reserved.

ALKERMES® is a registered trademark of Alkermes, Inc. and LYBALVI™ is a trademark used by Alkermes, Inc. under license. Printed in U.S.A

CLINICAL PHARMACOLOGY

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.

2. Pharmacodynamics-

Cardiac Electrophysiology-                                                                                             At doses up to 30 mg/30 mg (1.5 times and 3 times the maximum recommended daily dosage of olanzapine and samidorphan, respectively), LYBALVI does not prolong QTc interval to any clinically relevant extent.

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

Excretion -                                                                                                                 Primary Route of Elimination Metabolism Metabolism Urine (Unchanged) 7% 18% Urine (Unchanged + metabolites) 57% 67% Feces (Unchanged + metabolites) 30% 16%

High fat meal defined as meal containing approximately 900-1000 calories and 50% fat content. No clinically relevant food effect. d Presented as range of the mean across multiple studies.

Specific Populations -                                                                                                  Geriatric Patients The pharmacokinetics of olanzapine may be altered in geriatric patients 

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.

USE IN SPECIFIC POPULATIONS

1 Pregnancy-

Pregnancy Exposure Registry- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including LYBALVI, during pregnancy.

Overall published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes 

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

2 Lactation-                                                                                                                   Risk Summary- Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk. There is no information on the effects of olanzapine on milk production.

The development and health benefits of breastfeeding should be considered along with the mother's clinical need for LYBALVI and any potential adverse effects on the breastfed infant from LYBALVI or from the underlying maternal condition.

3. Females and Males of Reproductive Potential Infertility Females -                            Based on the pharmacologic action of olanzapine (D2 antagonism), treatment with LYBALVI may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.

4. Pediatric Use-                                                                                                               The safety and effectiveness of LYBALVI have not been established in pediatric patients.

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.

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.

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 

OVERDOSAGE -                                                                                                         Human Experience There is limited clinical experience with overdose with LYBALVI.

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.