For US Healthcare Professionals
Indications: LYBALVI® is indicated for the treatment of adults with schizophrenia or bipolar I disorder for acute treatment of manic or mixed episodes as monotherapy and as an adjunct to lithium or valproate, or as a maintenance monotherapy treatment.
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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.
LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products.
Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis,
including stroke, transient ischemia attack, and fatalities. See Boxed Warning above.
Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids:
LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers.
Vulnerability to Life-Threatening Opioid Overdose:
Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life-threatening or fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes. Inform patients of the potential consequences of trying to overcome the opioid blockade and the serious risks of taking opioids concurrently with LYBALVI or while transitioning off LYBALVI. In emergency situations, if a LYBALVI-treated patient requires opioid treatment as part of anesthesia or analgesia, discontinue LYBALVI. Opioids should be administered by properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. Patients with a history of chronic opioid use prior to treatment with LYBALVI may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Advise patients that this decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage.
Neuroleptic Malignant Syndrome,
a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatinine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),
a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue if DRESS is suspected.
including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required anti-diabetic treatment despite discontinuation of the suspect drug. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically.
Tardive Dyskinesia (TD):
Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered.
Orthostatic Hypotension and Syncope:
Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease.
LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI.
Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases):
Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors.
Use LYBALVI with caution in patients at risk for aspiration.
Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold.
Potential for Cognitive and Motor Impairment:
Because LYBALVI may cause somnolence, impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely.
Body Temperature Dysregulation:
Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).
Anticholinergic (Antimuscarinic) Effects:
Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications.
LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.
Risks Associated with Combination Treatment with Lithium or Valproate:
If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for a description of the risks for these products.
Most common adverse reactions observed in clinical trials were:
- Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache
- Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor
- Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine): dry mouth, dyspepsia, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia
LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling.
May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy.
LYBALVI is not recommended for patients with end-stage renal disease (eGFR of <15 mL/minute/1.73 m²).
To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
LYBALVI is indicated for the treatment of:
- Schizophrenia in adults
- Bipolar I disorder in adults
- Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
- Maintenance monotherapy treatment
Please see full Prescribing Information, including Boxed Warning, for LYBALVI.
ENLIGHTEN-1 was a 4-week, randomized, double-blind, placebo- and active-controlled, phase 3 clinical trial in 397 hospitalized patients with acute exacerbation of schizophrenia. Enrolled patients were 18 to 70 years of age with an overall baseline mean PANSS total score range of 100.6 to 102.7. On Days 1 and 2, patients randomized to LYBALVI received 10 mg/10 mg, and patients randomized to orally-administered olanzapine received 10 mg. Patients were instructed to take one tablet by mouth each day, preferably at bedtime. On Day 3, the dose was increased to 20 mg/10 mg for the LYBALVI group and 20 mg for the olanzapine group. At the end of Week 1, doses could be decreased for tolerability to 10 mg of olanzapine at the discretion of the investigator. Thereafter, no dose adjustments were permitted from Weeks 2 to 4. Olanzapine was an active control.1,2
Patients included in the study had a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), diagnosis of schizophrenia who met criteria for an acute exacerbation or relapse of schizophrenia symptoms, a PANSS score ≥80 with a score ≥4 on at least 3 of the following items from the PANSS: Item 1, delusions; Item 2, conceptual disorganization; Item 3, hallucinatory behavior; and Item 6, suspiciousness/persecution, and a CGI-S score ≥4 at baseline and screening; had a body mass index (BMI) of 18.0 to 40.0 kg/m² and abided by contraception methods stipulated in the protocol.1,2,4
Key exclusion criteria2:
- The presence of a clinically significant or unstable medical illness, condition; a history of diabetes; moderate or severe alcohol or drug use disorder; a positive urine drug screen for opioids, amphetamine/methamphetamine, phencyclidine, or cocaine at screening; or an assessment that the patient was at risk for suicide; previous exposure to olanzapine, mesoridazine, chlorpromazine, thioridazine, or a long-acting injectable antipsychotic medication within 6 months prior to screening (with the exception of those receiving 3-month paliperidone, which must not have been received within 12 months of screening)
- Initiation of first antipsychotic treatment within the past 12 months, <1 year had elapsed since the initial onset of active-phase of schizophrenia symptoms, or they received clozapine within 6 months prior to screening; history of clozapine use for treatment-resistant schizophrenia or an inadequate response to treatment with olanzapine; taking opioid agonists within 14 days, or opioid antagonists within 60 days, prior to screening
- Use of weight-loss drugs or hypoglycemic agents at screening, or the use of statins, if initiated or the dose changed within 3 months, was exclusionary
BIOEQUIVALENCE STUDY DESIGN
Phase 1 single-center, open-label, randomized, crossover study to assess the relative bioavailability of olanzapine in LYBALVI, olanzapine, and Zyprexa.
Eligible subjects were randomly assigned in a 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences (n=8 subjects per sequence group), in which they received single doses of 10 mg/10 mg LYBALVI, 10 mg olanzapine, or 10 mg Zyprexa on the first day of each treatment period, with a 14-day washout period between doses. The study had 3 treatment periods for each subject. Each treatment period included a 4-day inpatient stay and a 5-day outpatient follow-up (9 days total). Subjects fasted for ≥10 hours before receiving a single dose of study drug on the morning of Day 1 of each treatment period. Subjects remained inpatients until 48 hours post dosing for pharmacokinetic and safety assessments and were asked to return for 4 outpatient follow-up visits on Days 4 to 6 and 8 for further pharmacokinetic and safety assessments.2
OPEN-LABEL SAFETY EXTENSION STUDY DESIGN
Patients were eligible for enrollment in this phase 3, multicenter, open-label extension study after completing ENLIGHTEN-1. A total of 281 patients were enrolled in this study. Of these, 277 received ≥1 dose of study drug and 248 had ≥1 post-baseline PANSS assessment and the first visit occurred within 7 days of the last visit of the lead-in study.
The objective of the ENLIGHTEN-1 extension was to assess the long‑term safety and tolerability of LYBALVI. All patients started on LYBALVI 10 mg/10 mg and, based on investigator discretion, dose was increased to 15 mg/10 mg or 20 mg/10 mg.4
Key exclusion criteria4:
- Any finding that would compromise the safety of the patient or affect his or her ability to meet the visit schedule or visit requirements (based on investigator assessment)
- Use of medications contraindicated with olanzapine or that had drug-interaction potential with olanzapine
- Use of prohibited drugs
- Women who were pregnant or nursing
ENLIGHTEN-2 was a 24-week, randomized, double-blind, active-controlled, phase 3 clinical trial in 561 patients. Of the 561 patients who underwent randomization (LYBALVI, n=280; olanzapine, n=281), 538 had at least 1 postbaseline weight assessment (efficacy population).
Patients were 18 to 55 years of age, with stable body weight and randomized to receive either LYBALVI 10 mg/10 mg or 20 mg/10 mg (n=266) or olanzapine 10 mg or 20 mg (n=272). Patients were instructed to take one tablet by mouth each day, preferably at bedtime. Dosing was flexible for the first 4 weeks of the study and thereafter doses were fixed. The co-primary endpoints were change from baseline body weight and proportion of subjects with ≥10% weight gain from baseline at Week 24. Patients received study drugs orally, once-daily, preferably at bedtime. Patients who met DSM-5 criteria for a primary diagnosis of schizophrenia were enrolled. Patients were required to be outpatients, have a body mass index (BMI) of 18 to 30 kg/m², and have stable body weight for at least 3 months.1,3,4
Key exclusion criteria1,3:
- A history of treatment resistant schizophrenia, <1 year elapsed since initial onset of symptoms, naive to antipsychotic medication, active alcohol or substance use disorders (excluding marijuana/tetrahydrocannabinol), or any clinically significant or unstable medical illness
- Opioid agonist use within 14 days of screening, opioid antagonist use within 60 days of screening, or anticipated need for opioid treatment during the study were exclusionary, as was the use of olanzapine in the 60 days before screening
OPEN-LABEL SAFETY EXTENSION STUDY DESIGN
Within 7 days of ENLIGHTEN-2 trial completion, 265 patients continued to a 52-week, open‑label treatment period.
The primary objective of the ENLIGHTEN-2 extension was to assess the long‑term safety and tolerability of LYBALVI as assessed by the number of adverse reactions. Patients received either LYBALVI 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg during the open‑label period.4
MONOTHERAPY STUDY DESIGN
Oral olanzapine was studied in the treatment of manic or mixed episodes in 3 short-term (two 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 outcome in these studies was change from baseline in the Y‑MRS total score. One 3‑week placebo-controlled study (n=67), and two identically designed 3‑week placebo-controlled studies (n=67) involved a dose range of olanzapine (5 mg/day to 20 mg/day, once daily, starting at 10 mg/day). The 4-week placebo-controlled study (n=115) involved a dose range of olanzapine (5 mg/day to 20 mg/day, once daily, starting at 15 mg/day).1
MAINTENANCE MONOTHERAPY STUDY DESIGN
This study included 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 monotherapy 5 mg/day to 20 mg/day. Response during the open-label phase was defined as a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8.
Patients were randomized to either continuation of olanzapine at their same dose (n=225) or placebo (n=136) for observation of relapse. Patients were observed for time to relapse (increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression).1
ADJUNCTIVE STUDY DESIGN
Two 6-week, placebo-controlled combination trials (n=175 and n=169).
Evaluated efficacy of oral olanzapine with lithium or valproate in the treatment of outpatients with inadequately controlled acute manic or mixed episodes (Y-MRS ≥16). Patients were randomized to receive either olanzapine (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) or placebo, in combination with their original therapy.1
LYBALVI® Co-pay Savings Program Terms and Conditions:
Eligibility for Alkermes-Sponsored Co-pay Savings: This offer is only available to commercially insured patients 18 years or older with a LYBALVI prescription that is consistent with the Prescribing Information. Health plan requirements for a prior authorization and/or step therapies must be attempted prior to using this co-pay offer. This offer is not available to patients who are enrolled in, or covered by, any local, state, federal or other government program that pays for any portion of medication costs, including but not limited to Medicare, including Medicare Part D or Medicare Advantage plans; Medicaid, including Medicaid Managed Care and Alternative Benefit Plans under the Affordable Care Act; Medigap; VA; DOD; TRICARE; or a residential correctional program. Patients who become eligible for any government program that pays for any portion of medication costs will no longer be eligible for this program.
To the Patient: Present this card and prescription for LYBALVI to the pharmacist to participate in this program. When using this card, you certify that you understand the program rules and terms and conditions and that you meet, or are the legal guardian of a patient who meets, the program eligibility requirements. This offer is not available to patients who are enrolled in, or covered by, any local, state, federal or other government program that pays for any portion of medication costs, including but not limited to Medicare, including Medicare Part D or Medicare Advantage plans; Medicaid, including Medicaid Managed Care and Alternative Benefit Plans under the Affordable Care Act; Medigap; VA; DOD; TRICARE; or a residential correctional program. Patients who become eligible for any government program that pays for any portion of medication costs will no longer be eligible for this program. For questions about your eligibility or benefits, if your insurance has changed, or if you wish to discontinue your participation, call the LYBALVI Co-pay Savings Program at 1-855-820-9624 (8:00 AM-8:00 PM EST, Monday-Friday).
To the Pharmacist: When using this card, you certify that you have not submitted and will not submit a claim for reimbursement under any local, state, federal, or other government program for this prescription. Submit transaction to McKesson Corporation using BIN 610524. Submit commercial insurance as primary coverage, input co-pay savings card information as secondary coverage, and transmit using the COB segment of the NCPDP transaction. Applicable discounts will be displayed in the transaction response. Acceptance of this card and your submission of claims for LYBALVI are subject to the LoyaltyScript® Program terms and conditions posted at www.mckesson.com/mprstnc. Patient is not eligible if patient is enrolled in, or covered by, any local, state, federal, or other government program that pays for any portion of medication costs, including but not limited to Medicare, Medicaid, Medigap, VA, DOD, TRICARE, or a residential correctional program. The LYBALVI Co-pay Savings Program card is not valid for use with any other prescription drug discount or cash cards for LYBALVI. Claims submitted utilizing the program are subject to audit or validation. For questions regarding setup, claim transmission, patient eligibility, or other issues, call the LoyaltyScript® Program for the LYBALVI Co-pay Savings Program at 1‑855‑820‑9624 (8:00 AM-8:00 PM EST, Monday-Friday).
The LYBALVI® Patient Assistance Program provides uninsured patients who meet program eligibility criteria access to treatment at no charge, for up to 12 months.Eligibility criteria
- Patient must be uninsured
- Patient must provide proof of household size and annual gross income and certify accuracy that they meet financial criteria
- Prescription must be by a US licensed healthcare provider
- Shipment must be delivered to a location within the 50 states (excluding PR and US territories)
- Patient must be prescribed LYBALVI for an on-label use and be 18 years or older