Dosage & Administration
| Indication | Recommended Starting Dose (olanzapine/samidorphan) | Recommended Dose (olanzapine/samidorphan) |
| Schizophrenia | 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) | 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 | 10 mg/10 mg | 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg |
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Lybalvi Prescribing Information
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[see Warnings and Precautions ].
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
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)].
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.
Recommended Dosage in Bipolar I Disorder (Manic or Mixed Episodes)
Monotherapy: Initiate LYBALVI at 10 mg/10 mg or 15 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily. The maximum recommended dosage is 20 mg/10 mg once daily.
Dosage adjustments should occur at intervals of not less than 24 hours. When dosage adjustments are necessary, dose increments/decrements of 5 mg (based on the olanzapine component of LYBALVI) are recommended.
Maintenance Monotherapy: Administer LYBALVI at 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily.
Adjunctive to lithium or valproate: Initiate LYBALVI at 10 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg or 20 mg/10 mg, once daily.
Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of LYBALVI), depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily.
Administration Information
Administer LYBALVI orally once daily with or without food as a single tablet.
Do not divide tablets or combine strengths.
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 , Drug Interactions , Use in Specific Populations , and Clinical Pharmacology ]. If dose escalation is necessary, increase the dosage slowly in these patients.
LYBALVI tablets are available in four strengths .
| Tablet Strength | Tablet Color/Shape | Tablet Markings |
|---|---|---|
| 5 mg/10 mg (olanzapine/samidorphan) | Yellow, capsule-shaped | “OS” and “5” |
| 10 mg/10 mg (olanzapine/samidorphan) | Orange, capsule-shaped | “OS” and “10” |
| 15 mg/10 mg (olanzapine/samidorphan) | Blue, capsule-shaped | “OS” and “15” |
| 20 mg/10 mg (olanzapine/samidorphan) | Pink, capsule-shaped | “OS” and “20” |
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including LYBALVI, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/.
Risk Summary
Neonates exposed to antipsychotic drugs, including the olanzapine component of LYBALVI, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). 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 (see Data). There are no available data on the use of samidorphan or the combination of olanzapine and samidorphan in pregnant women to determine a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including LYBALVI, during pregnancy (see Clinical Considerations).
LYBALVI
In an animal reproduction study, oral administration of olanzapine and samidorphan to pregnant rats during the period of organogenesis produced adverse effects on embryofetal development and fetal toxicity at maternally toxic doses that are 6 times and >400 times the maximum recommended human dose (MRHD) of 20 mg/10 mg olanzapine/samidorphan in LYBALVI, respectively based on AUC. There were no adverse effects on embryofetal development at doses of olanzapine and samidorphan that are approximately 1 and 80 times, respectively, the MRHD based on AUC (see Data).
Olanzapine
In animal reproduction studies, there was no evidence of malformations in rats or rabbits when orally administered olanzapine at doses up to 9 and 30 times the MRHD dose (20 mg) based on mg/m2 body surface area, respectively. In an oral rat embryofetal developmental toxicity study, early resorptions and increased numbers of nonviable fetuses were observed at a dose 9 times the MRHD based on mg/m2 body surface area and gestation was prolonged at 5 times the MRHD based on mg/m2 body surface area. In an oral rabbit embryofetal developmental toxicity study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of olanzapine which is 30 times the MRHD based on mg/m2 body surface area (see Data).
Samidorphan
In animal reproduction studies, oral administration of samidorphan to pregnant rats and rabbits during the period of organogenesis caused fetal toxicities in rats only at maternally toxic doses that are >248 times the human exposure at the MRHD of 10 mg/day based on AUC. Oral administration of samidorphan to pregnant rats during pregnancy and lactation resulted in lower pup survival and decreased pup weights at 188 times the human exposure at the MRHD based on AUC (see Data).
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.
Clinical Considerations
Disease-Associated Maternal and/or Embryofetal Risk
There is risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.
Fetal/ Neonatal Risks
Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including the olanzapine component of LYBALVI, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.
Data
Human Data
Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.
Animal Data
LYBALVI
Olanzapine and samidorphan were orally administered to pregnant rats during the period of organogenesis at doses of 0.5/10, 2/50, 6/200, and 0/200 mg/kg/day (olanzapine/samidorphan) which are approximately <1/10 times to 6/448 times the MRHD of 20 mg/10 mg, olanzapine/samidorphan, respectively, based on AUC. Maternal toxicity consisting of decreased body weight and food consumption was observed at all dose levels. Administration of samidorphan alone (200 mg/kg/day) and 6/200 mg/kg/day olanzapine/samidorphan decreased mean fetal body weights, increased litter incidence of bent ribs and bent scapula; however, the incidence of bent scapula and bent ribs was not increased when samidorphan was administered in combination with olanzapine compared to the incidence with samidorphan alone. Administration of olanzapine/samidorphan at 6/200 mg/kg/day also increased resorptions and post-implantation loss, with correlating lower mean viable fetuses and litter size. The no observed adverse effect level (NOAEL) for embryofetal development is 2/50 mg/kg/day, which is approximately 1/80 times the MRHD of 20 mg/10 mg olanzapine/samidorphan respectively, based on AUC.
Olanzapine
Olanzapine was orally administered to pregnant rats and rabbits during the period of organogenesis at doses up to 18 mg/kg/day in rats and at doses up to 30 mg/kg/day in rabbits (9 times and 30 times the MRHD of 20 mg/day based on mg/m2 body surface area, respectively), and no evidence of malformations was observed. In an oral rat embryofetal developmental toxicity study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD based on mg/m2 body surface area). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD based on mg/m2 body surface area). In an oral rabbit embryofetal developmental toxicity study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of olanzapine at 30 mg/kg/day (30 times the MRHD based on mg/m2 body surface area).
Samidorphan
Samidorphan was orally administered to pregnant rats during the period of organogenesis at doses of 25, 100, and 300 mg/kg/day, which are approximately 29 to 742 times the MRHD of 10 mg/day based on AUC. Samidorphan was associated with an increased incidence of skeletal variations (unossified sternebrae and bent ribs) at maternally toxic doses of ≥100 mg/kg/day, and skeletal malformations (bent or misshapen forelimbs, hindlimbs, and/or scapula) at 300 mg/kg/day which are >248 and 742 times the MRHD based on AUC, respectively. The NOAEL for embryofetal development is 25 mg/kg/day, which is approximately 29 times the MRHD based on AUC.
Samidorphan did not cause adverse effects on embryofetal development when orally administered to pregnant rabbits during the period of organogenesis at doses of 10, 30, and 90 mg/kg/day, which are up to approximately 143 times the MRHD based on AUC.
Samidorphan was orally administered to pregnant rats during pregnancy and lactation at doses of 10, 30, or 100 mg/kg/day, which are approximately 7 to 188 times the MRHD based on AUC. Reduced pup survival, lower birth weights, and decreased pup body weight gains were observed at 100 mg/kg/day, which is 188 times the MRHD based on AUC. The NOAEL of 30 mg/kg/day is approximately 36 times the MRHD based on AUC. There were no adverse effects on pup developmental landmarks, learning, memory, reflexes, or fertility.
Lactation
Risk Summary
Olanzapine and samidorphan are present in human milk. A clinical lactation study in 12 healthy lactating women demonstrated that olanzapine and samidorphan are present in low levels in human milk (see Data). However, 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 (see Clinical Considerations). There are no data on the effects of samidorphan or the combination of olanzapine and samidorphan on the breastfed infant, or on milk production.
The developmental 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.
Clinical Considerations
Infants exposed to LYBALVI should be monitored for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements).
Data
A single dose milk-only lactation study was conducted in 12 healthy adult lactating women. Following a 5 mg/10 mg oral dose of olanzapine and samidorphan, the mean quantities in human milk were detected to be 0.002 mg and 0.006 mg, respectively. The calculated weight-adjusted infant daily oral dose for olanzapine (~ 0.0005 mg/kg) and samidorphan (0.001 mg/kg) was less than 1% of the weight-adjusted maternal dose for olanzapine (0.07 mg/kg) and samidorphan (0.15 mg/kg), respectively.
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 [see Warnings and Precautions ].
Pediatric Use
The safety and effectiveness of LYBALVI have not been established in pediatric patients.
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.
Olanzapine
Of the 2,500 patients in premarketing clinical studies with orally administered olanzapine, 11% (263) were 65 years of age or over. 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 [see Dosage and Administration , Warnings and Precautions ].
Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo.
- In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine, compared to patients treated with placebo.
- In five placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1,184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than in placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than with placebo (13% vs 7%).
Consider a lower dosage of the olanzapine component of LYBALVI in geriatric patients who may have decreased clearance or an exaggerated pharmacodynamic response to olanzapine (e.g., oversedation) [see Dosage and Administration ].
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 ].
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 ]. 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).
LYBALVI is contraindicated in patients:
- who are using opioids [see Warnings and Precautions ( 5.3, 5.4), Drug Interactions ( 7.3)].
- who are undergoing acute opioid withdrawal [see Warnings and Precautions , Drug Interactions ].
If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products [see Warnings and Precautions ].