b'6Table 3:Effects of Other Drugs on LYBALVI (contd) LYBALVI Olanzapinesignificantly greater than in placebo-treated patients: falls, somnolence, In an animal reproduction study, oral administration of olanzapine andOlanzapine was orally administered to pregnant rats and rabbits during theperipheral edema, abnormal gait, urinary incontinence, lethargy, increased Prevention orConsider increasing the dosage of the olanzapine componentsamidorphan to pregnant rats during the period of organogenesis producedperiod of organogenesis at doses up to 18 mg/kg/day in rats and at doses up toweight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations.Management: in LYBALVI when used concomitantly with CYP1A2 inducers. adverse effects on embryofetal development and fetal toxicity at maternally toxic30 mg/kg/day in rabbits (9 times and 30 times the MRHD of 20 mg/day basedThe rate of discontinuation due to adverse reactions was greater with Diazepam, Alcohol and CNS Acting Drugsdoses that are 6 times and 400 times the maximum recommended human doseon mg/m2 body surface area, respectively), and no evidence of malformationsolanzapine than with placebo (13% vs 7%).(MRHD) of 20 mg/10 mg olanzapine/samidorphan in LYBALVI, respectively basedwas observed. In an oral rat embryofetal developmental toxicity study, earlyConsider a lower dosage of the olanzapine component of LYBALVI in geriatric Concomitant use of diazepam, alcohol, or other CNS actingon AUC. There were no adverse effects on embryofetal development at doses ofresorptions and increased numbers of nonviable fetuses were observed at apatients who may have decreased clearance or an exaggerated pharmacodynamic Clinicaldrugs with LYBALVI may potentiate orthostatic hypotensionolanzapine and samidorphan that are approximately 1 and 80 times, respectively,dose of 18 mg/kg/day (9 times the MRHD based on mg/m2 body surface area).response to olanzapine (e.g., oversedation).Implication: observed with olanzapine.the MRHD based on AUC. 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,Hepatic Impairment: Olanzapine and samidorphan plasma exposures were found LYBALVI should be used with caution in patients receivingOlanzapineto be higher in subjects with moderate hepatic impairment than in subjects with Prevention orIn animal reproduction studies, there was no evidence of malformations in ratsfetal toxicity (manifested as increased resorptions and decreased fetal weight)normal hepatic function. The effect of severe hepatic impairment was not studied. concomitantly diazepam or other CNS acting drugs, or occurred at a maternally toxic dose of olanzapine at 30 mg/kg/day (30 times the Management: or rabbits when orally administered olanzapine at doses up to 9 and 30 times the2 The higher plasma exposure in patients with moderate hepatic impairment was using alcohol.MRHD dose (20 mg) based on mg/m2 body surface area, respectively. In an oralMRHD based on mg/mbody surface area).not expected to be clinically relevant. No dose adjustment of LYBALVI is needed in Anticholinergic Drugs rat embryofetal developmental toxicity study, early resorptions and increasedSamidorphanpatients with hepatic impairment.numbers of nonviable fetuses were observed at a dose 9 times the MRHD basedSamidorphan was orally administered to pregnant rats during the period of 2 Renal Impairment: Plasma exposure to olanzapine and samidorphan was higher Concomitant treatment with olanzapine and other drugson mg/mbody surface area and gestation was prolonged at 5 times the MRHDorganogenesis at doses of 25, 100, and 300 mg/kg/day, which are approximately2Clinicalwith anticholinergic activity can increase the risk for severebased on mg/m2 body surface area. In an oral rabbit embryofetal developmental29 to 742 times the MRHD of 10 mg/day based on AUC. Samidorphan wasin patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m ) Implication: compared to those with normal renal function. No dose adjustment of LYBALVI is gastrointestinal adverse reactions related to hypomotility. toxicity study, fetal toxicity (manifested as increased resorptions and decreasedassociated with an increased incidence of skeletal variations (unossifiedneeded in patients with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR fetal weight) occurred at a maternally toxic dose of olanzapine which is 30 timessternebrae and bent ribs) at maternally toxic doses of 100 mg/kg/day, and2Prevention orConsider increasing the dosage of the olanzapine component2 30 to 59 mL/minute/1.73 m ), or severe renal impairment (eGFR 15 to 29 mL/Management: in LYBALVI when used concomitantly with CYP1A2 inducers. the MRHD based on mg/mbody surface area. skeletal malformations (bent or misshapen forelimbs, hindlimbs, and/or scapula)minute/1.73 m2). Samidorphanat 300 mg/kg/day which are 248 and 742 times the MRHD based on AUC, Effects of LYBALVI on Other Drugs: Table 4 describes clinically significant drugIn animal reproduction studies, oral administration of samidorphan to pregnantrespectively. The NOAEL for embryofetal development is 25 mg/kg/day, which isThe effect of LYBALVI in patients with end-stage renal disorder was not studied. approximately 29 times the MRHD based on AUC.LYBALVI is not recommended for patients with end-stage renal disorder (eGFR of interactions where concomitant use of LYBALVI affects other drugs. rats and rabbits during the period of organogenesis caused fetal toxicities in15 mL/minute/1.73 m2).Table 4:Effects of LYBALVI on Other Drugs rats only at maternally toxic doses that are 248 times the human exposure atSamidorphan did not cause adverse effects on embryofetal development whenOVERDOSAGEthe MRHD of 10 mg/day based on AUC. Oral administration of samidorphan toorally administered to pregnant rabbits during the period of organogenesis at Antihypertensive Agents pregnant rats during pregnancy and lactation resulted in lower pup survival anddoses of 10, 30, and 90 mg/kg/day, which are up to approximately 143 times theHuman Experience: There is limited clinical experience with overdose with LYBALVI. decreased pup weights at 188 times the human exposure at the MRHD based MRHD based on AUC.In premarketing clinical trials of LYBALVI involving 861 patients, overdose of ClinicalLYBALVI may enhance the effects of certain on AUC.Samidorphan was orally administered to pregnant rats during pregnancy andLYBALVI was identified in 7 patients. This included 4 patients with accidental Implication: antihypertensive agents. The estimated background risk of major birth defects and miscarriage for thelactation at doses of 10, 30, or 100 mg/kg/day, which are approximately 7 to 188overdose, 2 with intentional overdose, and 1 due to a medication administration Monitor blood pressure and reduce dosage ofindicated populations is unknown. All pregnancies have a background risk oftimes the MRHD based on AUC. Reduced pup survival, lower birth weights, anderror. None of the reported overdoses was associated with a fatal outcome. There Prevention orantihypertensive drug in accordance with its approvedbirth defect, loss, or other adverse outcomes. In the U.S. general population, thedecreased pup body weight gains were observed at 100 mg/kg/day, which is 188was a reported ingestion of 11 tablets of LYBALVI 10 mg/10 mg (5.5 times and 11 Management: product labeling. estimated background risk of major birth defects and miscarriage in clinicallytimes the MRHD based on AUC. The NOAEL of 30 mg/kg/day is approximatelytimes the maximum recommended daily dosage of the olanzapine and samidorphan recognized pregnancies is 2 to 4% and 15 to 20%, respectively.36 times the MRHD based on AUC. There were no adverse effects on pupcomponents of LYBALVI, respectively). The patient was found unresponsive and Levodopa and Dopamine Agonists Clinical Considerations developmental landmarks, learning, memory, reflexes, or fertility. admitted to the hospital. Medical treatment included fluids, electrolytes, a diuretic, ClinicalLYBALVI may antagonize the effects of levodopa andDisease-Associated Maternal and/or Embryofetal RiskLactation and a detoxicant; the patient stabilized within 2 days. Implication: dopamine agonists. There is risk to the mother from untreated schizophrenia or bipolar I disorder,In postmarketing reports of overdose with olanzapine, a component of LYBALVI, including increased risk of relapse, hospitalization and suicide. SchizophreniaRisk Summary: Olanzapine is present in human milk. There are reports of excesssymptoms included agitation/aggressiveness, dysarthria, tachycardia, various Prevention orConcomitant use of LYBALVI is not recommended withand bipolar I disorder are associated with increased adverse perinatal outcomes,sedation, irritability, poor feeding and extrapyramidal symptoms (tremors andextrapyramidal symptoms, and reduced level of consciousness ranging from Management: levodopa and dopamine agonists. including preterm birth. It is not known if this is a direct result of the illness or otherabnormal muscle movements) in infants exposed to olanzapine through breastsedation to coma. Less commonly reported symptoms include: aspiration, comorbid factors. milk. There is no information on the effects of olanzapine on milk production. Therecardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia are no data on the presence of samidorphan or the combination of olanzapineand 1 patient experiencing sinus pause with spontaneous resumption of normal Opioids: LYBALVI is contraindicated in patients who are using opioids orFetal/Neonatal Risks and samidorphan in human milk, the effects on the breastfed infant or the effectsrhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/undergoing acute opioid withdrawal.Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia,on milk production. When samidorphan was administered to lactating rats,arrest, convulsion, hypertension, and hypotension. In 1 case of death, the amount LYBALVI increases the risk of precipitating acute opioid withdrawal in patients whohypotonia, tremor, somnolence, respiratory distress and feeding disorder havesamidorphan and a metabolite were detected in the plasma of nursing pups, likelyof acutely ingested olanzapine was reported to be possibly as low as 450 mg; are dependent on opioids. Prior to initiating LYBALVI, there should be at least abeen reported in neonates who were exposed to antipsychotic drugs, includingdue to the presence of samidorphan in milk. Infants exposed to LYBALVI shouldhowever, in another case, a patient was reported to survive an acute olanzapine 7-day opioid-free interval from the last use of short-acting opioids, and at least athe olanzapine component of LYBALVI, during the third trimester of pregnancy.be monitored for excess sedation, irritability, poor feeding and extrapyramidalingestion of approximately 2,000 mg.14-day opioid-free interval from the last use of long-acting opioids.These symptoms have varied in severity. Monitor neonates for extrapyramidal and/ symptoms (tremors and abnormal muscle movements).Management of Overdose: No specific antidotes for LYBALVI are known. In In emergency situations, if a LYBALVI-treated patient requires opioid treatment foror withdrawal symptoms and manage symptoms appropriately. Some neonatesThe development and health benefits of breastfeeding should be considered alongmanaging overdose, provide supportive care, including close medical supervision anesthesia or analgesia, discontinue LYBALVI. The opioid should be administeredrecovered within hours or days without specific treatment; others requiredwith the mothers clinical need for LYBALVI and any potential adverse effects on theand monitoring, and consider the possibility of multiple drug involvement. If an by properly trained individual(s), and the patient should be properly monitored in aprolonged hospitalization. breastfed infant from LYBALVI or from the underlying maternal condition. overdose occurs, consult a certified Poison Control Center (1-800-222-1222) for setting equipped and staffed for cardiopulmonary resuscitation.Data Females and Males of Reproductive Potentialadditional overdosage management recommendations.In non-emergency situations, if a LYBALVI-treated patient is expected to requireHuman DataInfertility To report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. atopioid treatment (e.g., for analgesia during or after an elective surgical procedure)Published data from observational studies, birth registries, and case reports on theFemales1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. discontinue LYBALVI at least 5 days before opioid treatment and start olanzapine oruse of atypical antipsychotics during pregnancy do not report a clear associationBased on the pharmacologic action of olanzapine (D2 antagonism), treatment withPATIENT COUNSELING INFORMATIONanother antipsychotic, if needed.with antipsychotics and major birth defects. A retrospective cohort study from aLYBALVI may result in an increase in serum prolactin levels, which may lead to aAdvise the patient to read the FDA-approved patient labeling (Medication Guide).Given that LYBALVI contains samidorphan, an opioid antagonist, opioid treatmentMedicaid database of 9258 women exposed to antipsychotics during pregnancy didreversible reduction in fertility in females of reproductive potential.may be less effective or ineffective shortly after LYBALVI discontinuation becausenot indicate an overall increased risk for major birth defects. This Brief Summary is based on LYBALVI full Prescribing Informationof the presence of samidorphan.Animal Data Pediatric Use: The safety and effectiveness of LYBALVI have not been established in(revised: May 2021).USE IN SPECIFIC POPULATIONS LYBALVIpediatric patients.Distributed by:Pregnancy Olanzapine and samidorphan were orally administered to pregnant ratsGeriatric Use: Clinical studies of LYBALVI did not include sufficient numbers ofAlkermes, Inc.during the period of organogenesis at doses of 0.5/10, 2/50, 6/200, andpatients 65 years of age and older to determine whether they responded differently852 Winter StreetPregnancy Exposure Registry: There is a pregnancy exposure registry that monitors0/200 mg/kg/day (olanzapine/samidorphan) which are approximately 1/10than younger adult patients. Waltham, MA 02451-1420pregnancy outcomes in women exposed to atypical antipsychotics, includingtimes to 6/448 times the MRHD of 20 mg/10 mg, olanzapine/samidorphan,Olanzapine: Of the 2,500 patients in premarketing clinical studies with orally LYBALVI, during pregnancy. Healthcare providers are encouraged to registerrespectively, based on AUC. Maternal toxicity consisting of decreased bodyadministered olanzapine, 11% (263) were 65 years of age or over. Elderly patients patients by contacting the National Pregnancy Registry for Atypical Antipsychoticsweight and food consumption was observed at all dose levels. Administrationwith dementia-related psychosis treated with antipsychotic drugs are at an at 1-866-961-2388 or visit https://womensmentalhealth.org/research/ of samidorphan alone (200 mg/kg/day) and 6/200 mg/kg/day olanzapine/ increased risk of death. LYBALVI is not approved for the treatment of patients with2021 Alkermes, Inc. All rights reserved. LYB-001755 Printed in the U.S.A.pregnancyregistry/atypicalantipsychotic/. samidorphan decreased mean fetal body weights, increased litter incidence ofdementia-related psychosis.ALKERMES is a registered trademark of Alkermes, Inc. andRisk Summary: Neonates exposed to antipsychotic drugs, including the olanzapinebent ribs and bent scapula; however, the incidence of bent scapula and bent ribsStudies in elderly patients with dementia-related psychosis have suggested thatLYBALVI is a registered trademark used by Alkermes, Inc., under license. component of LYBALVI, during the third trimester are at risk for extrapyramidal and/ was not increased when samidorphan was administered in combination withthere may be a different tolerability profile in this population compared to younger or withdrawal symptoms following delivery. Overall published epidemiologic studiesolanzapine compared to the incidence with samidorphan alone. Administrationpatients with schizophrenia. Elderly patients with dementia-related psychosis of pregnant women exposed to olanzapine have not established a drug-associatedof olanzapine/samidorphan at 6/200 mg/kg/day also increased resorptions andtreated with olanzapine are at an increased risk of death compared to placebo. risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.post-implantation loss, with correlating lower mean viable fetuses and litter size. I n placebo-controlled studies of olanzapine in elderly patients with dementia-There are no available data on the use of samidorphan or the combination ofThe no observed adverse effect level (NOAEL) for embryofetal development isrelated psychosis, there was a higher incidence of cerebrovascular adverse olanzapine and samidorphan in pregnant women to determine a drug-associated2/50 mg/kg/day, which is approximately 1/80 times the MRHD of 20 mg/10 mgevents (e.g., stroke, transient ischemic attack) in patients treated with risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.olanzapine/samidorphan respectively, based on AUC. olanzapine, compared to patients treated with placebo. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including LYBALVI, during pregnancy. In five placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1,184), the following adverse reactions werereported in olanzapine-treated patients at an incidence of at least 2% and'