b'5Monitor orthostatic vital signs in patients who are vulnerable to hypotension (e.g.,In the 4-week placebo-controlled trial, shifts from normal to high prolactin valuesthe 2 highest serum concentrations was 15.0 mg/dL. Hyperglycemia, as defined bypatients and in those treated with the active control: any extrapyramidal symptom elderly patients, patients with dehydration, hypovolemia, concomitant treatment(30 ng/mL for females; 20 ng/mL for males) occurred in 41.4% of females fasting glucose 126 mg/dL, has been observed in patients treated with LYBALVI. was 8%, akathisia was 3%.with antihypertensive medications or CNS depressants, patients with knownand 32.9% of males treated with LYBALVI, in 56.1% of females and 37.1% of In the 4-week placebo-controlled trial in adult patients with schizophrenia, Dystonia: Symptoms of dystonia, (prolonged abnormal contractions of muscle cardiovascular disease (history of myocardial infarction, ischemic heart disease,males treated with olanzapine, and in 10% of females and 4.8% of males treatedshifts in fasting glucose from normal to high occurred in 4% of patients treated groups) may occur in susceptible individuals during the first few days of treatment. heart failure, or conduction abnormalities), and patients with cerebrovascularwith placebo. with LYBALVI, 1% of patients treated with olanzapine, and no patients treated Dystonic symptoms include: spasm of the neck muscles, sometimes progressing todisease. LYBALVI has not been evaluated in patients with a recent history ofIn the 24-week, olanzapine-controlled study, shifts from normal to high prolactinwith placebo.tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion myocardial infarction or unstable cardiovascular disease. Such patients werevalues occurred in 32.9% of females and 22.5% of males treated with LYBALVI,In the 24-week olanzapine-controlled trial, patients treated with LYBALVI wereof the tongue. Although these symptoms can occur at low doses, they occurexcluded from the premarketing clinical trials. and in 41.7% of females and 28.5% of males treated with olanzapine. more likely to experience abnormal shifts in glycemic parameters than patientsmore frequently and with greater severity with high potency and at higher doses of Falls: Antipsychotics, including LYBALVI, may cause somnolence, posturalRisks Associated with Combination Treatment with Lithium or Valproate: treated with olanzapine (Table 2). first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed hypotension, motor and sensory instability, which may lead to falls and,If LYBALVI is administered with lithium or valproate, refer to the lithium or valproateTable 2:Changes in Glycemic Parameters in a 24-Week Trial of Patientsin males and younger age groups.consequently, fractures or other injuries. For patients with diseases, conditions,Prescribing Information for a description of the risks for these products including,with SchizophreniaAdverse Reactions in Patients with Bipolar Disorder: The safety of LYBALVI for or medications that could exacerbate these effects, complete fall riskbut not limited to, the warnings and precautions for lithium or valproate. the treatment of bipolar I disorder (mixed or manic) monotherapy and adjunct to assessments when initiating antipsychotic treatment and recurrently for patientsADVERSE REACTIONS LYBALVI Olanzapine lithium or valproate relies on information from adequate and well-controlled studies on long-term antipsychotic therapy. Clinical Studies Experience: Because clinical trials are conducted under widelyProportion of Patients with Shifts, % (n/N)* of olanzapine tablets in bipolar I disorder. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropeniavarying conditions, adverse reaction rates observed in clinical trials of a drugThe most common adverse reactions (incidence of at least 5% of patientshave been reported during treatment with antipsychotic agents, including LYBALVI.cannot be directly compared to rates in the clinical trials of another drug and mayGlucoseexposed to olanzapine and greater than or equal to twice the rate of placebo)Agranulocytosis (including fatal cases) has been reported with other agents in not reflect the rates observed in clinical practice. Normal to High (100 mg/dL12 (26/223)8 (18/219)from short-term trials of olanzapine (manic or mixed episodes) are somnolence,this class.Adverse Reactions in Patients with Schizophrenia: to 126 mg/dL)dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite,Possible risk factors for leukopenia and neutropenia include pre-existing low whiteImpaired (100 mg/dL andand tremor. blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug- Patient Exposure The most common adverse reactions (incidence of at least 5% of patients induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANCThe safety of LYBALVI was evaluated in 1262 patients (18 to 67 years of age)126 mg/dL) to High (12624 (9/38)11 (5/47) mg/dL)exposed to olanzapine and greater than or equal to twice the rate of placebo) from or a history of drug-induced leukopenia or neutropenia, perform a complete blooddiagnosed with schizophrenia in four double-blind, controlled studies and threeshort-term trials of olanzapine as adjunct to lithium or valproate (manic or mixed count (CBC) frequently during the first few months of therapy. In such patients,long-term safety extension studies of up to 3 years of duration. This experienceIncrease 10 mg/dL66 (174/265)57 (154/270)episodes) are dry mouth, weight gain, increased appetite, dizziness, back pain, consider discontinuation of LYBALVI at the first sign of a clinically significant declinecorresponds to approximately 910 person-years. In these studies, there were a totalconstipation, speech disorder, increased salivation, amnesia, paresthesia.in WBC in the absence of other causative factors.of 663 patients exposed to LYBALVI for at least 6 months, and 386 patients for atHemoglobin A1cPostmarketing Experience: The following adverse reactions have been identified Monitor patients with clinically significant neutropenia for fever or other symptomsleast one year. Normal (5.7%) to Impaired 42 (86/204)35 (68/197) (5.7% and 6.5%) during post-approval use of olanzapine. Because these reactions are reported or signs of infection and treat promptly if such symptoms or signs occur.Adverse Reactions in the Short-Term (4 week) Placebo-Controlled Trial in Adults withvoluntarily from a population of uncertain size, it is difficult to reliably estimate their Discontinue LYBALVI in patients with severe neutropenia (absolute neutrophil countSchizophrenia Normal to High frequency or evaluate a causal relationship to drug exposure. 1000/mm3) and follow their WBC until recovery. The most common adverse reactions (incidence of at least 5% of patients exposed(5.7% to 6.5%)0.5 (1/204)1.5 (3/197) allergic reactions (e.g., anaphylactoid reaction, angioedema, pruritus or Dysphagia: Esophageal dysmotility and aspiration have been associated withto LYBALVI and greater than twice the rate of placebo) are weight increased,Impaired (5.7% and 6.5%)urticaria) antipsychotic drug use. Antipsychotic drugs, including LYBALVI, should be usedsomnolence, dry mouth, and headache.to High (6.5%) 9.5 (6/63) 9.2 (7/76) cholestatic or mixed liver injury, hepatitis, jaundice cautiously in patients at risk for aspiration. Adverse reactions associated with the use of LYBALVI (incidence of 2% or greater Seizures: Like other antipsychotic drugs, LYBALVI may cause seizures. This riskand greater than in placebo-treated patients) are shown in Table 1. * n: number of patients with reported abnormal shifts; N: number of patients who haddiabetic coma, diabetic ketoacidosis is greatest in patients with a history of seizures or with conditions that lowerTable 1: Adverse Reactions Reported in 2% of LYBALVI-Treated Patients assessments at both baseline and endpoint for mean change, or normal at baseline and at leastdiscontinuation reaction (diaphoresis, nausea or vomiting)the seizure threshold. Conditions that lower the seizure threshold may be moreand Greater than Placebo in a 4-Week Schizophrenia Trial 1 post-baseline assessment for shift. Drug reaction with eosinophilia and systemic symptoms (DRESS) prevalent in older patients. Dyslipidemia: In the 4-week, placebo-controlled trial in adult patients with h yperlipidemia (random cholesterol levels of 240 mg/dL and random Potential for Cognitive and Motor Impairment: LYBALVI, like otherPlacebo LYBALVI schizophrenia, shifts in fasting triglycerides from normal to high occurred in 14% oftriglyceride levels of 1000 mg/dL have been reported)antipsychotics, may cause somnolence and has the potential to impair judgment,Adverse Reaction (N=134) % (10 mg/10 mg, 20 mg/10 mg)patients treated with LYBALVI and 4% of patients treated with placebo. n eutropenia thinking, or motor skills. In a LYBALVI placebo-controlled study, somnolence(N=134) % In the 24-week olanzapine-controlled study, mean changes in fasting total pancreatitis occurred in 9% of LYBALVI-treated patients compared to 2.2% in patients treatedWeight increased 3 19 cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were similar in with placebo.patients treated with LYBALVI and in patients treated with olanzapine. p riapism Patients should be cautioned about operating hazardous machinery, includingSomnolence 2 9 Weight Gain: In the 4-week placebo-controlled study in adult patients with r ash motor vehicles, until they are reasonably certain that LYBALVI therapy does notDry mouth 1 7 schizophrenia, mean changes in weight, and proportion of patients with 7%restless legs syndrome affect them adversely. weight increase, were greater in patients treated with LYBALVI and olanzapine r habdomyolysis Body Temperature Dysregulation: Atypical antipsychotics may disrupt the bodysHeadache 3 6 than in patients on placebo. In that study, mean weight gain was 3.0 kg in patients s alivary hypersecretionability to reduce core body temperature. Strenuous exercise, exposure to extremeBlood insulintreated with LYBALVI, 2.4 kg in patients treated with olanzapine, and 0.2 kg in s tuttering1heat, dehydration, and anticholinergic medications may contribute to an elevation inincreased 1 3 patients treated with placebo. The proportion of patients with 7% weight increase core body temperature; use LYBALVI with caution in patients who may experiencewas 26% in patients treated with LYBALVI, 20% in patients treated with olanzapine,venous thromboembolic events (including pulmonary embolism and deepthese conditions. Sedation 0 2 and 5% in patients treated with placebo.venous thrombosis) Anticholinergic (Antimuscarinic) Effects: Olanzapine, a component of LYBALVI,Dizziness 1 2 In the 24-week trial, LYBALVI-treated patients gained on average 4.2% of baseline1 Stuttering was only studied in oral and long-acting injection (LAI) formulations.exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials withbody weight. The proportion of patients treated with LYBALVI with 10% body oral olanzapine, olanzapine was associated with constipation, dry mouth, andNeutrophil count0 2 weight gain was 17.8%. DRUG INTERACTIONStachycardia, all adverse reactions possibly related to cholinergic antagonism. Suchdecreased Extrapyramidal Symptoms: In the 4-week placebo-controlled trial in adult patientsEffects of Other Drugs on LYBALVI: Table 3 describes clinically significant drug adverse reactions were not often the basis for discontinuations, but LYBALVI shouldwith schizophrenia, patients were assessed using the Simpson-Angus Rating Scaleinteractions where the concomitant use of other drugs affects LYBALVI.be used with caution in patients with a current diagnosis or prior history of urinaryAdverse reactions that led to discontinuation in LYBALVI-treated patients in(SAS) for extrapyramidal symptoms (EPS) (total score ranges from 1 to 14), theTable 3: E ffects of Other Drugs on LYBALVIretention, clinically significant prostatic hypertrophy, constipation, or a historythe short-term placebo-controlled trial in adults with schizophrenia includeBarnes Akathisia Rating Scale (BARS) for akathisia (total score ranges from 0 to of paralytic ileus or related conditions. In postmarketing experience, the risk forschizophrenia (1%) and abnormal liver function tests (1%). 14), and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias (totalStrong CYP3A4 Inducer severe adverse reactions (including fatalities) was increased with concomitant useAdverse Reactions in the Long-Term (24-week), Active-Controlled Trial in Adults score ranges from 0 to 28). The mean changes from baseline to last study visit forCoadministration of LYBALVI with a strong CYP3A4 inducer of anticholinergic medications. with Schizophrenia the SAS, BARS, and AIMS was similar in LYBALVI-treated patients and in placebo- Clinicaldecreases AUC infof olanzapine and samidorphan which may Hyperprolactinemia: As with other drugs that antagonize dopamine D 2receptors,In the 24-week, olanzapine-controlled trial in patients with stable schizophrenia,treated patients. The mean changes for LYBALVI- vs placebo-treated patients wereImplication: reduce LYBALVI efficacy. olanzapine, a component of LYBALVI, elevates prolactin levels, and the elevationadverse reactions associated with the use of LYBALVI (incidence of 2% or greater)0.00 vs -0.2 for AIMS, 0.0 vs -0.1 for BARS, and 0.0 vs -0.3 for SAS, respectively. can persist during chronic administration. Hyperprolactinemia may suppressinclude: weight increased (25%), somnolence (21%), dry mouth (13%), increasedThe rate of parkinsonism (SAS total score 3) was lower in patients treated withPrevention orConcomitant use of LYBALVI with strong CYP3A4 inducers is hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This,appetite (11%), waist circumference increased (6%), blood creatine phosphokinaseLYBALVI (4%) compared to those on placebo (10%). The rates of akathisia (BARSManagement: not recommended. in turn, may inhibit reproductive function by impairing gonadal steroidogenesisincreased (5%), headache (4%), lethargy (4%), sedation (4%), akathisia (3%),global clinical assessment score 2) and dyskinesia (AIMS score 3 on any of the in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, andfirst 7 items, or a score 2 on two or more of any of the first 7 items) were similarStrong CYP1A2 Inhibitor impotence have been reported in patients receiving prolactin-elevating compounds.alanine aminotransferase increased (3%), aspartate aminotransferase increasedin patients treated with LYBALVI and in those on placebo. Rates of akathisia were Long-standing hyperprolactinemia when associated with hypogonadism may lead(3%), constipation (3%), dizziness (3%), fatigue (3%), nausea (3%), blood pressure6.0% and 8.2% in patients treated with LYBALVI and placebo, respectively, and ClinicalConcomitant use of LYBALVI with a strong CYP1A2 inhibitor to decreased bone density in both female and male subjects.increased (3%), neutrophil count decreased (3%), blood insulin increased (2%),the rate of dyskinesia was 1.5% both in LYBALVI-treated and in Implication: increases olanzapine AUC and C max , which may increase risk Tissue culture experiments indicate that approximately one-third of human breastweight decreased (2%), and dyslipidemia (2%).placebo-treated patients.of LYBALVI adverse reactions.cancers are prolactin-dependent in vitro, a factor of potential importance if theAdverse reactions that led to LYBALVI treatment discontinuation in more thanThe frequency of reported adverse reactions related to extrapyramidal symptoms,Consider reducing the dosage of the olanzapine component in prescription of these drugs is considered in a patient with previously-detectedone patient include somnolence (2%), weight increased (2%), neutropenia (2%),including akathisia, restlessness, muscle spasms, bradykinesia, tremor,Prevention orLYBALVI when used concomitantly with strongbreast cancer. As is common with compounds which increase prolactin release,glycosylated hemoglobin increased (1%), schizophrenia (1%), and liver function extrapyramidal disorder, and parkinsonism was 2% both in LYBALVI-treated and inManagement: CYP1A2 inhibitors.an increase in mammary gland neoplasia was observed in the olanzapinetest abnormal (1%). placebo-treated patients. carcinogenicity studies conducted in mice and rats. Neither clinical studies norHyperglycemia: Mean increases in blood glucose have been observed in patientsCYP1A2 Inducer In the 24-week active-controlled trial, the mean change from baseline to the last epidemiologic studies conducted to date have shown an association betweentreated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinicalvisit for the SAS, BARS, and AIMS was similar in LYBALVI-treated patients and inClinicalConcomitant use of LYBALVI with CYP1A2 inducers decreases chronic administration of this class of drugs and tumorigenesis in humans, but theAntipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase ofthose treated with the active control. Extrapyramidal adverse reactions, includingImplication: olanzapine exposure, which may reduce LYBALVI efficacy. available evidence is too limited to be conclusive.serum glucose (fasting and nonfasting samples) from baseline to the average ofparkinsonism, akathisia, and dyskinesia, had a similar incidence in LYBALVI-treated'