olanzapine/samidorphan (Rx)

Brand and Other Names:Lybalvi
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

olanzapine/samidorphan

tablet

  • 5mg/10mg
  • 10mg/10mg
  • 15mg/10mg
  • 20mg/10mg

Schizophrenia

Indicated for treatment of schizophrenia in adults

Initial dose: Olanzapine 5 mg/samidorphan 10 mg OR olanzapine 10 mg/samidorphan 10 mg PO qDay

Maintenance dose: May adjust dosage at weekly intervals of 5 mg (based on the olanzapine component) depending on clinical response and tolerability; not to exceed olanzapine 20 mg/samidorphan 10 mg qDay

Bipolar I disorder

Adjunctive to lithium or valproate

  • Indicated for acute treatment of manic or mixed episodes as an adjunct to lithium or valproate in adults with bipolar I disorder
  • Initial dose: 1 tablet (olanzapine 10 mg/samidorphan 10 mg) PO qDay
  • Maintenance dose: May adjust dosage at weekly intervals of 5 mg (based on the olanzapine component) depending on clinical response and tolerability; not to exceed olanzapine 20 mg/samidorphan 10 mg qDay

Monotherapy

  • Indicated for acute treatment of manic or mixed episodes as monotherapy and maintenance monotherapy in adults with bipolar I disorder
  • Initial dose: Olanzapine 10 mg/samidorphan 10 mg OR olanzapine 15mg/samidorphan 10 mg PO qDay
  • Adjust dose in increments/decrements of 5 mg (based on olanzapine component), if necessary, at intervals ≥24 hr; not to exceed olanzapine 20 mg/samidorphan 10 mg qDay
  • Maintenance monotherapy: Not to exceed olanzapine 20 mg/samidorphan 10 mg qDay

Dosage Modifications

Hypotensive patients

  • Patients who have a higher risk of hypotensive reactions, are at risk of slower olanzapine metabolism, or may be more pharmacodynamically sensitive to olanzapine
  • If dose escalation is necessary, increase dose slowly

Renal impairment

  • Mild-to-severe (eGFR 15-89 mL/min/1.73 m2): No dosage adjustment necessary
  • Severe (eGFR 15 to 29 mL/minute/1.73 m2): Plasma exposure to olanzapine and samidorphan was higher compared with patients with normal renal function
  • End-stage renal disease (eGFR <15 mL/min/1.73 m2): Not studied; not recommended

Hepatic impairment

  • No dosage adjustment necessary
  • Moderate: Olanzapine and samidorphan plasma exposures were found to be higher compared with patients with normal hepatic function, but not clinically relevant
  • Severe: Not studied

Dosing Considerations

Initiation in patients using opioids

  • Contraindicated in patients using opioids or undergoing acute opioid withdrawal
  • Delay initiation if currently using opioids
    • Short-acting opioids: At least for 7 days after last opioid use
    • Long-acting opioids : At least for 14 days after last opioid use

Safety and efficacy not established

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Interactions

Interaction Checker

and olanzapine/samidorphan

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Schizophrenia

            • Glucose levels increase >10 mg/dL (66%)
            • Shift from hemoglobin (Hgb) A1c normal (<5.7%) to impaired (≥5.7 to < 6.5%) (42%)
            • Weight increased (19-25%)
            • Somnolence (21%)
            • Shifts in fasting triglycerides from normal to high (14%)
            • Increased appetite (11%)

            1-10%

            Schizophrenia

            • Shift from Hgb A1c impaired (≥5.7 to < 6.5%) to high (≥6.5%) (9.5%)
            • Somnolence (9%)
            • Dry mouth (7%)
            • Waist circumference increased (6%)
            • Headache (4-6%)
            • Blood creatine phosphokinase increased (5%)
            • Lethargy (4%)
            • Sedation (2-4%)
            • Dizziness (2-3%)
            • Akathisia (3%)
            • ALT increased (3%)
            • AST increased (3%)
            • Constipation (3%)
            • Fatigue (3%)
            • Nausea (3%)
            • Blood pressure (BP) increased (3%)
            • Neutrophil count decreased (2-3%)
            • Blood insulin increased (2-3%)
            • Weight decreased (2%)
            • Dyslipidemia (2%)
            • Schizophrenia (1%)
            • Abnormal liver function tests (1%)

            <1%

            Schizophrenia

            • Shift from Hgb A1c normal (<5.76%) to high (≥6.5%) (0.5%)

            Frequency Not Defined

            Schizophrenia

            • Dystonia symptoms including spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue

            Bipolar I disorder (monotherapy)

            ** Relies on studies of olanzapine tablets I bipolar I disorder**

            • Somnolence
            • Dry mouth
            • Dizziness
            • Asthenia
            • Constipation
            • Dyspepsia
            • Increased appetite
            • Tremor

            Bipolar I disorder (adjunctive therapy)

            ** Relies on studies of olanzapine tablets I bipolar I disorder**

            • Dry mouth
            • Weight gain
            • Increased appetite
            • Dizziness
            • Back pain
            • Constipation
            • Speech disorder
            • Increased salivation
            • Amnesia
            • Paresthesia

            Postmarketing Reports

            Allergic reactions (eg, anaphylactoid reaction, angioedema, pruritus or urticaria)

            Cholestatic or mixed liver injury, hepatitis, jaundice

            Diabetic coma, diabetic ketoacidosis

            Discontinuation reaction (diaphoresis, nausea, or vomiting)

            Drug reaction with eosinophilia and systemic symptoms (DRESS)

            Hyperlipidemia (random cholesterol levels ≥240 mg/dL and random triglyceride levels ≥1000 mg/dL reported)

            Neutropenia

            Pancreatitis

            Priapism

            Rash

            Restless legs syndrome

            Rhabdomyolysis

            Salivary hypersecretion

            Stuttering

            Venous thromboembolic events (including pulmonary embolism and deep venous thrombosis)

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            Warnings

            Black Box Warnings

            Increased mortality in elderly patients with dementia-related psychosis

            • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death
            • Not approved for treatment of patients with dementia-related psychosis

            Contraindications

            Patients using opioids

            Patients undergoing acute opioid withdrawal

            If administered with lithium or valproate, refer to lithium or valproate prescribing information for contraindications for these products

            Cautions

            Significantly greater increase of death reported in elderly patients with dementia-related psychosis treated with olanzapine; majority of deaths were either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia)

            Cerebrovascular adverse reactions (eg, stroke, transient ischemic attack), including fatalities, reported in olanzapine trials in elderly patients with dementia-related psychosis

            DRESS reported with exposure to olanzapine; may present with a cutaneous reaction (eg, rash, exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications (eg, hepatitis, nephritis, pneumonitis, myocarditis, pericarditis); discontinue treatment if DRESS is suspected

            Antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, fractures, or other injuries; complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

            Olanzapine was associated with constipation, dry mouth, and tachycardia, and all adverse reactions related to cholinergic antagonism; use with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related condition

            Atypical antipsychotics may disrupt the ability to reduce core body temperature; strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use with caution in patients who may experience these conditions

            May cause somnolence and has the potential to impair judgment, thinking, or motor skills; advise patients to exercise caution when operating hazardous machinery, including motor vehicles

            May cause seizures; use caution in patients with a history of seizures or with conditions that lower the seizure threshold

            Esophageal dysmotility and aspiration have been associated with antipsychotic drug use; use with caution in patients at risk for aspiration

            Refer to lithium or valproate prescribing information for a description of the risks for these products if used

            Hyperprolactinemia

            • Olanzapine elevates prolactin levels and elevation can persist during long-term administration
            • Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone, resulting in reduced pituitary gonadotropin secretion; may inhibit reproductive function by impairing gonadal steroidogenesis in both females and males
            • Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported
            • Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both females and males

            Tardive dyskinesia

            • Tardive dyskinesia may develop in patients treated with antipsychotic drugs; elderly patients appear to be at highest risk
            • Prescribe in a manner that is most likely to reduce the risk of tardive dyskinesia.
            • Reserve long-term antipsychotic treatment for patients
              • Who have a chronic illness that is responsive to antipsychotic drugs
              • For whom alternative, effective, but potentially less harmful treatments are unavailable or inappropriate
            • If long-term treatment is necessary, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response; periodically reassess the need to continue treatment
            • If signs and symptoms of tardive dyskinesia appear, consider discontinuation

            Opioids

            • Contraindicated
            • Olanzapine/samidorphan increases the risk of precipitation of acute opioid withdrawal in patients who are opioid-dependent
            • Emergency situations: If treated patient requires opioid treatment for anesthesia or analgesia, discontinue olanzapine/samidorphan; opioid should be administered by properly trained individual(s), and properly monitor patient in a setting equipped and staffed for cardiopulmonary resuscitation
            • Nonemergency situations: If treated patient is expected to require opioid treatment (eg, for analgesia during or after an elective surgical procedure), discontinue olanzapine/samidorphan at least 5 days before opioid treatment and start olanzapine or another antipsychotic, if needed
            • Samidorphan is an opioid antagonist; opioid treatment may be less effective or ineffective shortly after discontinuing olanzapine/samidorphan
            • Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers
            • Patients with a history of long-term opioid use before treatment with olanzapine/samidorphan have decreased opioid tolerance if therapy is interrupted or discontinued
            • Advise that decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage

            Neuroleptic malignant syndrome (NMS)

            • NMS reported in association with administration of antipsychotic drugs
            • Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability
            • Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure
            • If NMS is suspected, immediately discontinue therapy, provide intensive symptomatic treatment, and monitor

            Metabolic changes

            • Atypical antipsychotic drugs have been associated with metabolic changes that include 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
            • Monitor for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness
            • Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose (FBG) testing
            • Hyperglycemia may resolve once the atypical antipsychotic is discontinued; however, some patients required antidiabetic treatment despite discontinuation
            • Test FBG and fasting lipid profile at the beginning of treatment and periodically during treatment
            • Monitor weight prior to initiation and frequently thereafter

            Leukopenia, neutropenia, and agranulocytosis

            • Leukopenia and neutropenia reported during treatment
            • Agranulocytosis (including fatal cases) has been reported with other agents in this class
            • Possible risk factors for leukopenia and neutropenia include preexisting low white blood cell (WBC) count or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia
            • Perform a complete blood cell count frequently during the first few months of therapy
            • Consider discontinuation at the first sign of a clinically significant decline in WBC count in the absence of other causative factors
            • Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur
            • Discontinue therapy in patients with severe neutropenia (ANC <1000/mm3) and follow their WBC count until recovery

            Drug interaction overview

            • Strong CYP3A4 inducers
              • Not recommended
              • Strong CYP3A4 inducers decrease AUC and efficacy of olanzapine/samidorphan
            • Strong CYP1A2 inhibitors
              • Consider dosage reduction of olanzapine component
              • Strong CYP1A2 inhibitors increase olanzapine plasma concentrations and risk of adverse reactions of olanzapine/samidorphan
            • CYP1A2 inducers
              • Consider dosage increase of olanzapine component
              • Strong CYP1A2 inducers decrease effects of olanzapine and efficacy of olanzapine/samidorphan
            • CNS acting drugs
              • Use with caution
              • Diazepam, alcohol, or other CNS-acting drugs may potentiate the orthostatic hypotension observed with olanzapine
            • Anticholinergic drugs
              • Use with caution
              • Olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility
            • Antihypertensive agents
              • Monitor BP and reduce dosage of antihypertensive drug in accordance with its prescribing information
              • Olanzapine/samidorphan may enhance the effects of certain antihypertensive agents
            • Levodopa and dopamine agonists
              • Not recommended
              • Olanzapine/samidorphan may antagonize the effects of levodopa and dopamine agonists
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            Pregnancy & Lactation

            Pregnancy

            No data are available on use of samidorphan or olanzapine/samidorphan in pregnant females to determine drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Olanzapine

            • Neonates exposed to antipsychotic drugs, including olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery
            • Overall published epidemiologic studies of pregnant females exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Pregnancy exposure registry

            Infertility

            • Based on the pharmacologic action of olanzapine (D2 antagonism), an increase in serum prolactin levels may occur, which may lead to a reversible reduction in fertility in females of reproductive potential

            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
              • Unknown if a direct result of the illness or other comorbid factors
            • Fetal or 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, during the third trimester of pregnancy; symptoms vary 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

            Animal data

            • Oral administration of olanzapine and samidorphan to pregnant rats during organogenesis produced adverse effects on embryofetal development and fetal toxicity at maternally toxic doses that are 6x and >400x the maximum recommended human dose (MRHD) of olanzapine 20mg/samidorphan 10mg, respectively based on AUC
            • Olanzapine
              • Early resorptions and increased numbers of nonviable fetuses were observed at a dose 9x the MRHD based on mg/m2 body surface area (BSA) and gestation was prolonged at 5x the MRHD based on mg/m2 BSA
              • Fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of olanzapine, which is 30x the MRHD based on mg/m2 BSA
            • Samidorphan
              • Oral administration of samidorphan to pregnant rats and rabbits during organogenesis caused fetal toxicities in rats only at maternally toxic doses that are >248x 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 188x the human exposure at the MRHD based on AUC

            Lactation

            Olanzapine

            • 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

            Samidorphan

            • There are no data on the presence of samidorphan or olanzapine/samidorphan in human milk, effects on breastfed infants, or effects on milk production
            • When administered to lactating rats, samidorphan and a metabolite were detected in the plasma of nursing pups, likely due to the presence of samidorphan in milk
            • Monitor infants exposed to olanzapine/samidorphan for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements)

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Olanzapine: May act through combination of dopamine and serotonin type 2 receptor site antagonism

            Samidorphan: Opioid antagonist; mitigates weight gain associated with olanzapine

            Absorption

            Steady-state exposure (olanzapine20 mg/samidorphan 10mg)

            Peak plasma concentration

            • Olanzapine: 64.6 ng/mL
            • Samidorphan: 45.1 ng/mL

            Peak plasma time

            • Olanzapine: 4.5-7 hr
            • Samidorphan: 1-2 hr

            AUC

            • Olanzapine: 1,086 ng⋅hr/mL
            • Samidorphan: 364 ng⋅hr/mL

            Time to reach steady-state

            • Olanzapine: 7 days
            • Samidorphan: 5 days

            Accumulation at steady-state

            • Olanzapine: 2-fold
            • Samidorphan: 1.3-fold

            Effect of food

            • High-fat meal: Meal containing ~900-1000 calories and 50% fat content
            • Olanzapine
              • Cmax ratio: 0.88
              • AUC ratio: 0.93
            • Samidorphan
              • Cmax ratio: 0.85
              • AUC ratio: 1.03

            Distribution

            Protein bound

            • Olanzapine: 93%
            • Samidorphan: 23-33%

            Blood-to-plasma

            • Olanzapine: Not determined
            • Samidorphan: 0.8

            Metabolism

            Olanzapine

            • Primary pathways: UGT1A4, CYP1A2
            • Minor pathway: CYP2D6
            • Metabolites: 10-N-glucuronide and 4′-N-desmethyl-olanzapine; both lack pharmacological activity at therapeutic concentrations

            Samidorphan

            • Primary pathway: CYP3A4
            • Minor pathways: CYP3A5, CYP2C19, CYP2C8
            • Metabolites: N-dealkylated and cis-N-oxide metabolites; neither metabolite contributes to the pharmacological effects of samidorphan

            Elimination

            Half-life

            • Olanzapine: 35-52 hr
            • Samidorphan: 7-11 hr

            Clearance

            • Olanzapine: 15-22 L/hr; clearance was ~40% higher in smokers than in nonsmokers
            • Samidorphan: 35-45 L/hr

            Excretion

            • Olanzapine: Urine (57% [7% unchanged]); feces (30%)
            • Samidorphan: Urine (67% [18% unchanged]); feces (16%)
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            Administration

            Oral Administration

            Take with or without food as a single tablet

            Do not divide tablets or combine strengths

            Storage

            Store at room temperature of 20-25ºC (68-77ºF) in original bottle with desiccant; excursions permitted to 15-30ºC (59-86ºF)

            Keep bottle tightly closed and protect from moisture

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.