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OLANZapine

Pronunciation

Pronunciation

(oh LAN za peen)

Index Terms

  • LY170053
  • Olanzapine Pamoate
  • Zyprexa Zydis

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intramuscular:

ZyPREXA: 10 mg (1 ea) [contains tartaric acid]

Generic: 10 mg (1 ea)

Suspension Reconstituted, Intramuscular:

ZyPREXA Relprevv: 210 mg (1 ea); 300 mg (1 ea); 405 mg (1 ea) [contains polysorbate 80]

Tablet, Oral:

ZyPREXA: 2.5 mg, 5 mg, 7.5 mg, 10 mg

ZyPREXA: 15 mg [contains fd&c blue #2 aluminum lake]

ZyPREXA: 20 mg

Generic: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg

Tablet Dispersible, Oral:

ZyPREXA Zydis: 5 mg, 10 mg, 15 mg, 20 mg [contains aspartame, methylparaben sodium, propylparaben sodium]

Generic: 5 mg, 10 mg, 15 mg, 20 mg

Brand Names: U.S.

  • ZyPREXA
  • ZyPREXA Relprevv
  • ZyPREXA Zydis

Pharmacologic Category

  • Antimanic Agent
  • Second Generation (Atypical) Antipsychotic

Pharmacology

Olanzapine is a second generation thienobenzodiazepine antipsychotic which displays potent antagonism of serotonin 5-HT2A and 5-HT2C, dopamine D1-4, histamine H1, and alpha1-adrenergic receptors. Olanzapine shows moderate antagonism of 5-HT3 and muscarinic M1-5 receptors, and weak binding to GABA-A, BZD, and beta-adrenergic receptors. Although the precise mechanism of action in schizophrenia and bipolar disorder is not known, the efficacy of olanzapine is thought to be mediated through combined antagonism of dopamine and serotonin type 2 receptor sites.

Absorption

Oral: Well absorbed; not affected by food; tablets and orally disintegrating tablets are bioequivalent

Short-acting injection: Rapidly absorbed

Distribution

Vd: Extensive, 1000 L

Metabolism

Highly metabolized via direct glucuronidation and cytochrome P450 mediated oxidation (CYP1A2, CYP2D6); 40% removed via first pass metabolism

Excretion

Urine (57%, 7% as unchanged drug); feces (30%)

Clearance: Oral:

Children (10 to 18 years; n=8): Apparent: 9.6 ± 2.4 L/hour (Grothe 2000)

Adults: Apparent: 25 L/hour [12 to 47 L/hour (5th to 95th percentile)]; 40% increase in olanzapine clearance in smokers; 30% decrease in females

Onset of Action

Within 1 to 2 weeks for control of aggression, agitation, insomnia; 3 to 6 weeks for control of mania and positive psychotic symptoms. Adequate trial: Typically 6 weeks at maximum tolerated doses

Time to Peak

Maximum plasma concentrations after IM administration are 5 times higher than maximum plasma concentrations produced by an oral dose.

Extended-release injection: ~7 days

Short-acting injection: 15 to 45 minutes

Oral: Children (10 to 18 years; n=8): 4.7 ± 3.7 hours (Grothe 2000); Adults: ~6 hours

Half-Life Elimination

Oral and IM (short-acting): Children: (10 to 18 years; n=8): 37.2 ± 5.1 hours (Grothe 2000); Adults: 30 hours [21 to 54 hours (5th to 95th percentile)]; approximately 1.5 times greater in elderly

Extended-release injection: ~30 days

Protein Binding

Plasma: 93%, bound to albumin and alpha1-glycoprotein

Special Populations: Elderly

The half-life increases 1.5 times.

Special Populations: Gender

Clearance is approximately 30% lower in women.

Special Populations Note

Cigarette smoking: Clearance is approximately 40% higher in smokers.

Use: Labeled Indications

Oral: Treatment of the manifestations of schizophrenia; treatment of acute or mixed mania episodes associated with bipolar I disorder (as monotherapy or in combination with lithium or valproate); maintenance treatment of bipolar I disorder; in combination with fluoxetine for treatment-resistant or bipolar I depression

IM, extended-release (Zyprexa Relprevv): Treatment of schizophrenia

IM, short-acting (Zyprexa IntraMuscular): Treatment of acute agitation associated with schizophrenia and bipolar I mania

Use: Unlabeled

Treatment of psychosis/schizophrenia in children; prevention of chemotherapy-associated delayed nausea or vomiting; psychosis/agitation related to Alzheimer’s dementia; acute treatment of delirium

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to olanzapine or any component of the formulation

Dosing: Adult

Schizophrenia:

Oral: Initial: 5 to 10 mg once daily (increase to 10 mg once daily within 5 to 7 days); thereafter, adjust by 5 mg daily at 1-week intervals, up to a recommended maximum of 20 mg/day. Maintenance: 10 to 20 mg once daily. Doses up to 60 mg daily have been used in treatment-resistant schizophrenia; however, supporting evidence is limited (APA [Lehman 2004]).

Special risk patients: Initial: 5 mg once daily is recommended in patients who are debilitated, who have a predisposition to hypotensive reactions, who exhibit a combination of factors that may result in slower metabolism of olanzapine (eg, nonsmoking female patients ≥65 years), or who may be more pharmacodynamically sensitive to olanzapine; increase dose with caution as clinically indicated.

Extended-release IM injection: Note: Establish tolerance to oral olanzapine prior to changing to extended-release IM injection. Maximum dose: 300 mg every 2 weeks or 405 mg every 4 weeks

Patients established on oral olanzapine 10 mg daily: Initial dose: 210 mg every 2 weeks for 4 doses or 405 mg every 4 weeks for 2 doses; Maintenance dose: 150 mg every 2 weeks or 300 mg every 4 weeks

Patients established on oral olanzapine 15 mg daily: Initial dose: 300 mg every 2 weeks for 4 doses; Maintenance dose: 210 mg every 2 weeks or 405 mg every 4 weeks

Patients established on oral olanzapine 20 mg daily: Initial and maintenance dose: 300 mg every 2 weeks

Special risk patients: Initial: 150 mg every 4 weeks is recommended in patients who are debilitated, who have a predisposition to hypotensive reactions, who exhibit a combination of factors that may result in slower metabolism of olanzapine (eg, nonsmoking female patients ≥65 years), or who may be more pharmacodynamically sensitive to olanzapine; increase dose with caution as clinically indicated.

Bipolar I (acute mixed or manic episodes: Oral:

Monotherapy: Initial: 10 to 15 mg once daily; increase by 5 mg daily at intervals of not less than 24 hours. Maintenance: 5 to 20 mg daily; recommended maximum dose: 20 mg/day.

Combination therapy (with lithium or valproate): Initial: 10 mg once daily; dosing range: 5 to 20 mg daily

Agitation (acute, associated with bipolar disorder or schizophrenia): Short-acting IM injection: Initial dose: 10 mg (a lower dose of 5 to 7.5 mg may be considered when clinical factors warrant); additional doses (up to 10 mg) may be considered; however, 2 hours after the initial dose and 4 hours after the second dose should be allowed between doses to evaluate response (maximum total dose: 30 mg/day)

Special risk patients: Consider a lower dose of 2.5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, or who may be more pharmacodynamically sensitive to olanzapine.

Depression:

Depression associated with bipolar disorder (in combination with fluoxetine): Oral: Initial: 5 mg in the evening; adjust as tolerated to usual range of 5 to 12.5 mg daily. See "Note."

Treatment-resistant depression (in combination with fluoxetine): Oral: Initial: 5 mg in the evening; adjust as tolerated to range of 5 to 20 mg daily. See "Note."

Note (olanzapine/fluoxetine combination [Symbyax]): When using individual components of fluoxetine with olanzapine rather than fixed dose combination product (Symbyax), approximate dosage correspondence is as follows:

Olanzapine 2.5 mg + fluoxetine 20 mg = Symbyax 3/25

Olanzapine 5 mg + fluoxetine 20 mg = Symbyax 6/25

Olanzapine 12.5 mg + fluoxetine 20 mg = Symbyax 12/25

Olanzapine 5 mg + fluoxetine 50 mg = Symbyax 6/50

Olanzapine 12.5 mg + fluoxetine 50 mg = Symbyax 12/50

Special risk patients: Initial: 2.5 to 5 mg once daily is recommended in patients who have a predisposition to hypotensive reactions, who have hepatic impairment, who exhibit a combination of factors that may result in slower metabolism of olanzapine (eg, female, elderly, nonsmoking status), or who may be more pharmacodynamically sensitive to olanzapine; increase dose with caution as clinically indicated.

Chemotherapy-associated acute and delayed nausea or vomiting, prevention (off-label use): Oral: 10 mg on the day of chemotherapy (day 1) followed by 10 mg once daily days 2 to 4 (in combination with dexamethasone and palonosetron on day 1 only) (Navari 2007; Navari 2011).

Chemotherapy-associated breakthrough nausea or vomiting (off-label use): Oral: 10 mg once daily for 3 days (Navari 2013).

Delirium (off-label use): Oral: 5 mg once daily for up to 5 days (NICE 2010)

Delusional parasitosis (off-label use): Oral: Initial: 2.5 mg once daily; increase gradually based on response and tolerability up to 5 to 10 mg/day. Maximum: 20 mg/day (Freudenmann 2008; Heller 2013). Additional data may be necessary to further define the role of olanzapine in this condition.

Post-traumatic stress disorder (off-label use): Oral: Initial: 5 to 10 mg daily; adjust dose based on response and tolerability every 1 to 2 weeks, up to 20 mg daily (Carey 2012; Stein 2002).

Tourette syndrome (off-label use): Initial: 2.5 to 5 mg daily; increase gradually based on response and tolerability to a usual dosage range of 2.5 to 20 mg daily (Pringsheim 2012; Roessner 2011). After initial dosage, increments of 2.5 to 5 mg weekly or biweekly were commonly used for dosage adjustments in clinical trials up to a maximum dosage of 20 mg/day (Budman 2001; Onofrj 2000; Stamenkovic 2000).

Discontinuation of therapy: American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (APA [Lehman 2004]; Cerovecki 2013; CPA [Addington 2005]; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months, and the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA [Addington 2005]). Continuing anti-parkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, 3 strategies have been suggested: cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited, and results are conflicting (Cerovecki 2013; Remington 2005).

Dosing: Geriatric

Refer to adult dosing.

Short-acting IM, Oral: Consider lower starting dose of 2.5 to 5 mg daily for elderly patients; may increase as clinically indicated and tolerated with close monitoring of orthostatic blood pressure

Extended release IM: Consider lower starting dose of 150 mg every 4 weeks for elderly patients; increase dose with caution as clinically indicated.

Delirium (off-label use): Oral: Patients >60 years: Oral: 2.5 mg daily for up to 5 days (NICE 2010)

Psychosis/agitation associated with dementia (off-label use):

Short-acting IM: Initial dose: 2.5 or 5 mg; up to 2 additional doses of 1.25 or 2.5 mg may be considered, however, at least 2 hours after the initial dose and at least 1 hour after the second dose should be allowed between doses to evaluate response up to a maximum drug exposure of 12.5 mg per episode (Meehan 2002).

Oral: Initial: 2.5 to 5 mg daily, if necessary gradually increase based on response and tolerability not to exceed 10 mg daily. In patients without a clinically significant response after 4 weeks, taper and withdraw therapy. In patients with an adequate response, attempt to taper and withdraw therapy within 4 months, unless symptoms recurred with a previous taper attempt. Assess symptoms at least monthly during taper and for at least 4 months after withdrawal of therapy (APA [Reus 2016]; De Deyn 2004; Schneider 2006; Street 2000; Sultzer 2008; Verhey 2006).

Dosing: Pediatric

Bipolar I (acute mixed or manic episodes): Adolescents ≥13 years: Oral: Initial: 2.5 to 5 mg once daily; adjust by 2.5 to 5 mg daily to target dose of 10 mg daily; dosing range: 2.5 to 20 mg daily

Depression associated with bipolar I disorder (in combination with fluoxetine): Children and Adolescents 10 to 17 years: Oral: Initial: 2.5 mg once daily in the evening (in combination with fluoxetine); adjust dose, if needed, as tolerated; safety of doses >12 mg of olanzapine in combination with fluoxetine doses >50 mg has not been studied in pediatrics. Refer to adult dosing for "Note" for olanzapine/fluoxetine combination (Symbyax).

Schizophrenia: Adolescents ≥13 years: Oral: Initial: 2.5 to 5 mg once daily; adjust by 2.5 to 5 mg daily to target dose of 10 mg daily; dosing range: 2.5 to 20 mg daily

Chemotherapy-associated breakthrough or refractory nausea or vomiting (off-label use): Infants, Children, and Adolescents: Oral: 0.1 mg/kg/dose once daily (maximum 10 mg/dose); if necessary, may increase to 0.14 mg/kg/dose once daily (maximum 10 mg/dose) (Flank 2016).

Tourette syndrome (off-label use): Children and Adolescents: Initial: 2.5 to 5 mg once daily; increase gradually based on response and tolerability to a usual dosage of 2.5 to 12.5 mg once daily (AACAP [Murphy 2013]; Pringsheim 2012). After initial dosage, increments of 2.5 to 5 mg weekly or biweekly were used for dosage adjustments in clinical trials up to a maximum dosage of 20 mg/day (McCracken 2008; Stephens 2004)

Dosing: Renal Impairment

No dosage adjustment necessary. Not removed by dialysis.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling except when used in combination with fluoxetine (as separate components) the initial olanzapine dose should be limited to 2.5 to 5 mg daily. Use with caution (cases of hepatitis and liver injury have been reported with olanzapine use).

Reconstitution

Injection, extended-release: Dilute as directed to final concentration of 150 mg/mL. Shake vigorously to mix; will form yellow, opaque suspension. Following reconstitution, suspension may be stored at room temperature and used within 24 hours. Shake vigorously to resuspend prior to administration. If foam forms, let vial stand to allow foam to dissipate. Use immediately once suspension is in syringe. Suspension may be irritating to skin; wear gloves during reconstitution.

Injection, short-acting: Reconstitute 10 mg vial with 2.1 mL SWFI. Resulting solution is ~5 mg/mL. Use immediately (within 1 hour) following reconstitution. Discard any unused portion. Do not mix diazepam, lorazepam, or haloperidol in the same syringe.

Administration

Short-acting IM injection: For IM administration only; do not administer injection intravenously or subcutaneously; inject slowly, deep into muscle. If dizziness and/or drowsiness are noted, patient should remain recumbent until examination indicates postural hypotension and/or bradycardia are not a problem.

Extended-release IM injection: For IM gluteal injection only; do not administer IV or subcutaneously. After needle insertion into muscle, aspirate to verify that no blood appears. Do not massage injection site. Use diluent, syringes, and needles provided in convenience kit; obtain a new kit if aspiration of blood occurs.

Tablet: May be administered without regard to meals.

Orally-disintegrating: Remove from foil blister by peeling back (do not push tablet through the foil); place tablet in mouth immediately upon removal; tablet dissolves rapidly in saliva and may be swallowed with or without liquid. May be administered with or without food/meals.

Dietary Considerations

Tablets may be taken without regard to meals. Some products may contain phenylalanine.

Storage

Injection, extended-release: Store at controlled room temperature, not to exceed 30°C (86°F).

Injection, short-acting: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Protect from light.

Tablet and orally disintegrating tablet: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antihepaciviral Combination Products: May decrease the serum concentration of OLANZapine. Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Benzodiazepines: OLANZapine may enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

FluvoxaMINE: May decrease the metabolism of OLANZapine. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

LamoTRIgine: May enhance the sedative effect of OLANZapine. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Avoid combination

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Ritonavir: May decrease the serum concentration of OLANZapine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Valproate Products: May decrease the serum concentration of OLANZapine. Monitor therapy

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Oral: Unless otherwise noted, adverse events are reported for placebo-controlled trials in adult patients on monotherapy:

>10%:

Cardiovascular: Orthostatic hypotension (3% to ≥20%)

Central nervous system: Drowsiness (dose dependent; adolescents and adults 20% to 39%), extrapyramidal reaction (dose dependent; adults ≤32%; adolescents ≤10%), akathisia (adolescents and adults 3% to 27%), parkinsonian-like syndrome (14% to 20%; includes akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, maked facies, and tremor), dizziness (adults 11% to 18%; adolescents 7% to 8%), headache (adolescents 17%), fatigue (dose dependent; adolescents and adults 2% to 14%), insomnia (12%)

Endocrine & metabolic: Increased serum prolactin (adolescents 47%; adults 30%), weight gain (adults 5% to 6%; has been reported as high as 40%; adolescents 29% to 31%)

Gastrointestinal: Increased appetite (adolescents 17% to 29%; adults 3% to 6%), xerostomia (dose dependent; adults 3% to 22%; adolescents 4% to 7%), dyspepsia (adults 7% to 11%; adolescents 3%), constipation (adolescents and adults 4% to 11%)

Hepatic: Increased serum AST (adolescents 28%), decreased serum bilirubin (adolescents 22%), increased serum ALT (≥3 x ULN; adolescents and adults 5% to 12%)

Neuromuscular & skeletal: Weakness (dose dependent; 8% to 20%)

Miscellaneous: Accidental injury (12%)

1% to 10%:

Cardiovascular: Chest pain (3%), peripheral edema (3%), tachycardia (3%), hypertension (2%)

Central nervous system: Personality disorder (5% to 8%), abnormal gait (6%), hypertonia (3%), restlessness (adolescents 3%), falling (older adults ≥2%), articulation impairment (2%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (adolescents 10%; adults 2%), increased uric acid (4%), menstrual disease (2%; including amenorrhea, hypomenorrhea, delayed menstruation, oligomenorrhea), breast changes (male and female adolescents ≤2%; including discharge, enlargement, galactorrhea, gynecomastia, lactation disorder)

Gastrointestinal: Abdominal pain (6%; adolescents), vomiting (≤4%), diarrhea (3%; adolescents)

Genitourinary: Urinary incontinence (adults and older adults ≥2%), sexual disorder (2%; adolescents ≤1%; anorgasmia, delayed ejaculation, erectile dysfunction, changes in libido, abnormal orgasm, sexual dysfunction), urinary tract infection (2%)

Hematologic & oncologic: Bruise (5%)

Hepatic: Increased liver enzymes (adolescents ≤8%), increased serum alkaline phosphatase (≥1%)

Neuromuscular & skeletal: Tremor (4% to 7%; dose dependent), limb pain (adolescents and adults 5% to 6%), arthralgia (adults 5%; adolescents 2%), back pain (5%), muscle rigidity (2%; adolescents), dyskinesia (1%)

Ophthalmic: Amblyopia (3%)

Respiratory: Rhinitis (7%), cough (6%), nasopharyngitis (adolescents 4%), pharyngitis (4%), epistaxis (adolescents 3%), respiratory tract infection (adolescents 3%), sinusitis (adolescents 3%)

Miscellaneous: Fever (≤6%)

<1% (Limited to important or life-threatening): Accommodation disturbance, agranulocytosis, alopecia, anaphylactoid reaction, angioedema, ataxia, cerebrovascular accident, coma, confusion, diabetes mellitus, diabetic ketoacidosis, diabetic coma, hepatic injury (cholestatic or mixed), hepatitis, hyperbilirubinemia, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypoproteinemia, intestinal obstruction, jaundice, ketosis, leukocytosis (eosinophilia), leukopenia, liver steatosis, myopathy, neuroleptic malignant syndrome, neutropenia, osteoporosis, pancreatitis, priapism, pulmonary edema, pulmonary embolism, rhabdomyolysis, seizure, skin rash, suicidal tendencies, syncope, tardive dyskinesia, thrombocytopenia, tongue edema, transient ischemic attacks, urticaria, venous thrombosis, withdrawal syndrome

Injection: Frequency not always defined. Unless otherwise noted, adverse events are reported for placebo-controlled trials in adult patients on extended release IM injection (Zyprexa Relprevv). Also refer to adverse reactions noted with oral therapy.

Cardiovascular: Hypertension (2% to 3%), hypotension (short-acting solution for IM injection 2%), prolonged Q-T interval on ECG (2%), orthostatic hypotension (short-acting solution for IM injection 1%)

Central nervous system: Headache (13% to 18%), sedation (8% to 13%), drowsiness (both IM injection formulations 5% to 6%), akathisia (short-acting solution for IM injection 5%), dizziness (both IM injection formulations 4%), fatigue (3% to 4%), extrapyramidal reaction (solution for IM injection 2% to 4%), abnormality in thinking (3%), auditory hallucination (3%), parkinsonian-like syndrome (short-acting solution for IM injection 3%), restlessness (3%), pain (2% to 3%), abnormal dreams (2%), procedural pain (2%), sleep disorder (2%), dysarthria (1% to 2%)

Dermatologic: Acne vulgaris (2%)

Endocrine & metabolic: Weight gain (6% to 7%)

Gastrointestinal: Diarrhea (5% to 7%), vomiting (6%), xerostomia (2% to 6%), increased appetite (1% to 6%), nausea (long-acting IM formula 4% to 5%; short-acting solution for injection <1%), tooth infection (4%), toothache (3% to 4%), abdominal pain (3%), flatulence (1% to 2%)

Genitourinary: Vaginal discharge (4%)

Hepatic: Increased liver enzymes (3% to 4%)

Infection: Viral infection (2%)

Local: Pain at injection site (both IM injection formulations 1% to 4%), abscess at injection site

Neuromuscular & skeletal: Arthralgia (3%), back pain (5%), muscle spasm (1% to 3%), stiffness (4%), tremor (long-acting IM formula 3%; short-acting solution for injection 1%)

Otic: Otalgia (4%)

Respiratory: Cough (9%), nasal congestion (7%), nasopharyngitis (3% to 6%), upper respiratory tract infection (3% to 4%), pharyngolaryngeal pain (3%), sneezing (2%)

Miscellaneous: Fever (2%)

<1% (Limited to important or life-threatening): Delirium, increased creatine phosphokinase (short-acting solution for IM injection), postinjection delirium/sedation syndrome, sleep apnea syndrome (obstructive) (Health Canada 2016, Shirani 2011), syncope (short-acting solution for IM injection)

ALERT: U.S. Boxed Warning

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. Analyses of 17 placebo-controlled trials (modal duration, 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients between 1.6 and 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5%, compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patient is not clear. Olanzapine is not approved for treatment of patients with dementia-related psychosis.

Postinjection delirium/sedation syndrome (Zyprexa Relprevv):

Adverse reactions with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, have been reported following injections of olanzapine extended release (ER). Olanzapine ER must be administered in a registered health care facility with ready access to emergency response services. After each injection, patients must be observed at the health care facility by a health care provider for at least 3 hours. Because of this risk, olanzapine ER is available only through a restricted distribution program called Zyprexa Relprevv Patient Care Program, and requires health care provider, health care facility, patient, and pharmacy enrollment.

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems (including narrow-angle glaucoma). Relative to other neuroleptics, olanzapine has a moderate potency of cholinergic blockade (Richelson 1999).

• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.

• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of olanzapine for the unapproved use in elderly patients with dementia-related psychosis.

• CNS depression: May cause CNS depression, which impair physical and mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). May be moderate to highly sedating in comparison with other antipsychotics (APA [Lehman 2004]); dose-related effects have been observed.

• Dyslipidemia: Dose-related increases in cholesterol and triglycerides have been noted. Use with caution in patients with preexisting abnormal lipid profile.

• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer disease).

• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk.

• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Olanzapine may have a greater association with hyperglycemia than other atypical antipsychotics. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation.

• Hyperprolactinemia: May cause dose-related increases in prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown. Clinical manifestations of increased prolactin levels included menstrual-, sexual- and breast-related events.

• Multiorgan hypersensitivity reactions (drug reaction with eosinophilia and systemic symptoms [DRESS]): Potentially serious, sometimes fatal, multiorgan hypersensitivity reactions (DRESS) have been reported. Symptoms may include a cutaneous reaction (rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications (eg, hepatitis, nephritis, pneumonitis, myocarditis, pericarditis). Discontinue olanzapine if DRESS is suspected.

• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability.

• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use that may predispose to hypotension/bradycardia).

• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

• Weight gain: Significant weight gain (>7% of baseline weight) has been observed with antipsychotic therapy; incidence varies with product. Dose-related changes have been observed with olanzapine. Monitor waist circumference and BMI.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with severe cardiac disease, hemodynamic instability, prior myocardial infarction, ischemic heart disease, or hypercholesterolemia.

• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared with placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. (APA [Reus 2016]). Olanzapine is not approved for the treatment of dementia-related psychosis.

• Hepatic impairment: Use with caution in patients with hepatic disease or impairment; may increase transaminases (primarily ALT).

• Parkinson disease: Use with caution in patients with Parkinson disease; antipsychotic may aggravate motor disturbances (APA [Lehman 2004]; APA [Reus 2016]).

• Renal impairment: Use with caution in patients with renal disease.

• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications that may lower seizure threshold. Elderly patients may be at increased risk of seizures because of an increased prevalence of predisposing factors.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Adolescents: Use in patients ≥13 years of age may result in increased weight gain and sedation, as well as greater increases in LDL cholesterol, total cholesterol, triglycerides, prolactin, and liver transaminase levels when compared with adults. Adolescent patients should be maintained on the lowest dose necessary.

• Smokers: Olanzapine levels may be lower in patients who smoke. Smokers may require a daily dose 30% higher than nonsmokers in order to obtain an equivalent olanzapine concentration (Tsuda 2014); however, the manufacturer does not routinely recommend dosage adjustments.

Dosage form-specific concerns:

• Intramuscular formulations: There are two Zyprexa formulations for intramuscular injection: Zyprexa Relprevv is an extended-release formulation and Zyprexa IntraMuscular is short-acting.

Extended-release IM injection (Zyprexa Relprevv):

Postinjection delirium/sedation syndrome: [US Boxed Warning]: Sedation (including coma) and delirium (including agitation, anxiety, confusion, disorientation) have been observed following use of Zyprexa Relprevv; events associated with an inadvertent rapid rise in serum concentrations; administer at a registered health care facility where patients should be continuously monitored (≥3 hours) for symptoms of olanzapine overdose; symptom development highest in first hour but may occur within or after 3 hours; risk of syndrome is cumulative with each injection; recovery expected by 72 hours. Upon determining alert status, patient should be escorted to their destination and not drive or operate heavy machinery for the remainder of the day.

Unexplained deaths: Two unexplained deaths in patients who received Zyprexa Relprevv have been reported. The patients died 3 to 4 days after receiving an appropriate dose of the drug. Both patients were found to have high blood concentrations of olanzapine postmortem. It is unclear if these deaths were the result of postinjection delirium sedation syndrome (PDSS) (FDA Safety Communication 2013).

Restricted distribution program: Zyprexa Relprevv is only available under a restricted distribution program. Only prescribers, health care facilities, and pharmacies registered with the program are able to prescribe, distribute, or dispense Zyprexa Relprevv for patients who are enrolled in and meet all conditions of the program.

Short-acting IM injection (Zyprexa IntraMuscular): Patients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation have been ruled out. Closely monitor for orthostasis prior to any repeat dosing. Concurrent use of IM/IV benzodiazepines is not recommended (fatalities have been reported, though causality not determined).

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Discontinuation of therapy: When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).

Monitoring Parameters

Mental status; vital signs (as clinically indicated); blood pressure (baseline; repeat 3 months after antipsychotic initiation, then yearly); weight, height, BMI, waist circumference (baseline; repeat at 4, 8, and 12 weeks after initiating or changing therapy, then quarterly; consider switching to a different antipsychotic for a weight gain ≥5% of initial weight); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with pre-existing low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease (baseline; repeat annually); fasting plasma glucose level/HbA1c (baseline; repeat 3 months after starting antipsychotic, then yearly); fasting lipid panel (baseline; repeat 3 months after initiation of antipsychotic; if LDL level is normal repeat at 2-5 year intervals or more frequently if clinical indicated); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (at each visit for the first 12 weeks after the antipsychotic is initiated or until the dose is stable, then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 12 months; high-risk patients every 6 months); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004)

Extended-release IM injection: Sedation/delirium for 3 hours after each dose

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Olanzapine crosses the placenta and can be detected in cord blood at birth (Newport 2007). Information related to olanzapine use in pregnancy is limited (Goldstein 2000). Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization. Olanzapine may cause hyperprolactinemia, which may decrease reproductive function in both males and females.

The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to a typical antipsychotic that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008). Evaluate risk factors for gestational diabetes and weight gain if considering use of olanzapine in a pregnant woman (NICE 2007).

Healthcare providers are encouraged to enroll women 18 to 45 years of age exposed to olanzapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388 or http://www.womensmentalhealth.org/pregnancyregistry).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience agitation, loss of strength and energy, constipation, dry mouth, nausea, weight gain, increased appetite, back pain, or injection site irritation. Have patient report immediately to prescriber signs of infection, signs of high blood sugar (confusion, fatigue, more thirst, hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), anxiety, confusion, severe fatigue, weakness, severe headache, abnormal movements twitching, change in balance, difficulty swallowing, difficulty speaking, mood changes, suicidal ideation, behavioral changes, severe dizziness, passing out, bradycardia, tachycardia, lack of sweating, seizures, drooling, vision changes, memory impairment, chest pain, swelling in the arms or legs, burning or numbness feeling, swollen glands, enlarged breasts, nipple discharge, sexual dysfunction, amenorrhea, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot), or signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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