Olanzapine

Olanzapine
Names
Trade namesZyprexa, others[1]
IUPAC name
  • 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
Clinical data
Drug classAtypical antipsychotic[2]
Main usesPsychosis[3]
Side effectsWeight gain, movement disorders, dizziness, feeling tired, constipation, dry mouth[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth, intramuscular injection
    Defined daily dose10 mg[4]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa601213
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • CA: ℞-only
    • NZ: Prescription medicine
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetics
    Bioavailability60-65%[5][6][7]
    Protein binding93%[8]
    MetabolismLiver (direct glucuronidation and CYP1A2 mediated oxidation)
    Elimination half-life33 hours, 51.8 hours (elderly)[8]
    ExcretionUrine (57%; 7% as unchanged drug), faeces (30%)[8][9]
    Chemical and physical data
    FormulaC17H20N4S
    Molar mass312.439 g·mol−1
    3D model (JSmol)
    Melting point195 °C (383 °F)
    Solubility in waterPractically insoluble in water mg/mL (20 °C)
    SMILES
    • CN1CCN(CC1)C/2=N/c4ccccc4Nc3sc(C)cc\23
    InChI
    • InChI=1S/C17H20N4S/c1-12-11-13-16(21-9-7-20(2)8-10-21)18-14-5-3-4-6-15(14)19-17(13)22-12/h3-6,11,19H,7-10H2,1-2H3 checkY
    • Key:KVWDHTXUZHCGIO-UHFFFAOYSA-N checkY

    Olanzapine, sold under the trade name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder.[2] For schizophrenia, it can be used for both new onset disease and long-term maintenance.[2] It is taken by mouth or by injection into a muscle.[2]

    Common side effects include weight gain, movement disorders, dizziness, feeling tired, constipation, and dry mouth.[2] Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, high blood sugar, seizures, gynecomastia, erectile dysfunction, and tardive dyskinesia.[2] In older people with dementia, its use increases the risk of death.[2] Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth.[2] Although how it works is not entirely clear, it blocks dopamine and serotonin receptors.[2]

    Olanzapine was patented in 1971 and approved for medical use in the United States in 1996.[2][10] It is available as a generic medication.[2] It is on the World Health Organization's List of Essential Medicines.[11] In the United States, the wholesale cost is less than US$0.25 per dose as of 2018.[12] In 2017, it was the 239th most commonly prescribed medication in the United States, with more than two million prescriptions.[13][14]

    Medical uses

    Schizophrenia

    The first-line psychiatric treatment for schizophrenia is antipsychotic medication; with olanzapine being one such medication.[15] Olanzapine appears to be effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia.[16][17][18][19] The usefulness of maintenance therapy, however, is difficult to determine as more than half of people in trials quit before the six-week completion date.[20] Treatment with olanzapine (like clozapine) may result in increased weight gain and increased glucose and cholesterol levels when compared to most other second-generation antipsychotic drugs used to treat schizophrenia.[17][21]

    Comparison

    National Institute for Health and Care Excellence, the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on a person's preference and the drug's side effect profile.[22][23][24] The U.S. Agency for Healthcare Research and Quality concludes that olanzapine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but that it is superior for the treatment of negative and depressive symptoms.[25] It has a lower risk of causing movement disorders than typical antipsychotics.[16]

    In a 2013 comparison of 15 antipsychotic drugs in schizophrenia, olanzapine was ranked third in efficacy. It was 5% more effective than risperidone (4th), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (1st).[16] A 2013 review of first episode schizophrenia concluded that olanzapine is superior to haloperidol in providing a lower discontinuation rate, and in short-term symptom reduction, response rate, negative symptoms, depression, cognitive function, discontinuation due to poor efficacy, and long-term relapse, but not in positive symptoms or on the Clinical Global Impressions score. In contrast, pooled second generation antipsychotics showed superiority to first generation antipsychotics only against the discontinuation, negative symptoms (with a much larger effect seen among industry- compared to government-sponsored studies), and cognition scores. Olanzapine caused less extrapyramidal side effects, less akathisia, but caused significantly more weight gain, serum cholesterol increase, and triglyceride increase than haloperidol.[26] A 2012 review concluded that among 10 atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first generation antipsychotics.[27] A 2011 review concluded that neither first- nor second generation antipsychotics produce clinically meaningful changes in Clinical Global Impression scores but found that olanzapine and amisulpride produce larger effects on the PANSS and BPRS batteries than five other second generation antipsychotics or pooled first generation antipsychotics.[28] A 2010 Cochrane systematic review found that olanzapine may have a slight advantage in effectiveness when compared to aripiprazole, quetiapine, risperidone and ziprasidone.[21] No differences in effectiveness was detected when comparing olanzapine to amisulpride and clozapine.[21]

    A 2014 meta analysis of 9 published trials having minimum duration 6 months and median duration 52 weeks concluded that olanzapine, quetiapine, and risperidone had better effects on cognitive function than amisulpride and haloperidol.[29]

    Bipolar disorder

    Olanzapine is recommended by the National Institute of Health and Care Excellence as a first line therapy for the treatment of acute mania in bipolar disorder.[30] Other recommended first lines are haloperidol, quetiapine and risperidone.[30] It is recommended in combination with fluoxetine as a first line therapy for acute bipolar depression; and as a second line treatment by itself for the maintenance treatment of bipolar disorder.[30]

    The Network for Mood and Anxiety Treatments (CANMAT) recommends olanzapine as a first line maintenance treatment in bipolar disorder and the combination of olanzapine with fluoxetine as second line treatment for bipolar depression.[31]

    A 2014 meta analysis concluded that olanzapine plus fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis.[32]

    Other uses

    Evidence does not support the use of atypical antipsychotics, including olanzapine, in eating disorders.[33]

    Olanzapine has not been rigorously evaluated in generalized anxiety disorder, panic disorder, delusional parasitosis, or post-traumatic stress disorder. Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder.[34] It has also been used for Tourette syndrome and stuttering.[35]

    Olanzapine has been studied for the treatment of hyperactivity, aggressive behavior, and repetitive behaviors in autism.[36]

    Olanzapine is frequently prescribed off-label for the treatment of insomnia, including difficult falling asleep and staying asleep. The daytime sedation experienced with olanzapine is generally comparable to quetiapine and lurasidone, which is a frequent complaint in clinical trials. In some cases, the sedation due to olanzapine impaired the ability of people to wake up at a consistent time every day. There does appear to be some evidence of efficacy for treating insomnia, but long-term studies (especially for safety) are still needed.[37]

    Olanzapine has been recommended to be used in antiemetic regimes in people receiving chemotherapy which has a high-risk for vomiting.[38]

    Dosage

    The defined daily dose is 10 mg by mouth or by injection.[4] In adults it is generally started at 5 mg a day and if needed increased to 10 mg per day with a maximum dose of 20 mg per day.[3] In older people half the dose should be used.[3] Treatment of chronic psychosis should generally be for at least a year.[3]

    Side effects

    See also: List of adverse effects of olanzapine
    Pleural biopsy demonstrates a chronic inflammatory cell infiltrate and eosinophils induced via olanzapine

    The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in the blood lipid and blood sugar profiles (see section metabolic effects). A recent meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APD compared with a SMD of 0.74[16] Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine[39] but may include tremors and muscle rigidity.

    It is recommended that it not be used by IM injection in acute myocardial infarction; bradycardia; recent heart surgery; severe hypotension; sick sinus syndrome; and unstable angina.[40]

    Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce non-trivial high blood sugar in people with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the body's natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.[8][9][41][42][43]

    Other side effects include galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction (impotence).[44]

    Paradoxical effects

    Olanzapine is used therapeutically to treat serious mental illness. Occasionally, it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, thoughts, or behavior; hallucinations and excessive thoughts about suicide have also been linked to olanzapine use.[45]

    Metabolic effects

    The US Food and Drug Administration requires all atypical antipsychotics to include a warning about the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs' ability to induce weight gain, although there are some reports of metabolic changes in the absence of weight gain.[46][47] Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures.[48][49][50][51][52] The effect is dose dependent in humans[53] and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis.[54] Olanzapine may decrease insulin sensitivity,[55][56] though one 3-week study seems to refute this.[57] It may also increase triglyceride levels.[49]

    Despite weight gain, a large multi-center randomized National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs.[58] One small, open-label, non-randomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain,[59] but this has not been substantiated in a blinded experimental setting.

    Post-injection delirium/sedation syndrome

    Post-injection delirium/sedation syndrome (PDSS) is a rare syndrome that is specific to the long-acting injectable formulation of olanzapine, olanzapine pamoate.[60] The incidence of PDSS with olanzapine pamoate is estimated to be 0.07% of administrations, and is unique among other second-generation, long-acting antipsychotics (e.g. paliperidone palmitate), which don't appear to carry the same risk.[60] PDSS is characterized by symptoms of delirium (e.g. confusion, difficulty speaking, and uncoordinated movements) and sedation.[60] While not all people with PDSS will exhibit both delirium and sedation, most of them will (83%).[60] Although less specific to PDSS, a majority of cases (67%) involved a feeling of general discomfort.[60] It is thought that PDSS may occur due to accidental injection and absorption of olanzapine pamoate into the bloodstream, where it can act more rapidly, as opposed to slowly distributing out from muscle tissue.[60] Utilizing the proper, intramuscular injection technique for olanzapine pamoate helps to decrease the risk of PDSS, though it does not eliminate the risk entirely.[60] This is why the FDA advises that people that are injected with olanzapine pamoate be watched for 3 hours after administration, in the event that PDSS occurs.[60]

    Pregnancy and lactation

    Olanzapine is associated with the highest placental exposure of any atypical antipsychotic.[61] Despite this, the available evidence suggests it is safe during pregnancy, although the evidence is insufficiently strong to say anything with a high degree of confidence.[61] Olanzapine is associated with weight gain which according to recent studies may put olanzapine-treated patients' offspring at a heightened risk for neural tube defects (e.g. spina bifida).[62][63] Breastfeeding in women taking olanzapine is advised against due to the fact that olanzapine is secreted in breast milk with one study finding that the exposure to the infant (in mg per kg of body weight, that is) is about 1.8% that to the mother.[8]

    Elderly

    Citing an increased risk of stroke, in 2004 the Committee on the Safety of Medicines (CSM) in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis.[64] However, a BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.[65] Evidence suggested that elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone.[66]

    Cancer

    Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumors found were in either the liver or mammary glands of the animals.[67]

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[68] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[69] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[69] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[69] Symptoms generally resolve after a short period of time.[69]

    There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[70] It may also result in reoccurrence of the condition that is being treated.[71] Rarely tardive dyskinesia can occur when the medication is stopped.[69]

    Overdose

    Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 2000 mg.[72] Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post-mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death).[73] There is no known specific antidote for olanzapine overdose, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case.[72] Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs and less toxic than the MAOIs and TCAs.[61]

    Interactions

    Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs which inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance.[74] Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ration of olanzapine by 33% compared to olanzapine alone.[73] Another enzyme inducer, ritonavir, has also been shown to decrease the body's exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5'-diphospho-glucuronosyltransferase (UGT).[73] Probenecid increases the total exposure (area under the curve, or AUC) and maximum plasma concentration (Cmax) of olanzapine.[73] Although olanzapine's metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapine's clearance.[73]

    Pharmacology

    Pharmacodynamics

    See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
    Olanzapine[75]
    SiteKi (nM)ActionRef
    5-HT1A2,063–2,720Antagonist[76][77]
    5-HT1B509–660ND[75][77]
    5-HT1D540–1,582ND[75][77]
    5-HT1E2,010–2,408ND[75][77]
    5-HT1F310ND[77]
    5-HT2A1.32–24.2Inverse agonist[78][79]
    5-HT2B11.8–12.0Inverse agonist[80][81]
    5-HT2C6.4–29Inverse agonist[79][81]
    5-HT3202Antagonist[75]
    5-HT5A1,212Full Agonist[75]
    5-HT66.0–42Antagonist[75][82]
    5-HT7105–365Antagonist[75][83]
    α1A109–115Antagonist[75][76]
    α1B263Antagonist[75]
    α2A192–470Antagonist[77][83]
    α2B82–180Antagonist[76][77]
    α2C29–210Antagonist[76][77]
    β1>10,000ND[75][77]
    β2>10,000ND[75][77]
    D135–118Antagonist[79][83]
    D23.00–106Antagonist[84][85]
    D2L31–38Antagonist[77][79]
    D2S21–52Antagonist[77][86]
    D37.8–91Antagonist[84][85]
    D41.6–50Antagonist[84][87]
    D4.217–102Antagonist[88][89]
    D4.421–60Antagonist[86]
    D574–90Antagonist[75][79]
    H10.65–4.9Inverse agonist[75][77]
    H244Antagonist[75]
    H33,713Antagonist[75]
    H4>10,000Antagonist[75]
    M12.5–73Antagonist[90][91]
    M248–622Antagonist[82]
    M313–126Antagonist[81][82]
    M410–350Antagonist[82][90]
    M56.0–82Antagonist[82][90]
    σ1>5,000ND[77]
    σ2NDNDND
    Opioid>10,000ND[77]
    nACh>10,000ND[75]
    NMDA
    (PCP)    		>10,000ND[75]
    SERT≥3,676ND[75][87]
    NET>10,000ND[75]
    DAT>10,000ND[75]
    VDCC>10,000ND[75][77]
    VGSC>5,000ND[77]
    hERG6,013Blocker[92]
    Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except H3 (guinea pig), σ1 (guinea pig), opioid (rodent), NMDA/PCP (rat), VDCC, and VGSC.[75]

    Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the non-benzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone and perospirone.

    Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study.[93] P-glycoprotein transports a myriad of drugs across a numerous of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semi-permeable membrane which filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein.[94] A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and it is fairly common for pharmaceuticals to be either substrates of P-GP, or to inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood brain barrier to P-GP substrates and subsequently increase the central activity of the substrate while reducing the local effects on the GI tract. The mediation of olanzapine in the central nervous system by P-GP means that any other substance or drug which interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.[95]

    Olanzapine is a potent antagonist of the muscarinic M3 receptor,[96] which may underlie its diabetogenic side effects.[97][98] Additionally, olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.[39][99]

    The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation, in addition it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, however it offers no protection against the development of tardive dyskinesia. In common with other second generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its higher affinity for the 5HT2A receptor over the D2 receptor.[100]

    Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation.[101]

    Pharmacokinetics

    Metabolism

    Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6. By these mechanisms more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect.[39] The clearance of olanzapine appears to vary by sex; women have approximately 25% lower clearance than men.[73] The clearance of olanzapine also varies by race; in self-identified African-Americans or Black individuals, olanzapine's clearance was 26% higher.[73] There does not appear to be a difference in the clearance between individuals identifying as Caucasian, Chinese, or Japanese.[73] Routine, pharmacokinetic monitoring of olanzapine plasma levels is generally unwarranted, though unusual circumstances (e.g. the presence of drug-drug interactions) or a desire to determine if a patient is taking their medicine or not may prompt its use.[73]

    Miscellaneous

    Pharmacokinetics of long-acting injectable antipsychotics
    MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
    Aripiprazole lauroxilAristadaAtypicalWatera441–1064 mg/4–8 weeks24–35 days ?54–57 days7.9–10.0
    Aripiprazole monohydrateAbilify MaintenaAtypicalWatera300–400 mg/4 weeks7 days ?30–47 days4.9–5.2
    Bromperidol decanoateImpromen DecanoasTypicalSesame oil40–300 mg/4 weeks3–9 days ?21–25 days7.9[102]
    Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days ?19 days9.0[103]
    Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[103][104]
    Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[105][106][107]
    Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days ?6.4–7.4[106]
    FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days ?5.2–5.8[108]
    Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[109][110]
    Olanzapine pamoateZyprexa RelprevvAtypicalWatera150–405 mg/2–4 weeks7 days ?30 days–
    Oxyprothepin decanoateMeclopinTypical ? ? ? ? ?8.5–8.7
    Paliperidone palmitateInvega SustennaAtypicalWatera39–819 mg/4–12 weeks13–33 days25–139 days ?8.1–10.1
    Perphenazine decanoateTrilafon DekanoatTypicalSesame oil50–200 mg/2–4 weeks ? ?27 days8.9
    Perphenazine enanthateTrilafon EnanthateTypicalSesame oil25–200 mg/2 weeks2–3 days ?4–7 days6.4–7.2[111]
    Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days ?14–21 days8.5–11.6[104]
    Pipotiazine undecylenatePiportil MediumTypicalSesame oil100–200 mg/2 weeks ? ? ?8.4
    RisperidoneRisperdal ConstaAtypicalMicrospheres12.5–75 mg/2 weeks21 days ?3–6 days–
    Zuclopentixol acetateClopixol AcuphaseTypicalViscoleob50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
    Zuclopentixol decanoateClopixol DepotTypicalViscoleob50–800 mg/2–4 weeks4–9 days ?11–21 days7.5–9.0
    Note: All by intramuscular injection. Footnotes: a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank. Sources: Main: See template.

    Society and culture

    Zyprexa (olanzapine) 10 mg tablets (AU)

    Regulatory status

    Olanzapine is approved in the United States by the Food and Drug Administration (FDA) for:

    • Long-term treatment—in combination with fluoxetine—of resistant depression (March 2009).[115]
    • Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate)
    • Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults
    • Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults[116]
    • Treatment of the manifestations of psychotic disorders (September 1996[117] – March 2000).[118]
    • Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000).[118]
    • Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).[118]
    • Maintaining treatment response in schizophrenic patients who had been stable for approximately eight weeks and were then followed for a period of up to eight months (November 2000).[118]

    The drug became generic in 2011. Sales of Zyprexa in 2008 were $2.2 billion in the US, and $4.7 billion worldwide.[119]

    Controversy and litigation

    Eli Lilly has faced many lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa, as well as by various governmental entities, insurance companies, and others. Lilly produced a large number of documents as part of the discovery phase of this litigation, which started in 2004; the documents were ruled to be confidential by a judge and placed under seal, and later themselves became the subject of litigation.[120]

    In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits,[121] and in early 2007, Lilly settled around 18,000 suits for $500 million, which brought the total Lilly had paid to settle suits related to the drug to $1.2 billion.[122][123]

    A December 2006 New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzapine's side effects.[122][124] The company denied these allegations and stated that the article had been based on cherry picked documents.[122][123] The documents were provided to the Times by Jim Gottstein, a lawyer who represented mentally ill patients, who obtained them from a doctor, David Egilman, who was serving as an expert consultant on the case.[120] After the documents were leaked to online peer-to-peer file sharing networks by Will Hall and others in the psychiatric survivors movement who obtained copies, in 2007 Lilly filed a protection order to stop the dissemination of some of the documents, which Judge Jack B. Weinstein of the Brooklyn Federal District Court granted. Judge Weinstein also criticized the New York Times reporter, Gottstein, and Egilman in the ruling.[120] The Times of London also received the documents and reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales.[123] On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board he belonged to was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose."[123]

    Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007 he agreed to pay Lilly $100,000 in return for the company's agreement to drop the threat of charges.[125]

    In September 2008 Judge Weinstein issued an order to make public Lilly's internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.[120]

    In March 2008 Lilly settled a suit with the state of Alaska[126] and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.[125]

    In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion.[127][128]

    Trade names

    Olanzapine is generic and is available under many trade names worldwide.[1]

    List of trade names for olanzapine[1]
    AAedon, Alonzap, Amulsin, Anzap, Anzatric, Anzorin, Apisco, Apo-Olanzapine, Apo-Olanzapine ODT, Apsico, Arenbil, Arkolamyl
    BBenexafrina, Bloonis
    CCaprilon, Cap-Tiva, Clingozan
    DDeprex, Domus, Dopin
    EEgolanza, Elynza, Emzypine, Epilanz-10, Exzapine
    FFontanivio, Fordep
    G
    H
    IIrropia
    JJolyon-MD
    KKozylex
    LLanopin, Lanzapine, Lanzep, Lapenza, Lapozan, Lazap, Lazapir, Lazapix, Lezapin-MD, Lopez
    MMarathon, Meflax, Midax
    NNiolib, Nodoff, Norpen Oro, Nykob, Nyzol
    OOferta, Oferta-Sanovel, Olace, Oladay, Oladay-F, Olaffar, Olan, Olanap, Olancell, Olandix, Olandoz, Olandus, Olankline, Olanpax, Olanstad, Olanza, Olanza Actavis, Olanza Actavis ODT, Olanzalet, Olanzalux, Olanzamed, Olanzapin 1A Pharma, Olanzapin AbZ, Olanzapin Accord, Olanzapin Actavis, Olanzapin AL, Olanzapin Apotex, Olanzapin Aristo, Olanzapin axcount, Olanzapin beta, Olanzapin Bluefish, Olanzapin Cipla, Olanzapin easypharm, Olanzapin Egis, Olanzapin G.L., Olanzapin Genera, Olanzapin Genericon, Olanzapin Helvepharm, Olanzapin Hennig, Olanzapin Heumann, Olanzapin HEXAL, Olanzapin Krka, Olanzapin Lilly, Olanzapin Mylan, Olanzapin Niolib, Olanzapin Orion, Olanzapin PCD, Olanzapin PharmaS, Olanzapin Ranbaxy, Olanzapin ratiopharm, Olanzapin ReplekFarm, Olanzapin Rth, Olanzapin Sandoz, Olanzapin Spirig HC, Olanzapin Stada, Olanzapin SUN, Olanzapin Teva, Olanzapin Viketo, Olanzapin Zentiva, Olanzapina Accord, Olanzapina Actavis, Olanzapina Actavis PTC, Olanzapina Aldal, Olanzapina Almus, Olanzapina Alter, Olanzapina Angenerico, Olanzapina Anipaz, Olanzapina Apotex, Olanzapina APS, Olanzapina Arrowblue, Olanzapina Aspen, Olanzapina Aurobindo, Olanzapina Basi, Olanzapina Bexalabs, Olanzapina Blixie, Olanzapina Bluefish, Olanzapina Bluepharma, Olanzapina Cantabria, Olanzapina Ceapharma, Olanzapina Ciclum, Olanzapina Cinfa, Olanzapina Cipla, Olanzapina Combix, Olanzapina Doc Generici, Olanzapina Dr. Reddy's, Olanzapina Eulex, Olanzapina Eurogenerici, Olanzapina Fantex, Olanzapina Farmoz, Olanzapina Flas Pharma Combix, Olanzapina Genedec, Olanzapina Generis, Olanzapina Germed, Olanzapina Glenmark, Olanzapina Green Avet, Olanzapina Helm, Olanzapina Kern Pharma, Olanzapina Krka, Olanzapina La Santé, Olanzapina Labesfal, Olanzapina Leugim, Olanzapina Lilly, Olanzapina LPH, Olanzapina Mabo, Olanzapina Medana, Olanzapina Medis, Olanzapina Medley, Olanzapina Mylan, Olanzapina Nakozap, Olanzapina Nolian, Olanzapina Normon, Olanzapina Ozilormar, Olanzapina Parke-Davis, Olanzapina Pensa, Olanzapina Pensa Pharma, Olanzapina Pharmakern, Olanzapina Polipharma, Olanzapina Polpharma, Olanzapina Qualigen, Olanzapina Ranbaxy, Olanzapina Ratio, Olanzapina Ratiopharm, Olanzapina Reconir, Olanzapina Reddy, Olanzapina Rospaw, Olanzapina Sabacur, Olanzapina Sandoz, Olanzapina Sarb, Olanzapina Stada, Olanzapina Sun, Olanzapina TAD, Olanzapina Technigen, Olanzapina Terapia, Olanzapina Teva, Olanzapina Tevagen, Olanzapina tolife, Olanzapina Torrent, Olanzapina Vegal, Olanzapina Vida, Olanzapina Winthrop, Olanzapina Wynn, Olanzapina Kraz, Olanzapina Zentiva, Olanzapina Zerpi, Olanzapina Zonapir, Olanzapin-Actavis, Olanzapin-CT, Olanzapine 1A Pharma, Olanzapine Accord, Olanzapine Actavis, Olanzapine Adamed, Olanzapine Alter, Olanzapine Alvogen, Olanzapine Apotex, Olanzapine Arrow Génériques, Olanzapine Auro, Olanzapine Aurobindo, Olanzapine Biogaran, Olanzapine Bluefish, Olanzapine CF, Olanzapine Clonmel, Olanzapine Cristers, Olanzapine Dexcel, Olanzapine EG, Olanzapine Egis, Olanzapine Evolugen, Olanzapine Galenicum, Olanzapine Generichealth, Olanzapine Glenmark, Olanzapine GSK, Olanzapine Isomed, Olanzapine Jacobsen, Olanzapine Jubilant, Olanzapine Lekam, Olanzapine Lesvi, Olanzapine Medana, Olanzapine Mylan, Olanzapine Neopharma, Olanzapine Niolib, Olanzapine Nyzol, Olanzapine Odis Mylan, Olanzapine ODT Generichealth, Olanzapine ODT Sanis Health, Olanzapine ODT Teva, Olanzapine ODT-DRLA, Olanzapine Orion, Olanzapine Polpharma, Olanzapine Prasco, Olanzapine Ranbaxy, Olanzapine Ratiopharm, Olanzapine Sandoz, Olanzapine Sanis Health, Olanzapine Sanovel, Olanzapine Stada, Olanzapine Sun, Olanzapine Synthon, Olanzapine Teva, Olanzapine Torrent, Olanzapine Zentiva, Olanzapine Zentiva Lab, Olanzapine Zydus, Olanzapine-DRLA, Olzapine
    P
    Q
    R
    S
    T
    U
    V
    W
    X
    Y
    ZZyprexa, Zolafren

    Dosage forms

    Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 milligrams. Zyprexa (and generic olanzapine) is available as an orally-disintegrating "wafer" which rapidly dissolves in saliva. It is also available in 10 milligram vials for intramuscular injection.[74]

    Cost

    In the United States, the wholesale cost is less than US$0.25 per dose as of 2018.[12]In 2017, it was the 239th most commonly prescribed medication in the United States, with more than two million prescriptions.[13][14]

    • Olanzapine costs (US)
      Olanzapine costs (US)
    • Olanzapine prescriptions (US)
      Olanzapine prescriptions (US)

    Research

    Olanzapine has been studied as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV).[129]

    In general, olanzapine appears to be about as effective as aprepitant for the prevention of CINV, though there are some concerns for its use in this population. For example, concomitant use of metoclopramide or haloperidol increases the risk for extrapyramidal symptoms (EPS). Otherwise, olanzapine appears to be fairly well tolerated for this indication, with somnolence being the most common side effect.[130]

    Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education (PRIME) study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo.[131] In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.[132]

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