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*oral formulation combined with fluoxetine: acute treatment of depressive episodes associated with Bipolar I Disorder in adults, acute treatment of treatment resistant depression in adults <ref>treatment resistant depression defined as Major Depressive Disorder in adult patients who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode</ref>
*oral formulation combined with fluoxetine: acute treatment of depressive episodes associated with Bipolar I Disorder in adults, acute treatment of treatment resistant depression in adults <ref>treatment resistant depression defined as Major Depressive Disorder in adult patients who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode</ref>


approved for the ''treatment of the manifestations of psychotic disorders'' on [[September 6]], [[1996]]<ref>
approved for the ''treatment of the manifestations of psychotic disorders'' on [[September 6]], [[1996]]<ref> ref name = NDA 20-592
{{cite web
{{cite web
| title = NDA 20-592
| title = NDA 20-592
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}}</ref>
}}</ref>


approved in combination with fluoxetine for the ''treatment of depressive episodes associated with Bipolar disorder'' on [[December 24]], [[2003]]<ref>
approved in combination with fluoxetine for the ''treatment of depressive episodes associated with Bipolar disorder'' on [[December 24]], [[2003]]<ref> ref name= NDA 21-520
{{cite web
{{cite web
| title = NDA 21-520
| title = NDA 21-520

Revision as of 01:30, 7 September 2009

Olanzapine
Clinical data
Pregnancy
category
  • C
Routes of
administration		oral, intramuscular
ATC code
Legal status
Legal status
  • US: WARNING[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability87% [2]
MetabolismHepatic (direct glucuronidation and CYP mediated oxidation)
Elimination half-life21–54 hours
Excretionurine 57%, feces 30%
Identifiers
  • 2-methyl-4-(4-methyl-1-piperazinyl)-
    10    H-thieno[2,3-b][1,5]benzodiazepine
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.125.320 Edit this at Wikidata
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)
  • CN1CCN(CC1)C1=c2cc(C)sc2=Nc2ccccc2N1

Olanzapine (trade names Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, Rexapin or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA for the treatment of: schizophrenia and Bipolar disorder. The olanzapine formulations are manufactured and marketed by the pharmaceutical company Eli Lilly and Company, whose patent for olanzapine proper expires in 2011. Sales of Zyprexa in 2008 were $2.2B in the US alone, and $4.7B in total.[3]

Indications and Usage

  • 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 valproate)
  • intramuscular formulation: acute agitation associated with Schizophrenia and Bipolar I Mania in adults
  • oral formulation combined with fluoxetine: acute treatment of depressive episodes associated with Bipolar I Disorder in adults, acute treatment of treatment resistant depression in adults [4]

approved for the treatment of the manifestations of psychotic disorders on September 6, 1996[5]

approved in combination with fluoxetine for the treatment of depressive episodes associated with Bipolar disorder on December 24, 2003[6]

approved for acute manic episodes and maintenance treatment in Bipolar disorder on January 14, 2004[7]

and as part of Symbyax for treatment resistant depression on March 23, 2009.[8]

Off-label uses are listed below.

Dosage and administration

Olanzapine is available as a tablet in strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg and orally disintegrating wafers (known as Zydis), which dissolve on the tongue, in strengths of 5 mg, 10 mg, 15 mg and 20 mg. It is also available as a rapid-acting intramuscular injection for short-term acute use.

Dose may be adjusted depending on the person' response to the drug. The dose also will depend on certain medical problems the person may have. It is generally recommended to be taken once daily before bed as it is highly sedating. However, sedation tends to diminish as treatment is pursued.

Dosage forms and strengths

  • Tablets (not scored): 2.5, 5, 7.5, 10, 15, 20 mg
  • Orally Disintegrating Tablets (not scored): 5, 10, 15, 20 mg
  • Intramuscular Injection: 10 mg vial

Pharmacology

Olanzapine is structurally similar to clozapine, and is classified as a thienobenzodiazepine. Olanzapine has a higher affinity for 5-HT2 serotonin receptors than D2 dopamine receptors.

Like most atypical antipsychotics, compared to the older typical ones, olanzapine has a lower affinity for histamine, cholinergic muscarinic and alpha adrenergic receptors. The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism at serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia, and with therapeutic effects. Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at 5-HT2C receptors have also been implicated in weight gain.


Metabolism

Olanzapine is metabolized by the cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be decreased or increased by agents that induce (e.g. cigarette smoke) or inhibit (e.g. fluvoxamine or ciprofloxacin) CYP1A2 activity respectively.

Side effects

As with all neuroleptic drugs, olanzapine can cause tardive dyskinesia and rare, but life-threatening, neuroleptic malignant syndrome.

Other recognised side effects may include:

Metabolic effects

The 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.[citation needed] Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures.[10][11][12][13] The effect is not dose dependent. Olanzapine may directly affect adipocyte function, promoting fat deposition.[14] There are some case reports of olanzapine-induced diabetic ketoacidosis.[15] Olanzapine may decrease insulin sensitivity[16] though one 3-week study seems to refute this.[17] It may also increase triglyceride levels.[11]

Despite weight gain, a large multi-center randomized NIMH study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs.[18] One small, open-label, non-randomized study suggest that taking olanzapine by orally dissolving tablets may induce less weight gain,[19] but this has not been substantiated in a blinded experimental setting.

Off-label uses

Case-reports, open-label, and small pilot studies suggest efficacy of olanzapine for the treatment of some anxiety spectrum disorders (e.g. generalized anxiety disorder,[20] panic disorder,[21] post-traumatic stress disorder[22]); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa) and as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette syndrome and stuttering. Olanzapine is also used in many addiction clinics as a sleep aid (usually 2.5–5 mg) due to its low abuse profile and zero addictive properties.[23]

Prevention of psychosis

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.[24] In this study, patients receiving olanzapine had a lower risk of progressing to psychosis, although the difference did not reach statistical significance. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.[25]

Use in 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.[26] However, a BBC investigation in June 2008 found that this warning was being widely ignored by doctors.[27]

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 1500 mg.[28] There is no specific, known 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.[28]

Animal studies

In a placebo-compared study of six Macaque monkeys receiving olanzapine between 17 and 27 months, a significant brain volume and weight decreases (8-11%) were detected.[29] In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss,[30] with the neurons spared but positioned more closely compared to the controls. [clarification needed] However according to this study the neurons does not seem to be completeley spared. The gray matter shrinking found was 14.6%, but the neuron density increase was only 10.2% which corresponds to approximately a loss of 5% of the neurons.

Controversy, lawsuits and settlements

Further information: Eli Lilly Controversy

According to a New York Times article published on December 17, 2006,[31] "Eli Lilly has engaged in a decade-long effort to play down the health risks of Zyprexa, its best-selling medication for schizophrenia, according to hundreds of internal Lilly documents and e-mail messages among top company managers", most of which had been disclosed as the result of lawsuits by the mentally ill against the company though some had been stolen.[32] These had been sent to a number of journalists by a lawyer advocate for mentally ill opponents of psychiatric treatment. Eli Lilly filed a protection order to stop the dissemination of certain Eli Lilly documents about Zyprexa which they, and the judge, believed to be confidential and "not generally appropriate for public consumption".[32] Temporary injunctions required those who had been received the documents to return them and that the documents be removed from websites which had posted them.[33] In his final judgement, Judge Weinstein issued a permanent judgement against further dissemination of the documents and requiring their return by a number of parties named by Lilly.[32] These health risks include an increased risk for diabetes through Zyprexa's links to obesity and its tendency to raise blood sugar. Zyprexa is Lilly’s top-selling drug, with sales of $4.2 billion last year.

The documents, given to The New York Times by Jim Gottstein, a lawyer representing mentally ill patients, show that Lilly executives kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes. The Times of London also obtained copies of the documents and reported that as early as October 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales.[34] In another document, dated 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."[34]

Lilly’s own published data, which it told its sales representatives to play down in conversations with doctors, has shown that 30 percent of patients taking Zyprexa gain 22 pounds or more after a year on the drug, another study showed 16% of Zyprexa patients gained at least 30 kg (66 pounds) in one year, and some patients have reported gaining 100 pounds or more. But Lilly was concerned that Zyprexa’s sales would be hurt if the company was more forthright about the fact that the drug might cause unmanageable weight gain or diabetes, according to the documents, which cover the period 1995 to 2004. In 2006, Lilly paid $700 million to settle 8,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. Thousands more suits are still pending.[35]

In 2002, British and Japanese regulatory agencies warned that Zyprexa may be linked to diabetes, but even after the FDA issued a similar warning in 2003, Lilly did not publicly disclose their own findings.

Eli Lilly agreed on January 4, 2007 to pay up to $500 million to settle 18,000 lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa. Including earlier settlements over Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who claim they were injured by the drug. At least 1,200 suits are still pending, the company said. About 20 million people worldwide have taken Zyprexa since its introduction in 1996.[36] On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order.[37]

On January 15, 2009 Eli Lilly plead guilty to a misdemeanor charge of illegally marketing Zyprexa for off-label use, and agreed to pay $1.4 billion.[38] Although Lilly had evidence that it is not effective for dementia, Zyprexa was marketed for elderly Alzheimer's patients.[39] The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.[40]

In order to make up for the costs for settling the lawsuits and shrinking sales figures for Zyprexa in the U.S.A. the company increased the prices for this medication in Germany in May 2007 by 18 percent.[41][42]

See also

Note and References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ Burton, Michael E.; Shaw, Leslie M.; Schentag, Jerome J.; Evans, William E. (May 1, 2005). Applied Pharmacokinetics & Pharmacodynamics: Principles of Therapeutic Drug Monitoring. Lippincott Williams & Wilkins; Fourth Edition edition. p. 815. ISBN 978-0781744317. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help)
  3. ^ "Lilly 2008 Annual Report" (PDF). Lilly. 2009. Retrieved 2009-08-06.
  4. ^ treatment resistant depression defined as Major Depressive Disorder in adult patients who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode
  5. ^ ref name = NDA 20-592 "NDA 20-592" (PDF). Food and Drug Administration. 1996-09-06. Retrieved 2009-09-06.
  6. ^ ref name= NDA 21-520 "NDA 21-520" (PDF). Food and Drug Administration. 2003-12-24. Retrieved 2009-09-06.
  7. ^ "NDA 20-592 / S-019" (PDF). Food and Drug Administration. 2004-01-14. Retrieved 2007-10-31.
  8. ^ http://www.forbes.com/feeds/hscout/2009/03/23/hscout625355.html
  9. ^ Makkos Z, Csonka A (2006). "[Akathisia in the course of olanzapine treatment]". Neuropsychopharmacol Hung (in Hungarian). 8 (4): 215–7. PMID 17211056. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Moyer, Paula (2005-10-25). "CAFE Study Shows Varying Benefits Among Atypical Antipsychotics". Medscape Medical News. WebMD. Retrieved 2007-12-03.
  11. ^ a b AstraZeneca Pharmaceuticals (4 April 2006). "Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First Episode Psychosis: A Randomised Double Blind 52 Week Comparison". AstraZeneca Clinical Trials. AstraZeneca PLC. Retrieved 2007-12-03. At week 12, the olanzapine-treated group had more weight gain, a higher increase in [ body mass index ], and a higher proportion of patients with a BMI increase of at least 1 unit compared with the quetiapine and risperidone groups (p<=0.01). {{cite web}}: Check date values in: |date= (help)
  12. ^ Wirshing DA, Wirshing WC, Kysar L, Berisford MA. (1999) Novel antipsychotics: comparison of weight gain liabilities. Journal of Clinical Psychology 60 358-63
  13. ^ "NIMH study to guide treatment choices for schizophrenia" (Press release). National Institute of Mental Health. 19 September 2005. Retrieved 2006-12-18. {{cite press release}}: Check date values in: |date= (help)
  14. ^ Engl J, Rettenbacher M, Fleischhacker WW, Ebenbichler CF (2007). "Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis". Neuropsychopharmacology. Nov;32(11):2431-2; author reply 2433-4. 32 (11): 2431–2.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Fulbright, April R. (2006). "Complete Resolution of Olanzapine-Induced Diabetic Ketoacidosis" (abstract). Journal of Pharmacy Practice. 19 (4). Thousand Oaks, CA: SAGE Publications: 255–258. doi:10.1177/0897190006294180. Retrieved 2007-12-02. Olanzapine has been associated with diabetic ketoacidosis and also with weight gain, lipid abnormalities, and the development of type 2 diabetes.
  16. ^ Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, Lackner E, Joukhadar C, Müller M, Kasper S. (2008). "Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers". Neuropsychopharmacology. 33 (7): 1633–41. {{cite journal}}: |access-date= requires |url= (help)CS1 maint: multiple names: authors list (link)
  17. ^ Sowell, Margaret (August 8, 2003). "Evaluation of Insulin Sensitivity in Healthy Volunteers Treated with Olanzapine, Risperidone, or Placebo: A Prospective, Randomised Study Using the Two-Step Hyperinsulinemic, Euglycemic Clamp". Journal of Clinical Endocrinology & Metabolism. 88 (12). The Endocrine Society: 5875–5880. doi:10.1210/jc.2002-021884. PMID 14671184. Retrieved 2007-12-02. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  18. ^ Carey, Benedict (September 20, 2005). "Little Difference Found in Schizophrenia Drugs". New York Times. The New York Times Company. Retrieved 2007-12-03. {{cite news}}: Check date values in: |date= (help)
  19. ^ de Haan L, van Amelsvoort T, Rosien K, Linszen D (2004). "Weight loss after switching from conventional olanzapine tablets to orally disintegrating olanzapine tablets". Psychopharmacology (Berl). 175 (3): 389–90. doi:10.1007/s00213-004-1951-2. PMID 15322727.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA, Mick E, Kinrys G, Oppenheimer J. (2006). "Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study". Biol Psychiatry. 59 (3): 211–5. doi:10.1016/j.biopsych.2005.07.005. PMID 16139813.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Sepede G, De Berardis D, Gambi F, Campanella D, La Rovere R, D'Amico M, Cicconetti A, Penna L, Peca S, Carano A, Mancini E, Salerno RM, Ferro FM. (2003). "Olanzapine augmentation in treatment-resistant panic disorder: a 12-week, fixed-dose, open-label trial". J Clin Psychopharmacol. 107 (5): 394–6. PMID 16415705.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Jakovljević M, Sagud M, Mihaljević-Peles A. (2006). "Olanzapine in the treatment-resistant, combat-related PTSD—a series of case reports". Acta Psychiatrica Scandinavica. 26 (1): 45–9. doi:10.1111/j.1600-0447.1951.tb10961.x. PMID 12752037.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ {{url=http://www.forbes.com/2004/09/08/cx_mh_0908seroquel.html/id=Template:Antiphyscotic used as sleeping pill | accessdate=2005-12-11}}
  24. ^ McGlashan, T.H. (1 May 2003). "The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design". Schizophrenia Research. 61 (1). Amsterdam: Elsevier: 7–18. doi:10.1016/S0920-9964(02)00439-5. PMID 12648731. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  25. ^ McGlashan, Thomas H. (2006). "Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis". American Journal of Psychiatry. 163 (5). Arlington, VA: American Psychiatric Association: 790–99. doi:10.1176/appi.ajp.163.5.790. PMID 16648318. Retrieved 2007-12-03. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  26. ^ "Important Safety Information for Olanzapine". Zyprexa package insert. Eli Lilly & Company. 2007. Retrieved 2007-12-03. Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. [...] ZYPREXA (olanzapine) is not approved for the treatment of elderly patients with dementia-related psychosis.
  27. ^ "Doctors 'ignoring drugs warning'". BBC News. 17 June 2008. Retrieved 2008-06-22. {{cite news}}: Check date values in: |date= (help); Cite has empty unknown parameter: |coauthors= (help)
  28. ^ a b "Symbyax (Olanzapine and fluoxetine) drug overdose and contraindication information". RxList: The Internet Drug Index. WebMD. 2007. Retrieved 2007-12-03.
  29. ^ Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA (2005). "The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys". Neuropsychopharmacology. 30 (9): 1649–61. doi:10.1038/sj.npp.1300710. PMID 15756305. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, Lewis DA (2008). "Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys". Biol. Psychiatry. 63 (8): 759–65. doi:10.1016/j.biopsych.2007.08.018. PMC 2386415. PMID 17945195. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  31. ^ [http://www.nytimes.com/2006/12/17/business/17drug.html The New York Times December 17, 2006
  32. ^ a b c U:\Cases\Civil L-Z\In re Zyprexa\Documents Leak\Injunction Memo & Order\FINAL INJUNCTION MEMO 2.13.07.wpd
  33. ^ http://www.eff.org/files/filenode/zyprexa/eli-lilly-order.pdf
  34. ^ a b Eli Lilly was Concerned by Zyprexa Side-Effects from 1998, The Times (London), January 23, 2007
  35. ^ [1] Mother Wonders if Psychosis Drug Helped Kill Son, New York Times, January 4, 2007
  36. ^ [2] Lilly to Pay Up to $500 Million to Settle Claims. The New York Times, January 4, 2007
  37. ^ Press Releases: January, 2007 | Electronic Frontier Foundation
  38. ^ [3] Lilly settles Zyprexa suit for $1.42 billion. The Associated Press, January 15, 2009
  39. ^ Cronin Fisk, Martha, Lopatto, Elizabeth and Feeley, Jef (June 1, 2009). "Lilly Sold Drug for Dementia Knowing It Didn't Help, Files Show". Bloomberg L.P. Retrieved 2009-09-03.{{cite news}}: CS1 maint: multiple names: authors list (link)
  40. ^ Berenson, Alex (December 18, 2006). "Drug Files Show Maker Promoted Unapproved Use". The New York Times. Retrieved 2009-09-03.
  41. ^ [http://frontal21.zdf.de/ZDFde/inhalt/28/0,1872,7008412,00.html?dr=1 Tödliche Nebenwirkungen? - Umstrittenes Medikament bringt satte Gewinne]
  42. ^ Zyprexa - Umstrittenes Medikament bringt satte Gewinne

Manufacturer site

Consumer information

Controversy

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