Olanzapine detailed information

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Olanzapine detailed information
Clinical data
Pregnancy
category
  • C
Routes of
administration		oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability?
MetabolismHepatic
Elimination half-life21–54 hours
Excretion?
Identifiers
CAS Number
PubChem CID
DrugBank
E number{{#property:P628}}
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Chemical and physical data
FormulaC17H20N4S
Molar mass312.439


Overview

Olanzapine (Zyprexa, Zyprexa Zydis, or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA in 1996[1] for the treatment of schizophrenia, acute manic episodes in bipolar disorder, acute agitation associated with both these disorders, maintenance treatment in bipolar disorder, and, as the Symbyax formulation, for the treatment of depressive episodes associated with bipolar disorder. Off-label uses are listed below.

Olanzapine is manufactured and marketed by the pharmaceutical company Eli Lilly and Company, whose patent for olanzapine proper ends in 2011.

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.

Dosing 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's response to the drug. The dose will also 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.

Pharmacokinetics

Olanzapine displays linear kinetics. Its elimination half-life ranges from 21 to 54 hours. Steady state plasma concentrations are achieved in about a week. Olanzapine undergoes extensive first pass metabolism and bioavailability is not affected by food.

In extreme cases olanzapine can also be administered through an intravenous injection of 10 milligrams.

Metabolism

Olanzapine is metabolized by the cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be increased or decreased 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:

  • akathisia
  • amblyopia
  • dry mouth
  • dizziness
  • sedation
  • insomnia
  • orthostatic hypotension
  • weight gain (90% of users experience weight gain) (see below)
  • increased appetite
  • runny nose
  • low blood pressure
  • impaired judgment, thinking, and motor skills
  • impaired spatial orientation
  • impaired responses to senses
  • seizure
  • trouble swallowing
  • dental problems and discoloration of teeth
  • missed periods
  • problems with keeping body temperature regulated
  • apathy, lack of emotion

Weight gain

Olanzapine induces substantial weight gain. A similar high degree of weight gain is induced by clozapine. Smaller amounts of weight gain are induced by risperidone and quetiapine. Ziprasidone and aripiprazole are considered to be weight neutral antipsychotics. Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics. 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, and recent (2007) evidence suggests that olanzapine may directly affect adipocyte function, promoting fat deposition. There are some case reports of olanzapine-induced diabetic ketoacidosis. There are data showing that olanzapine can decrease insulin sensitivity.[citation needed] Triglyceride levels rose from 99 to 166 in one year with olanzapine, in the CAFE study. In the same study where the median patient age was 23, 46% of male patients on Zyprexa had a waist size of 40" or greater after one year, and 80% saw a 7% or greater weight increase. Impaired glucose metabolism, high triglycerides, and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The results of a large, random-design study funded by NIH's National Institute of Mental Health (NIMH) were published in September 2005. The 18-month study, which involved 1,400 participants at 57 sites around the country, found that "patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those participants taking the other drugs."[2] However, the study also found that olanzapine helped more patients control symptoms for significantly longer than the other drugs. Specifically, after 18 months, the researchers found, 64 percent of the patients taking olanzapine had stopped, while at least 74 percent had quit each of the other medications.[7]. Data from a small, open-label, non-randomized study seem to suggest that taking olanzapine by orally dissolving tablets may not be associated with the same degree of weight gain as conventional tablet formulations;[3] however this has not been substantiated in a blinded experimental setting.

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.

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,[4] panic disorder,[5] post-traumatic stress disorder[6]); 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's syndrome and Stuttering.

Olanzapine has been marketed for dementia by Eli Lilly though it has never been shown to help with the symptoms of dementia. Lilly instructed its sales representatives to suggest that physicians prescribe Zyprexa to older patients with symptoms of dementia. One document states "dementia should be first message" for primary care doctors, since they "do not treat bipolar" or schizophrenia, but "do treat dementia". Three months after its launch, Lilly's Zyprexa campaign, called "Viva Zyprexa", led to 49,000 new prescriptions. In 2002, the company changed the name of the primary care campaign to "Zyprexa Limitless" and began to focus on people with mild bipolar disorder who had previously been diagnosed as depressed, despite the fact that Zyprexa has been FDA approved only for the treatment of mania in bipolar disorder, not depression.[7]

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.[8]

PRIME

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.[9]

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.[10]

Legal

According to a New York Times article published on December 17 2006,[11] 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. These documents and e-mail messages were soon made publicly available as a location hidden Tor service[12], and then made available on the public Internet. Eli Lilly got a temporary restraining order from a US District Court signed on January 4 2007 to stop the dissemination or downloading of Eli Lilly documents about Zyprexa, and this allowed them to get a few US-based websites to remove them; on January 8 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order[13]. The documents can now only be downloaded from public Internet sites outside the US.[14][15][16]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.[17] 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."

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 30kg (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.[18]

Lilly told its sales representatives to suggest that doctors prescribe Zyprexa to older patients with symptoms of dementia. One document states "dementia should be first message" for primary care doctors, since they "do not treat bipolar" or schizophrenia, but "do treat dementia." Three months after its launch, the Zyprexa campaign, called 'Viva Zyprexa', led to 49,000 new prescriptions. In 2002, the company changed the name of the primary care campaign to 'Zyprexa Limitless' and began to focus on people with mild bipolar disorder who had previously been diagnosed as depressed -- even though Zyprexa has been approved only for the treatment of mania in bipolar disorder, not depression.[19]

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.[20]

See also

Footnotes

  1. ↑ "Electronic Orange Book". Food and Drug Administration. April 2007. Retrieved May 24, 2007.
  2. ↑ "NIMH study to guide treatment choices for schizophrenia" (Press release). National Institute of Mental Health. 19 September 2005. Retrieved 2006-12-18.
  3. ↑ 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. PMID 15322727.
  4. ↑ 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. PMID 16139813.
  5. ↑ 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.
  6. ↑ Jakovljević M, Sagud M, Mihaljević-Peles A. (2006). "Olanzapine in the treatment-resistant, combat-related PTSD--a series of case reports". Acta Psychiatr Scand. 26 (1): 45–9. PMID 12752037.
  7. ↑ [1] New York Times, Dec 18, 2006
  8. ↑ Symbyax: Overdosage and Contraindications
  9. ↑ McGlashan T, Zipursky R, Perkins D, Addington J, Miller T, Woods S, Hawkins K, Hoffman R, Lindborg S, Tohen M, Breier A (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". Schizophr Res. 61 (1): 7–18. PMID 12648731.
  10. ↑ McGlashan T, Zipursky R, Perkins D, Addington J, Miller T, Woods S, Hawkins K, Hoffman R, Preda A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, Breier A (2006). "Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis". Am J Psychiatry. 163 (5): 790–9. PMID 16648318.
  11. ↑ [http://www.nytimes.com/2006/12/17/business/17drug.html The New York Times December 17 2006
  12. ↑ The Zyprexa Memos (Requires Tor)
  13. ↑ [2]
  14. ↑ ZyprexaKills: Download the documents and memos as multi-page tiff files
  15. ↑ Canadian journalist Rob Wipond: Download the documents and memos as multi-page tiff files
  16. ↑ Swiss/German web site Boocompany.com: Download or browse the documents and memos as pdf files and OCR-generated searchable ASCII text files
  17. ↑ [3] Eli Lilly was Concerned by Zyprexa Side-Effects from 1998, The Times (London), January 23 2007
  18. ↑ [4] Mother Wonders if Psychosis Drug Helped Kill Son, New York Times, January 4 2007
  19. ↑ [5] New York Times, Dec 18, 2006
  20. ↑ [6] Lilly to Pay Up to $500 Million to Settle Claims. The New York Times, January 4 2007

External links

Manufacturer site

Consumer information

Controversy

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