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Revision as of 15:08, 4 January 2007 by 67.82.232.151 (talk) (→Legal)(diff) ← Previous revision | Latest revision (diff) | Newer revision → (diff) Pharmaceutical compound | |
| Clinical data | |
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| Pregnancy category |
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| Routes of administration | oral |
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| Legal status | |
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| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Hepatic |
| Elimination half-life | 21-54 hours |
| Excretion | ? |
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IUPAC name
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.125.320  |
| Chemical and physical data | |
| Formula | C17H20N4S |
| Molar mass | 312.439 g·mol |
Olanzapine (oh-LAN-za-peen, sold as Zyprexa®, Zyprexa Zydis®, or in combination with fluoxetine, as Symbyax®) was the third atypical antipsychotic to gain approval by the Food and Drug Administration (FDA) and has become one of the most commonly used atypical antipsychotics. Olanzapine has been approved by the FDA for the treatment of schizophrenia, acute mania in bipolar disorder, agitation associated with schizophrenia and bipolar disorder, and as maintenance treatment in bipolar disorder and psychotic depression.
It has also been established in treating depression off-label because of its mood-stabilizing properties and its ability to increase the efficacy of antidepressants. Olanzapine is manufactured and marketed by the pharmaceutical company Eli Lilly and Company. It is available as a pill that comes in the strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg and as Zydis orally disintegrating tablets in the 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.
Case-reports, open-label, and small pilot studies suggest efficacy of olanzapine for the treatment of some anxiety spectrum disorders (e.g. general anxiety disorder, panic disorder, post-traumatic stress disorder); 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 with psychotic features.
Pharmacology
Olanzapine is structurally similar to clozapine, and is classified as a thienobenzodiazepine. Olanzapine has a high affinity for dopamine and serotonin 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 mechanism of action of olanzapine is unknown, however it is theorized that olanzapine's antipsychotic activity is mediated primarily by antagonism at dopamine receptors(does not allow dopamine to activate the dopamine receptors), specifically D2. Serotonin antagonism may also play a role in the effectiveness of olanzapine, but the significance of 5-HT2A antagonism is debated among researchers. Antagonism at muscarinic, histaminic and alpha adrenergic receptors likely explains some of the side effects of olanzapine, such as anticholinergic effects, weight gain, sedation and orthostatic hypotension.
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.
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
Adverse events reported in the package insert for olanzapine include dry mouth, dizziness, sedation, insomnia, orthostatic hypotension and akathisia. Olanzapine is reported to cause extrapyramidal symptoms, tardive dyskinesia and neuroleptic malignant syndrome, although at a reduced rate when compared to the classical anti-psychotics .
Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics. Additionally there are some case reports of olanzapine-induced diabetic ketoacidosis. There is data showing that olanzapine can decrease insulin sensitivity. In addition, increased triglyceride levels may also be an issue with olanzapine. 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 data suggests that olanzapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.
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.
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."
Data from a small, open-label, non-randomized study seems to suggest that taking olanzapine by orally dissolving tablets may not be associated with the same degree of weight gain as conventional tablet formulations; however this has not been substantiated in a blinded experimental setting.
According to information made available from the U.S. National Library of Medicine the effects of olanzapine on children under the age of eighteen have not been thoroughly researched. Additionally, it is not clearly understood what effect, if any, olanzapine might have on the unborn child of a mother who is being treated with the drug. Laboratory tests have shown that olanzapine can penetrate the placenta in animals. It is also unknown whether or not olanzapine is transferable in human breast-milk. Olanzapine does, however, pass in the breast-milk of laboratory animals.
The effects of olanzapine, in conjunction with other drugs has not been fully studied. Alcohol and any other centrally acting drugs should be avoided while taking olanzapine.
The sedative effects lend to olanzapine's potential as a date rape drug.
Overdose
Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness and coma. Death has been reported after an acute overdose of 450mg, but also survival after an acute overdose of 1500mg.
Legal
On December 7, 2006 Judge Weinstein requested more information regarding a defective product lawsuit against Eli Lilly in regards to Zyprexa so that he may make a decision on remanding the suit. Weinstein's order pertains to the Class Action Fairness Act of 2005 and how the law could be expanded to include the ongoing Zyprexa mass lawsuits. Over 8,000 claimants and a large number of attorneys are involved in the mass tort case against the pharmaceutical firm. Many of theses claimants had their Zyprexa drug and the resulting diabetes paid for by the state Medicaid and the state governments that paid for the medication have found interest in also receiving compensation. Eli Lilly had agreed to a set number of necessary litigants for the $700 million dollar payout to proceed.
According to a New York Times article published on December 17, 2006, 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 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 Times by 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.
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, 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.
External links
Manufacturer site
- Zyprexa.com - 'Zyprexa (Olanzapine): Opening the Door to Possibility' (Eli Lilly's official Zyprexa brand website)
Consumer information
- NIH.gov - 'Olanzapine for schizophrenia', Duggan Lorna, Fenton M, Rathbone J, Dardennes R, El-Dosoky A, Indran S., Cochrane Review (2005)
- MedLibrary.org - 'Information on Zyprexa and How to Use It, Precautions and Other Medications to Avoid While Taking, MedLibrary
- NIH.gov - 'Olanzapine (Systemic)' Drug Information, MedlinePlus
- PsychEducation.org - 'Zyprexa (olanzapine)' (updated April, 2004)
Controversy
- MindFreedom.org - 'Info on "Zyprexa Kills" Campaign', MindFreedom International
- MindFreedom.org - 'Eli Lilly Said to Play Down Risk of Top Pill', Alex Berenson, New York Times (December 17, 2006)
- Zyprexa.pbwiki.com - 'Zyprexa Kills' campaign (with links to the Eli Lilly Memos)
- - Joysoup.net
- - See Eli Lilly court injunctions sent out to public advocates
References
- "Zyprexa package insert" (PDF). Eli Lilly and Company. 13 November 2006. Retrieved 2006-12-18.
Notes
- "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.
- "NIMH study to guide treatment choices for schizophrenia" (Press release). National Institute of Mental Health. 19 September 2005. Retrieved 2006-12-18.
- de Haan, L (2004). "Weight loss after switching from conventional olanzapine tablets to orally disintegrating olanzapine tablets". Psychopharmacology. 175 (3): 389–390. PMID 15322727.
{{cite journal}}:|access-date=requires|url=(help); Cite has empty unknown parameter:|quotes=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - Thomson Healthcare (18 April 2005). "Olanzapine (Systemic)". MedlinePlus. United States National Library of Medicine. Retrieved 2006-12-18.
- Berenson, Alex (17 December 2006). "Eli Lilly Said to Play Down Risk of Top Pill". The New York Times. Retrieved 2006-12-18.
- Mother Wonders if Psychosis Drug Helped Kill Son, New York Times January 4, 2007