Olanzapine
Systematic (IUPAC) name
2-methyl-4-(4-methyl-1-piperazinyl)- 10H-thieno[2,3-b][1,5]benzodiazepine
Identifiers
CAS number	132539-06-1
ATC code	N05AH03
PubChem	4585
DrugBank	132539-06-1
Chemical data
Formula	C17H20N4S
Mol. mass	312.439
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic
Half life	21-54 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	C
Legal status	Prescription only
Routes	oral

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.

Olanzapine is manufactured and marketed by the pharmaceutical company Eli Lilly and Company.

It has also been used to treat Tourette Syndrome.

Contents 1 Pharmacology 2 Dosing and administration 3 Pharmacokinetics 4 Metabolism 5 Side effects 6 Off-label uses 7 Overdose 8 PRIME 9 Legal 10 External links 10.1 Manufacturer site 10.2 Consumer information 10.3 Controversy 11 References 11.1 Notes

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.

Olanzapine's antipsychotic activity is mediated primarily by antagonism at serotonin receptors. Antagonism of muscarinic (M) receptors is associated with extrapyramidal effects such as tardive dyskinesia. Antagonizing H₁ histamine receptors causes sedation.

Dosing and administration

Olanzapine is available as a pill in strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg and as Zydis orally disintegrating tablets 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 usually taken once a day in the evening.

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

This is not a complete list of possible side effects. If you have questions or develop any side effects that concern you, talk to your doctor and/or pharmacist.

• dry mouth
• dizziness
• sedation
• insomnia
• orthostatic hypotension
• akathisia
• weight gain (90% of users experience weight gain)
• runny nose
• low blood pressure
• impaired judgment, thinking, and motor skills
• seizure
• trouble swallowing
• missed periods
• problems in keeping your body temperature regulated
• permanent feelings of hunger (see weight gain)

Development of the incurable neurological disorder tardive dyskinesia is a significant risk with olanzapine.

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

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 are data showing that olanzapine can decrease insulin sensitivity.^{[citation needed]} 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.

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."^[1] 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.[6]

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;^[2] 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.^[3]

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.^{[Package Insert]}

The sedative effects lend to olanzapine's possible abuse as a date rape drug.^{[citation needed]}

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. 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.

Olanzapine has been marketed for dementia by Eli Lilly^{[citation needed]} though it has never been shown to help with the symptoms of dementia.

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.

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.^[4]

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.^[5]

Legal

According to a New York Times article published on December 17, 2006,^[6] 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^[7], and then made available on the public Internet. Eli Lilly got a temporary restraining order from a US District Court signed on January 4th, 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^[8]. The documents can now only be downloaded from public Internet sites outside the US.^[9][10][11]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.^[12] 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, 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.^[13]

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.^[14]

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 4th, 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.^[15]

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
• nytyimes.com - '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)
• ZyprexaKills.ath.cx - Leaked Memos on BitTorrent
• [7] - Joysoup.net [with links to ELI LILLY MEMOS]
• [8] - See Eli Lilly court injunctions sent out to public advocates [with links to Eli Lilly Memos]
• [9] Eli Lilly Rep Talks about Zyprexa - Youtube
• NYTimes.com - Lilly Settles With 18,000 Over Zyprexa (Jan 5, 2007)
• Zyprexa Injury Clock Ticking Away - Signs of the Times (2007)

References

1. ^{Package Insert}  Zyprexa package insert (PDF). Eli Lilly and Company (13 November 2006). Retrieved on December 18, 2006.

Notes

v • d • e Antipsychotics (N05A)
Phenothiazine typical antipsychotics	Chlorpromazine, Fluphenazine, Mesoridazine, Perphenazine, Prochlorperazine, Promazine, Thioridazine, Trifluoperazine
Other typical antipsychotics	Chlorprothixene, Droperidol, Flupentixol, Benperidol,Haloperidol, Loxapine, Molindone, Pimozide, Sulforidazine, Thiothixene
Atypical antipsychotics	Amisulpride, Aripiprazole, Clozapine, Melperone,Olanzapine, Quetiapine, Risperidone, Paliperidone, Sertindole, Sulpiride, Ziprasidone, Zotepine