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Olanzapine
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Olanzapine (Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA for the treatment of: schizophrenia on September 6, 1996; depressive episodes associated with bipolar disorder, as part of the Symbyax formulation, on December 24, 2003; acute manic episodes and maintenance treatment in bipolar disorder on January 14, 2004.
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Encyclopedia
Olanzapine (Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA for the treatment of: schizophrenia on September 6, 1996; depressive episodes associated with bipolar disorder, as part of the Symbyax formulation, on December 24, 2003; acute manic episodes and maintenance treatment in bipolar disorder on January 14, 2004. Off-label uses are listed below.
The olanzapine formulations are manufactured and marketed by the pharmaceutical company Eli Lilly and Company, whose patent for olanzapine proper expires 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' 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.
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:
- Aggressiveness
- akathisia inability to remain still
- dry mouth
- dizziness
- irritation
- sedation
- insomnia
- urinary retention
- 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
Of the atypical antipsychotics, olanzapine and clozapine are the most likely to induce weight gain. The effect is not dose dependent. The amount of weight gain experienced will be reduced by keeping an eye on one's diet and sugar consumption. Smaller amounts of weight gain are induced by risperidone and quetiapine. Ziprasidone and aripiprazole are considered to be weight neutral antipsychotics.
Recently the Food and Drug Administration required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with these drugs. 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 that suggest that olanzapine can decrease insulin sensitivity. though there are other studies that seem to refute this
Triglyceride levels rose from 99 to 166 in one year with olanzapine, in the CAFE ("Comparison of Atypicals for First-Episode Psychosis") study. Of the three drugs administered in that study, "olanzapine was associated with the greatest increases in body weight and related measures." 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% gained 7% or more over their baseline weight compared with 57.6% of those receiving risperidone and 50% of those receiving quetiapine." 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 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." 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."
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; however 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, 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 without psychotic features. It has also been used for Tourette's 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 .
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. 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.
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. However, a BBC investigation in June 2008 found that this warning was being widely ignored by doctors.
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. 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.
Animal studies
In a placebo-compared study of six macaques receiving olanzapine for up to 27 months, a significant brain volume and weight decreases were detected. In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss, with the neurons spared but positioned more closely compared to the controls.
Controversy, lawsuits and settlements
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", most of which had been disclosed as the result of lawsuits by the mentally ill against the company though some had been stolen. 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". 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. 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. 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. 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 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.
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. On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order. The documents can now only be downloaded from public Internet sites outside the US.
On January 15, 2009 Eli Lilly plead guility to a misdemeanor charge of illegally marketing Zyprexa for off-label use, and agreed to pay $1.4 billion.
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.
See also
Note and References
External links
Manufacturer site
- - 'Zyprexa (Olanzapine): Opening the Door to Possibility' (Eli Lilly's official Zyprexa brand website)
Consumer information
- - 'Olanzapine for schizophrenia', Duggan Lorna, Fenton M, Rathbone J, Dardennes R, El-Dosoky A, Indran S., Cochrane Review (2005)
- - 'Information on Zyprexa and How to Use It, Precautions and Other Medications to Avoid While Taking, MedLibrary
- - 'Olanzapine (Systemic)' Drug Information, MedlinePlus
- - 'Zyprexa (olanzapine)' (updated April, 2004)
Controversy
- - Call for transparency in the pharmaceutical industry, on Daily Kos.
- - 'Info on "Zyprexa Kills" Campaign', MindFreedom International
- - Lilly Settles With 18,000 Over Zyprexa, Alex Berenson, New York Times (December 17, 2006)
- - 'Zyprexa Kills' campaign (with links to the Eli Lilly Memos)
- - Leaked Memos on BitTorrent
- Eli Lilly Rep Talks about Zyprexa
- - Signs of the Times (2007)
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