Brand Name: Zyprexa
Zyprexa (Olanzapine) is an atypical antipsychotic used to treat Schizophrenia and acute mania in Bipolar patients. Uses, dosage, side effects of Zyprexa.
ZYPREXA® Olanzapine Tablets
ZYPREXA® ZYDIS® Olanzapine Orally Disintegrating Tablets
ZYPREXA® IntraMuscular Olanzapine for Injection
Contents:
Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Drug Interactions
Adverse Reactions
Overdose
Dosage
Supplied
Zyprexa Patient Information
Warning
| Increased Mortality in Elderly Patients with Dementia-Related Psychosis - Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
ZYPREXA (olanzapine) is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS).
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Description
ZYPREXA (olanzapine) is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular weight of 312.44. The chemical structure is:
Olanzapine is a yellow crystalline solid, which is practically insoluble in water.
ZYPREXA tablets are intended for oral administration only.
Each tablet contains olanzapine equivalent to 2.5 mg (8 µmol), 5 mg (16 µmol), 7.5 mg (24 µmol), 10 mg (32 µmol), 15 mg (48 µmol), or 20 mg (64 µmol). Inactive ingredients are carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, and other inactive ingredients. The color coating contains Titanium Dioxide (all strengths), FD&C Blue No. 2 Aluminum Lake (15 mg), or Synthetic Red Iron Oxide (20 mg). The 2.5, 5.0, 7.5, and 10 mg tablets are imprinted with edible ink which contains FD&C Blue No. 2 Aluminum Lake.
ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) is intended for oral administration only.
Each orally disintegrating tablet contains olanzapine equivalent to 5 mg (16 µmol), 10 mg (32 µmol), 15 mg (48 µmol) or 20 mg (64 µmol). It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid. ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) also contains the following inactive ingredients: gelatin, mannitol, aspartame, sodium methyl paraben and sodium propyl paraben.
ZYPREXA IntraMuscular (olanzapine for injection) is intended for intramuscular use only. Each vial provides for the administration of 10 mg (32 µmol) olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH.
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Clinical Pharmacology
Pharmacodynamics
Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT 2A/2C (K i =4 and 11 nM, respectively), dopamine D 1-4 (K i =11-31 nM), muscarinic M 1-5 (K i =1.9-25 nM), histamine H 1 (K i =7 nM), and adrenergic (alpha) 1 receptors (K i =19 nM). Olanzapine binds weakly to GABA A , BZD, and (beta) adrenergic receptors (K i >10 µM).
The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism. The mechanism of action of olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder is unknown.
Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M 1-5 receptors may explain its anticholinergic effects. Olanzapine's antagonism of histamine H 1 receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic (alpha) 1 receptors may explain the orthostatic hypotension observed with this drug.
Pharmacokinetics
Oral Administration
Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that ZYPREXA tablets and ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) dosage forms of olanzapine are bioequivalent.
Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr).
Administration of olanzapine once daily leads to steady-state concentrations in about one week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age ( see Special Populations ).
Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and (alpha) 1 -acid glycoprotein.
Metabolism and Elimination -- Following a single oral dose of 14 C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4'-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.
Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.
Intramuscular Administration
ZYPREXA IntraMuscular results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.
Special Populations
Renal Impairment -- Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.
Hepatic Impairment -- Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine.
Age -- In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (>65 years) than in non-elderly subjects (
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