Olanzapine Olanzapine

Drug and discussionDrug and discussion

IntroductionIntroduction

OlanzapineOlanzapine an atypical antipsychotic approved for the treatment an atypical antipsychotic approved for the treatment of schizophrenia and bipolar disorder. Olanzapine is structurally of schizophrenia and bipolar disorder. Olanzapine is structurally similar to clozapine, but is classified as a thienobenzodiazepine. similar to clozapine, but is classified as a thienobenzodiazepine.

It is a Serotonin dopamine antagonists (SDAs) and also known as It is a Serotonin dopamine antagonists (SDAs) and also known as second-generation or atypical antipsychotic drugs. These drugs second-generation or atypical antipsychotic drugs. These drugs include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), clozapine (Clozaril), and ziprasidone (Geodon). (Seroquel), clozapine (Clozaril), and ziprasidone (Geodon).

ACTIONACTION structurally and pharmacologically similar to the atypical structurally and pharmacologically similar to the atypical

antipsychotic clozapine.antipsychotic clozapine. mechanism of action is not completely understood. mechanism of action is not completely understood. Antipsychotic effects may be related to blockade of dopamine Antipsychotic effects may be related to blockade of dopamine

(D1, D2, D3, D4), serotonin (5HT2, 5HT3, 5HT6), histamine (D1, D2, D3, D4), serotonin (5HT2, 5HT3, 5HT6), histamine (H1), alpha-1 adrenergic and muscarinic (M1-M5, particularly (H1), alpha-1 adrenergic and muscarinic (M1-M5, particularly M1) receptors. M1) receptors.

Typical antipsychotics strongly block dopamine receptors. Typical antipsychotics strongly block dopamine receptors. In contrast, olanzapine blocks serotonin receptors (5HT2) more In contrast, olanzapine blocks serotonin receptors (5HT2) more

strongly than dopamine (D2) receptors. Blockade of 5HT2 strongly than dopamine (D2) receptors. Blockade of 5HT2 receptors is mechanism for effects on negative symptoms in receptors is mechanism for effects on negative symptoms in schizophrenia. schizophrenia.

Muscarinic blocking (anticholinergic) effects and lower affinity Muscarinic blocking (anticholinergic) effects and lower affinity for dopamine receptors may possibly account for the decreased for dopamine receptors may possibly account for the decreased incidence of extrapyramidal symptoms (EPS) seen with incidence of extrapyramidal symptoms (EPS) seen with olanzapine.olanzapine.

Effect on prolactin levels is minimal.Effect on prolactin levels is minimal.

PHARMACOKINETICS:PHARMACOKINETICS:

Well absorbed after oral administration; absorption is not changed Well absorbed after oral administration; absorption is not changed by food. Peak plasma levels occur 5-8 hours after an oral dose. by food. Peak plasma levels occur 5-8 hours after an oral dose.

Plasma levels appear to have a correlation with therapeutic effect, Plasma levels appear to have a correlation with therapeutic effect, requiring about 23 ng/mL for an antischizophrenic effect. requiring about 23 ng/mL for an antischizophrenic effect.

Onset of antipsychotic effects is seen 1-2 weeks of treatment. Onset of antipsychotic effects is seen 1-2 weeks of treatment. Half-life ranges from 21-54 hours (mean 30 hours). Half-life ranges from 21-54 hours (mean 30 hours). Highly protein bound (about 93%) with a volume of distribution of Highly protein bound (about 93%) with a volume of distribution of

10-18 L/kg. 10-18 L/kg. Metabolized in the liver to inactive metabolites mainly by Metabolized in the liver to inactive metabolites mainly by

Cytochrome P450, isozyme CYP1A2, Flavin-containing Cytochrome P450, isozyme CYP1A2, Flavin-containing Monooxygenase (FMO) 3, and N-glucuronidation.Monooxygenase (FMO) 3, and N-glucuronidation.

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Minor pathways involve CYP2D6 and possibly CYPS2C19 Minor pathways involve CYP2D6 and possibly CYPS2C19 isozymes. About 40% is metabolized in the first pass through the isozymes. About 40% is metabolized in the first pass through the liver. liver.

Because of the number of possible routes of metabolism, inhibition Because of the number of possible routes of metabolism, inhibition of cytochrome oxidase pathways does not markedly affect of cytochrome oxidase pathways does not markedly affect elimination of olanzapine. elimination of olanzapine.

About 57% of a dose is excreted in urine principally as metabolites About 57% of a dose is excreted in urine principally as metabolites (only 7% as unchanged drug) and about 30% in the feces.(only 7% as unchanged drug) and about 30% in the feces.

In single dose studies, half-life was not affected by decreased renal In single dose studies, half-life was not affected by decreased renal function or clinically significant cirrhosis (in smokers). function or clinically significant cirrhosis (in smokers).

In general, olanzapine elimination is slower in women, the elderly In general, olanzapine elimination is slower in women, the elderly and non-smokers. In a small single dose study, mean half-life in and non-smokers. In a small single dose study, mean half-life in elderly women was 55 hours, compared to a mean of 49 hours in elderly women was 55 hours, compared to a mean of 49 hours in elderly men. elderly men.

Olanzapine is not removed by dialysis.Olanzapine is not removed by dialysis.

USESUSES Approved for the treatment of acute mania, also are Approved for the treatment of acute mania, also are

useful as adjunctive therapy in treatment-resistant useful as adjunctive therapy in treatment-resistant depression posttraumatic stress disorder (PTSD)and depression posttraumatic stress disorder (PTSD)and behavioral disturbances associated with dementia.behavioral disturbances associated with dementia.

Bipolar Disorder- Olanzapine is effective as Bipolar Disorder- Olanzapine is effective as monotherapy for the treatment of mania and mixed monotherapy for the treatment of mania and mixed states its also effective for the same conditions when states its also effective for the same conditions when combined with lithium or valproate. olanzapine is combined with lithium or valproate. olanzapine is effective for both psychotic and no psychotic patients.effective for both psychotic and no psychotic patients.

IM use olanzapine indicated for agitation that can be IM use olanzapine indicated for agitation that can be associated with schizophrenia or mania. associated with schizophrenia or mania.

Its augment antidepressants in the acute Its augment antidepressants in the acute management of major depression. management of major depression.

Olanzapine is potentially use in treatment-refractory Olanzapine is potentially use in treatment-refractory patients because it has a biochemical profile similar to patients because it has a biochemical profile similar to that of clozapine and is more effective at treating that of clozapine and is more effective at treating negative symptoms than haloperidol. negative symptoms than haloperidol.

OTHER USESOTHER USES

Olanzapine has been found to be effective in autism Olanzapine has been found to be effective in autism and in producing weight gain in patients with anorexia and in producing weight gain in patients with anorexia nervosa. nervosa.

Outwardly aggressive or violent behavior some times Outwardly aggressive or violent behavior some times seen in Acquired immunodeficiency syndrome (AIDS), seen in Acquired immunodeficiency syndrome (AIDS), Tourette's disorder, Huntington's disease, and Lesch-Tourette's disorder, Huntington's disease, and Lesch-Nyhan syndrome. Risperidone n olanzapine is used to Nyhan syndrome. Risperidone n olanzapine is used to control aggression and self-injury in children.control aggression and self-injury in children.

Pregnancy- no increased risk of malformation or Pregnancy- no increased risk of malformation or neonatal complications, except for lower birth weight in neonatal complications, except for lower birth weight in the exposed group. neonates exposed to olanzapine the exposed group. neonates exposed to olanzapine showed trends toward lower birth weights and more showed trends toward lower birth weights and more neonatal intensive care unit admissions than neonates neonatal intensive care unit admissions than neonates exposed to other antipsychotic medication. exposed to other antipsychotic medication.

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Oleanzapine have also been co administered with Oleanzapine have also been co administered with sympathomimetics, such as methylphenidate or sympathomimetics, such as methylphenidate or dextroamphetamine, to children with attention-dextroamphetamine, to children with attention-deficit/hyperactivity disorder (ADHD) who are deficit/hyperactivity disorder (ADHD) who are comorbid for either opposition-defiant disorder or comorbid for either opposition-defiant disorder or conduct disorder. Olanzapine also useful in conduct disorder. Olanzapine also useful in persons who have severe tardive dyskinesia. persons who have severe tardive dyskinesia.

Also its use to suppresses the abnormal Also its use to suppresses the abnormal movements of tardive dyskinesia, but does not movements of tardive dyskinesia, but does not appear to worsen the movement disorder. appear to worsen the movement disorder.

Its effective for treating psychotic depression and Its effective for treating psychotic depression and for psychosis secondary to head trauma, for psychosis secondary to head trauma, dementia, or treatment drugs. dementia, or treatment drugs.

ADVERSE EFFECTSADVERSE EFFECTS

Increased Mortality in Dementia Patients - Olanzapine Increased Mortality in Dementia Patients - Olanzapine has been associated with increased mortality in has been associated with increased mortality in patients treated for psychosis associated with patients treated for psychosis associated with dementia. increased risk of cerebrovascular events in dementia. increased risk of cerebrovascular events in dementia patients including stroke and transient dementia patients including stroke and transient ischemic attacks.ischemic attacks.

Weight Gain - patients gained approximately 2 lb per Weight Gain - patients gained approximately 2 lb per week.week.

Hyperlipidemia - Patients treated with olanzapine Hyperlipidemia - Patients treated with olanzapine may experience serious increases in total cholesterol, may experience serious increases in total cholesterol, LDL cholesterol, and triglycerides. LDL cholesterol, and triglycerides.

ADVERSE EFFECTSADVERSE EFFECTS

Hyperglycemia, Insulin Resistance, Diabetes Mellitus - More impaired in olanzapine as compared to other antipsychotic, elevations in blood glucose that are life-threatening some times. Also olanzapine is associated with an increase in insulin resistance in both obese and non obese patients. olanzapine treatment is associated with an increased risk for the development of type 2 diabetes mellitus.

Somnolence, dry mouth, dizziness, constipation, dyspepsia, increased appetite, akathisia, and tremor are associated with olanzapine use. There is transaminase elevation, but no jaundice. A dose-related risk exists of extrapyramidal side effects.

RECOMMENDED TESTSRECOMMENDED TESTS

Regular assessment of blood sugar. Close monitoring in LDL, TGS, level in

obese and in pt with k/c/o DM, HTN. Pt.

Dosage and AdministrationDosage and Administration

Olanzapine is available as 2.5-, 5-, 7.5-, 10-, 15-, and 20-Olanzapine is available as 2.5-, 5-, 7.5-, 10-, 15-, and 20-mg tablets; as 5-, 10-, 15-, and 20-mg orally mg tablets; as 5-, 10-, 15-, and 20-mg orally disintegrating tablets and vials with 10 mg of disintegrating tablets and vials with 10 mg of olanzapine.olanzapine.

Treatment of Schizophrenia-Treatment of Schizophrenia- Its effective at dosages Its effective at dosages between 7.5 and 20.0 mg per day administered once between 7.5 and 20.0 mg per day administered once daily without regard to meals. A 5 to 10 mg is well daily without regard to meals. A 5 to 10 mg is well tolerated in most adult patients recommended initial tolerated in most adult patients recommended initial dose is then adjusted as necessary within the range of 5 dose is then adjusted as necessary within the range of 5 to 20 mg per day.to 20 mg per day.

Maintenance in Schizophrenia-dosesMaintenance in Schizophrenia-doses of 10 to 20 mg daily of 10 to 20 mg daily of olanzapine are sufficient to prevent psychotic relapse of olanzapine are sufficient to prevent psychotic relapse in stabilized patients.in stabilized patients.

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Treatment of Bipolar DisorderTreatment of Bipolar Disorder - Patients with mania or - Patients with mania or mixed states can usually be started on 10 to 15 mg daily of mixed states can usually be started on 10 to 15 mg daily of oral olanzapine. Doses can be increased to 20 or 25 mg oral olanzapine. Doses can be increased to 20 or 25 mg daily. Similar doses can be prescribed when olanzapine is daily. Similar doses can be prescribed when olanzapine is added to lithium or valproate. Patients with bipolar disorder added to lithium or valproate. Patients with bipolar disorder who have been stabilized can usually be maintained on 5 to who have been stabilized can usually be maintained on 5 to 10 mg of olanzapine daily.10 mg of olanzapine daily.

Special PopulationsSpecial Populations - Patients who are debilitated or - Patients who are debilitated or vulnerable to hypotension should be started on 5 mg or vulnerable to hypotension should be started on 5 mg or less. Doses of 5 to 10 mg orally may effective for less. Doses of 5 to 10 mg orally may effective for schizophrenia or bipolar disorder in these individuals. schizophrenia or bipolar disorder in these individuals.

IM Olanzapine in Agitation Associated with Schizophrenia or IM Olanzapine in Agitation Associated with Schizophrenia or Bipolar Disorder -Bipolar Disorder - IM doses of 2.5 to 10 mg have been IM doses of 2.5 to 10 mg have been effective in reducing agitation. In most cases, 10 mg IM is effective in reducing agitation. In most cases, 10 mg IM is an appropriate initial dose. an appropriate initial dose.

Drug InteractionsDrug Interactions Fluvoxamine and cimetidin increase, whereas Fluvoxamine and cimetidin increase, whereas

carbamazepine and phenytoin decrease serum carbamazepine and phenytoin decrease serum concentrations of olanzapine. concentrations of olanzapine.

Ethanol increases olanzapine absorption by more Ethanol increases olanzapine absorption by more than 25 percent, leading to increased sedation. than 25 percent, leading to increased sedation. Olanzapine has little effect on the metabolism of Olanzapine has little effect on the metabolism of other drugs.other drugs.