Olanzapine

Usage

• Medical Conditions: Olanzapine is prescribed for the treatment of schizophrenia, moderate to severe manic episodes associated with bipolar I disorder, and maintenance therapy for bipolar I disorder to prevent the recurrence of manic or mixed episodes. It is also used in combination with fluoxetine for the treatment of depressive episodes associated with bipolar I disorder. Olanzapine is sometimes used off-label for agitation, chemotherapy-induced nausea and vomiting, and other conditions.
• Pharmacological Classification: Atypical antipsychotic.
• Mechanism of Action: Olanzapine acts as an antagonist at multiple receptors, primarily dopamine and serotonin receptors (including dopamine D1, D2, D3, D4, and serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6 receptors), and also at muscarinic, histamine H1, and alpha-1 adrenergic receptors. Its therapeutic effects are primarily thought to be mediated through dopamine and serotonin receptor antagonism.

Alternate Names

• International/Regional Variations: The generic name “olanzapine” is widely used internationally.
• Brand Names: Zyprexa, Zyprexa Zydis (orodispersible tablets), Zyprexa Relprevv (extended-release injection), and Lybalvi (combination with samidorphan).

How It Works

• Pharmacodynamics: Olanzapine primarily affects the central nervous system by blocking dopamine and serotonin receptors. This action helps regulate mood, thoughts, and behavior in patients with schizophrenia and bipolar disorder. The drug also has some anticholinergic, antihistaminic, and alpha-1 adrenergic blocking effects.
• Pharmacokinetics:
  • Absorption: Olanzapine is well-absorbed orally, reaching peak plasma concentrations in approximately 5 to 8 hours. Food does not significantly affect its absorption.
  • Metabolism: Olanzapine is extensively metabolized in the liver primarily by CYP1A2 and to a lesser extent by CYP2D6. Smoking can induce CYP1A2 and lead to increased olanzapine metabolism.
  • Elimination: Olanzapine and its metabolites are primarily eliminated in the urine (57%) and feces (30%). The elimination half-life of olanzapine is variable, averaging around 30 hours, but can range from 21 to 54 hours, and may be prolonged in the elderly and those with hepatic or renal impairment.
• Mode of Action: Olanzapine’s primary mode of action involves blocking dopamine and serotonin receptors in the brain. By binding to these receptors, it reduces the effects of these neurotransmitters.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Olanzapine binds to several dopamine and serotonin receptor subtypes, including D1, D2, D3, D4, 5-HT2A, 5-HT2C, 5-HT3, and 5-HT6. It also has some affinity for muscarinic, histamine H1, and alpha-1 adrenergic receptors.
• Elimination Pathways: Primarily hepatic metabolism (CYP1A2 and CYP2D6) followed by excretion of metabolites in urine and feces.

Dosage

Standard Dosage

Adults:

• Schizophrenia: Initial dose is 5-10 mg orally once daily, usually titrated to a target dose of 10 mg/day. Dose adjustments can be made in 5 mg increments at intervals of not less than 1 week. The maximum dose is generally 20 mg/day, although higher doses (up to 40 mg/day) may be used in treatment-resistant cases with careful monitoring.
• Bipolar Mania (Monotherapy): Initial dose is 10 or 15 mg orally once daily. Dose adjustments can be made in 5 mg increments/decrements at intervals of not less than 24 hours. Maintenance dose is 5-20 mg orally once daily. Maximum dose: 20 mg/day.
• Bipolar Mania (Adjunctive Therapy with Lithium or Valproate): Initial dose is 10 mg orally once daily. Adjustments can be made as clinically indicated, not to exceed 20 mg/day.
• Bipolar Depression (with Fluoxetine): Initial dose is 5 mg olanzapine with 20 mg fluoxetine once daily in the evening. Your doctor may adjust the dose as needed, but the maximum is typically 18 mg olanzapine with 75 mg fluoxetine daily.

Children:

• Olanzapine is not approved for use in children younger than 13 years for the treatment of schizophrenia and bipolar I disorder.
• Schizophrenia (13-17 years): Initial: 2.5 to 5 mg once daily. Target: 10 mg once daily; further dose adjustments in 2.5-5 mg increments at intervals not less than 1 week. Maximum: 20 mg/day.
• Bipolar I Disorder (13-17 years): Initial: 2.5 to 5 mg once daily. Target: 10 mg once daily; further dose adjustments in 2.5-5 mg increments as needed. Maximum: 20 mg/day.

Special Cases:

• Elderly Patients: A lower starting dose (5 mg/day) is recommended for patients 65 years or older.
• Patients with Renal Impairment: No routine dose adjustment is necessary, but a lower initial dose may be considered. Not recommended for patients with end-stage renal disease.
• Patients with Hepatic Dysfunction: No routine dose adjustment is necessary, but a lower initial dose may be considered in moderate hepatic impairment.
• Patients with Comorbid Conditions: Caution is advised in patients with cardiovascular disease, diabetes, prostatic hypertrophy, narrow-angle glaucoma, history of paralytic ileus, or seizures.

Clinical Use Cases

Olanzapine is not specifically indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. Other medications are generally preferred for these purposes. However, olanzapine may be used for agitation or delirium in these settings on a case-by-case basis under careful supervision. For agitation associated with schizophrenia or bipolar mania, short-acting intramuscular olanzapine can be used (2.5-10 mg/dose). Additional doses up to a maximum of 30 mg/day may be given, but with caution due to the risk of orthostatic hypotension.

Dosage Adjustments

Dose adjustments may be required based on individual patient response, tolerability, age, concurrent medications, and the presence of renal or hepatic impairment. Slow titration and careful monitoring are crucial, especially in special populations.

Side Effects

Common Side Effects:

• Somnolence, dizziness, weight gain, increased appetite, dry mouth, constipation, orthostatic hypotension, akathisia, extrapyramidal symptoms, hyperprolactinemia, asthenia, peripheral edema, elevated liver enzymes, and hyperglycemia.

Rare but Serious Side Effects:

• Neuroleptic malignant syndrome (NMS), tardive dyskinesia, seizures, severe neutropenia, DRESS syndrome, hyperglycemia, diabetic ketoacidosis, hyperosmolar coma, venous thromboembolism, and suicidal thoughts or behavior.

Long-Term Effects:

• Weight gain, metabolic syndrome, diabetes, dyslipidemia, cardiovascular disease, tardive dyskinesia.

Adverse Drug Reactions (ADR):

• NMS, severe hypersensitivity reactions, agranulocytosis, severe dyslipidemia, life-threatening hyperglycemia, and QT prolongation.

Contraindications

• Hypersensitivity to olanzapine.
• Dementia-related psychosis in elderly patients.
• Comatose states.
• Angle-closure glaucoma.
• Concurrent use of strong CYP1A2 inhibitors.
• Use with caution in patients with:
  • Parkinson’s disease.
  • Cardiovascular disease.
  • Seizures.
  • Prostatic hypertrophy.
  • Pheochromocytoma.

Drug Interactions

• CYP1A2 Inducers (e.g., smoking, carbamazepine, rifampin): Can decrease olanzapine levels.
• CYP1A2 Inhibitors (e.g., fluvoxamine, ciprofloxacin): Can increase olanzapine levels.
• CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine): Can moderately increase olanzapine levels.
• Alcohol, CNS depressants: Additive sedative effects.
• Antihypertensives: Increased risk of hypotension.
• Dopamine agonists: May antagonize effects.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (FDA). Not assigned since 2015 when letters A, B, C, D and X were replaced by PLLR (Pregnancy and Lactation Labeling Rule).
• Fetal Risks: Increased risk of extrapyramidal and/or withdrawal symptoms in neonates exposed to antipsychotics during the third trimester.
• Breastfeeding: Olanzapine is excreted in breast milk. Weigh the benefits of breastfeeding against potential risks to the infant. Consider alternative medications if necessary.

Drug Profile Summary

• Mechanism of Action: Dopamine and serotonin receptor antagonist.
• Side Effects: Somnolence, weight gain, dizziness, dry mouth, constipation, metabolic changes.
• Contraindications: Hypersensitivity, dementia-related psychosis in the elderly.
• Drug Interactions: CYP1A2 inducers/inhibitors, CNS depressants, antihypertensives.
• Pregnancy & Breastfeeding: Use with caution. Monitor infants for adverse effects.
• Dosage: Schizophrenia: 5-20 mg/day; Bipolar mania: 5-20 mg/day.
• Monitoring Parameters: Weight, blood glucose, lipids, liver function tests, extrapyramidal symptoms, prolactin levels, complete blood count.

Popular Combinations

• Fluoxetine: For treatment-resistant depression in bipolar I disorder.
• Lithium or Valproate: For the treatment of acute manic or mixed episodes in bipolar I disorder.

Precautions

• Monitor for metabolic changes (weight gain, hyperglycemia, dyslipidemia), NMS, extrapyramidal symptoms, QT prolongation, and suicidal thoughts/behavior.
• Advise patients to avoid alcohol and other CNS depressants.
• Caution is necessary in elderly patients, patients with renal or hepatic impairment, and patients with cardiovascular disease, seizures, or diabetes.
• Avoid abrupt discontinuation; taper dose gradually.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Olanzapine?

A: The standard adult dose for schizophrenia and bipolar mania is 5-20 mg/day. Lower doses are recommended for elderly patients (starting at 5 mg/day) and those with renal or hepatic impairment. Dosage for adolescents (13-17) is 2.5-20 mg/day.

Q2: How should Olanzapine be administered?

A: Olanzapine is available in oral tablets, orally disintegrating tablets, and an extended-release intramuscular injection. Oral formulations should be administered once daily, with or without food. Intramuscular injections are administered by a healthcare professional.

Q3: What are the most common side effects of Olanzapine?

A: Common side effects include drowsiness, weight gain, dizziness, increased appetite, dry mouth, constipation, and extrapyramidal symptoms.

Q4: What are the serious side effects of Olanzapine?

A: Serious side effects include neuroleptic malignant syndrome, tardive dyskinesia, seizures, metabolic syndrome, severe neutropenia, and suicidal ideation.

Q5: Can Olanzapine be used during pregnancy?

A: Olanzapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Monitor neonates for extrapyramidal and/or withdrawal symptoms.

Q6: What are the drug interactions with Olanzapine?

A: Olanzapine interacts with CYP1A2 inducers/inhibitors (smoking, carbamazepine, ciprofloxacin), CYP2D6 inhibitors (fluoxetine, paroxetine), alcohol, and CNS depressants.

Q7: How should Olanzapine be discontinued?

A: Olanzapine should be tapered gradually to minimize the risk of withdrawal symptoms and relapse.

Q8: What monitoring parameters are important for patients on Olanzapine?

A: Monitor weight, blood glucose, lipids, complete blood count, liver enzymes, prolactin, and extrapyramidal symptoms regularly.

Q9: What patient education is essential for Olanzapine?

A: Educate patients about potential side effects, drug interactions, the importance of adherence, and the need to report any unusual symptoms to their healthcare provider. Advise against driving or operating machinery until the effects of the medication are known.

Q10: What are the advantages of using the extended-release injection?

A: The extended-release injection (Zyprexa Relprevv) offers improved adherence in patients who have difficulty taking oral medication regularly. However, post-injection delirium/sedation syndrome (PDSS) can occur and requires monitoring for at least 3 hours post-injection in a healthcare setting.

As of today, February 16, 2025, this information is current, but medical knowledge is constantly evolving. Always consult with the latest guidelines and research when making clinical decisions.