Olanzapine

Dosage for Olanzapine is highly individualized based on the specific condition being treated, the severity of symptoms, and the patient's clinical response.

• Schizophrenia: The typical starting dose for adults is 5 mg to 10 mg once daily. The target dose is generally 10 mg per day, though some patients may require adjustments up to a maximum of 20 mg per day. Dose increases, if necessary, should occur at intervals of no less than 24 hours.
• Bipolar I Disorder (Monotherapy): The recommended starting dose is 10 mg to 15 mg once daily. If used as an adjunct to lithium or valproate, the starting dose is usually 10 mg once daily.
• Bipolar Maintenance: Patients should generally continue the dose they were stabilized on during the acute phase, typically ranging from 5 mg to 20 mg per day.
• Treatment-Resistant Depression: When used with fluoxetine, Olanzapine is usually started at 5 mg in the evening, with fluoxetine started at 20 mg.

Olanzapine is approved for use in adolescents (ages 13 to 17) for schizophrenia and bipolar I disorder. However, clinicians are advised to start with lower doses because adolescents are more sensitive to weight gain and lipid changes.

• Schizophrenia/Bipolar I: The suggested starting dose is 2.5 mg to 5 mg once daily. The target dose is 10 mg per day. While the dose can be increased to 20 mg, clinical trials have shown that doses above 10 mg do not necessarily provide additional benefit in this age group but do increase side effects.

Renal Impairment

While Olanzapine is not significantly cleared by the kidneys in its active form, dosage adjustments are generally not required for patients with renal failure. However, a lower starting dose (5 mg) may be considered for patients with severe renal impairment to ensure tolerability.

Hepatic Impairment

Patients with significant hepatic impairment (cirrhosis, Child-Pugh Class A or B) should be started on a lower dose of 5 mg per day. Dose escalation should be performed with extreme caution, as the liver is the primary site of metabolism.

Elderly Patients

In patients over the age of 65, the clearance of Olanzapine may be reduced. A starting dose of 5 mg per day is recommended, particularly if other factors (such as female gender or non-smoking status) are present that might further slow metabolism.

• Consistency: Take Olanzapine exactly as prescribed by your doctor. It is typically taken once daily, with or without food. Taking it at the same time each evening can help manage daytime sleepiness.
• ODT Formulation: If using the orally disintegrating tablet (Zyprexa Zydis), ensure your hands are dry before handling the tablet. Peel back the foil (do not push the tablet through) and place it on your tongue immediately. It will dissolve in seconds and can be swallowed with saliva.
• Swallow Whole: Standard tablets should be swallowed whole with a glass of water. Do not crush or chew them unless specifically instructed by your pharmacist.
• Storage: Store Olanzapine at room temperature (68°F to 77°F), away from light and moisture. Keep all medication out of the reach of children.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and resume your regular dosing schedule. Never take two doses at once to make up for a missed one, as this increases the risk of toxicity.

Olanzapine overdose can be life-threatening. Symptoms of overdose include extreme drowsiness, slurred speech, agitation, increased heart rate (tachycardia), jerky muscle movements, and loss of consciousness. In severe cases, it can lead to cardiac arrest or respiratory depression.

If an overdose is suspected, call 911 or your local emergency services immediately. There is no specific antidote for Olanzapine; treatment in an emergency room typically involves gastric lavage, administration of activated charcoal, and supportive care to monitor heart and lung function.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or stop taking the medication without medical guidance, as sudden discontinuation can lead to a return of symptoms or withdrawal-like effects.

Olanzapine is associated with several common side effects that often appear early in treatment. Many of these are dose-dependent.

• Somnolence (Drowsiness): This is the most frequently reported side effect. Patients often feel significantly tired or 'drugged' during the first few weeks of therapy. This usually improves over time but may require a dose adjustment if it interferes with daily functioning.
• Weight Gain: Olanzapine is known for causing significant weight gain. Clinical trials have shown that patients can gain an average of 2.6 kg (5.7 lbs) within the first 6 weeks, and long-term gain can exceed 10-15% of initial body weight. This is driven by increased appetite and metabolic changes.
• Increased Appetite: Many patients report a 'voracious' hunger, particularly for carbohydrates and sweets.
• Dry Mouth (Xerostomia): A result of the drug's anticholinergic properties.
• Dizziness and Orthostatic Hypotension: A feeling of lightheadedness when standing up quickly, caused by a drop in blood pressure.

• Peripheral Edema: Swelling of the hands, ankles, or feet.
• Constipation: Slowed digestive motility due to muscarinic receptor blockade.
• Tremor and Akathisia: A feeling of inner restlessness or the need to move constantly.
• Elevated Liver Enzymes: Asymptomatic increases in ALT and AST are common and usually transient.
• Speech Impairment: Slurring or slowing of speech.

• Seizures: Olanzapine lowers the seizure threshold; caution is needed in patients with a history of epilepsy.
• Priapism: A painful, prolonged erection that requires emergency medical intervention.
• Bradycardia: An unusually slow heart rate.
• Photosensitivity: Increased sensitivity of the skin to sunlight, leading to easier burning.

> Warning: Stop taking Olanzapine and call your doctor immediately if you experience any of these.

• Neuroleptic Malignant Syndrome (NMS): A potentially fatal reaction characterized by high fever, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure).
• Tardive Dyskinesia (TD): A serious condition involving uncontrollable, repetitive muscle movements, usually in the face, tongue, or jaw. This may become permanent even after stopping the drug.
• Hyperglycemia and Diabetes: Olanzapine can cause extreme elevations in blood sugar, leading to ketoacidosis, coma, or death. Symptoms include extreme thirst, frequent urination, and fruity-smelling breath.
• DRESS Syndrome: Drug Reaction with Eosinophilia and Systemic Symptoms. This is a severe skin reaction that can affect internal organs. Look for rash, fever, and swollen lymph nodes.
• Suicidal Thoughts: Especially in children and young adults, there may be an increase in thoughts of self-harm during the initial weeks of treatment.

Prolonged use of Olanzapine requires vigilant monitoring for metabolic syndrome. This includes a combination of significant weight gain, high blood pressure, high blood sugar, and abnormal cholesterol levels (dyslipidemia). These factors significantly increase the long-term risk of cardiovascular disease and Type 2 Diabetes. Additionally, long-term use may lead to hyperprolactinemia (elevated prolactin levels), which can cause menstrual irregularities in women, breast enlargement in men (gynecomastia), and sexual dysfunction.

Elderly Patients with Dementia-Related Psychosis: The FDA has issued a Black Box Warning stating that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Most deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Olanzapine is NOT approved for the treatment of patients with dementia-related psychosis.

Report any unusual symptoms to your healthcare provider. Regular blood tests and physical exams are necessary to monitor for these effects.

Olanzapine is a powerful medication that affects multiple organ systems. Patients must be aware that this drug can impair judgment, thinking, and motor skills. It is essential to avoid activities requiring high alertness, such as driving or operating heavy machinery, until you are certain of how the medication affects you. Furthermore, Olanzapine can impair the body's ability to regulate core temperature; patients should avoid becoming overheated or dehydrated.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Clinical trials have demonstrated that elderly patients with dementia who are treated with atypical antipsychotics like Olanzapine have a significantly higher risk of death compared to those receiving a placebo. The causes of death vary but are often related to cardiovascular events or infections like pneumonia. Olanzapine is not indicated for this population, and healthcare providers must weigh the risks heavily if considering off-label use.

• Metabolic Changes: All atypical antipsychotics can cause metabolic changes, but Olanzapine is among those with the highest risk. This includes hyperglycemia (high blood sugar), dyslipidemia (abnormal cholesterol/triglycerides), and significant weight gain. Patients with pre-existing diabetes must monitor their blood glucose very closely.
• Orthostatic Hypotension: Olanzapine may induce low blood pressure when changing positions (sitting to standing), which can lead to fainting (syncope) and falls. This is most common during the initial dose-titration period.
• Seizures: Use with caution in patients with a history of seizures or conditions that lower the seizure threshold (e.g., Alzheimer's dementia).
• Anticholinergic Effects: Olanzapine has significant 'drying' effects. It should be used with caution in patients with urinary retention, prostatic hypertrophy (enlarged prostate), or narrow-angle glaucoma.
• Hyperprolactinemia: Like other dopamine D2 antagonists, Olanzapine elevates prolactin levels. Chronic elevation may be associated with decreased bone density and reproductive dysfunction.

Because of the metabolic risks, the American Diabetes Association and the American Psychiatric Association recommend the following monitoring schedule for patients on Olanzapine:

• Weight/BMI: Baseline, then monthly for the first 3 months, then quarterly.
• Waist Circumference: Baseline and annually.
• Blood Pressure: Baseline and periodically.
• Fasting Plasma Glucose or HbA1c: Baseline, at 3 months, then annually.
• Fasting Lipid Profile: Baseline, at 3 months, then every 5 years (or more frequently if clinically indicated).

Due to its sedative effects and potential for dizziness, Olanzapine can significantly impair your ability to drive or operate complex machinery. This risk is highest during the first few weeks of treatment or following a dose increase. Do not drive until you know how Olanzapine affects your reaction time.

Patients should strictly avoid alcohol while taking Olanzapine. Alcohol can worsen the sedative effects of the medication, leading to extreme drowsiness and an increased risk of respiratory depression or accidental injury.

Never stop taking Olanzapine abruptly. Sudden discontinuation can lead to 'cholinergic rebound' (nausea, vomiting, sweating) and a rapid return of psychotic or manic symptoms. Your doctor will provide a tapering schedule to gradually reduce the dose over several weeks to ensure safety.

> Important: Discuss all your medical conditions, especially heart disease, liver problems, or a history of diabetes, with your healthcare provider before starting Olanzapine.

While there are few absolute contraindications, Olanzapine should not be used with medications that significantly prolong the QT interval or those that cause profound CNS depression without intensive monitoring. Specifically, the use of Olanzapine with parenteral (injectable) benzodiazepines is generally avoided due to the risk of excessive sedation and cardiorespiratory depression.

• CYP1A2 Inducers (e.g., Carbamazepine, Smoking): These can significantly increase the clearance of Olanzapine, lowering its concentration in the blood and reducing its effectiveness. If a patient starts or stops smoking while on Olanzapine, the dose may need a major adjustment.
• CYP1A2 Inhibitors (e.g., Fluvoxamine, Ciprofloxacin): These drugs block the metabolism of Olanzapine, leading to dangerously high levels in the blood and increasing the risk of toxicity.
• CNS Depressants (e.g., Opioids, Benzodiazepines, Sleep Aids): Combining Olanzapine with other sedating medications can lead to profound respiratory depression and extreme lethargy.
• Antihypertensive Agents: Because Olanzapine can cause orthostatic hypotension, combining it with blood pressure medications may cause dangerously low blood pressure.

• Levodopa and Dopamine Agonists: Olanzapine may antagonize (block) the effects of these medications, which are commonly used to treat Parkinson’s disease, potentially worsening Parkinsonian symptoms.
• Anticholinergic Drugs (e.g., Benztropine, Oxybutynin): Combining these with Olanzapine increases the risk of 'anticholinergic toxicity,' which includes confusion, blurred vision, and severe constipation.

• Grapefruit: Unlike many other medications, Olanzapine does not have a major interaction with grapefruit juice, as it is not primarily metabolized by CYP3A4.
• Caffeine: High intake of caffeine can inhibit CYP1A2, potentially increasing Olanzapine levels. Conversely, suddenly stopping caffeine can lower levels.
• High-Fat Meals: While food does not affect the total amount of drug absorbed, very high-fat meals might slightly delay the time to peak concentration, though this is rarely clinically significant.

• St. John’s Wort: This herbal supplement is a potent inducer of various enzymes and may decrease the effectiveness of Olanzapine.
• Valerian and Kava: These herbs have sedative properties and can increase the drowsiness caused by Olanzapine.
• Melatonin: May increase the sedative effect; use with caution.

• Liver Function Tests: Olanzapine can cause asymptomatic elevations in transaminases (ALT/AST). While usually harmless, significant elevations may require drug discontinuation.
• Prolactin Levels: Olanzapine typically increases serum prolactin levels, which can interfere with certain endocrine diagnostic tests.
• Glucose and Lipids: Olanzapine frequently causes elevations in blood sugar and triglycerides, which will be reflected in laboratory results.

For each major interaction, the mechanism usually involves the Cytochrome P450 system (specifically CYP1A2) or additive pharmacodynamic effects (such as sedation or blood pressure lowering). Management strategies include dose titration, frequent blood level monitoring, or choosing alternative medications.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. Even over-the-counter cold medicines can interact with Olanzapine.

Olanzapine is absolutely contraindicated in patients with a known hypersensitivity to the drug or any of its inactive ingredients. An allergic reaction may manifest as a skin rash, hives, swelling of the face or tongue (angioedema), or difficulty breathing. If a patient has previously experienced DRESS syndrome or Stevens-Johnson Syndrome with Olanzapine, they must never take it again.

Relative contraindications require a careful risk-benefit analysis by a physician:

• Dementia-Related Psychosis: Due to the Black Box Warning regarding increased mortality, Olanzapine should generally be avoided in this population unless no other options exist and the family is fully informed of the risks.
• Cardiovascular Disease: Patients with a history of heart failure, recent myocardial infarction (heart attack), or conduction abnormalities should be treated with caution due to the risk of orthostatic hypotension and potential QT prolongation.
• Narrow-Angle Glaucoma: The anticholinergic properties of Olanzapine can increase intraocular pressure, potentially worsening this condition.
• History of Paralytic Ileus: Olanzapine can further slow down the digestive tract, which may lead to a life-threatening bowel obstruction in susceptible patients.
• Hepatic Impairment: Because the liver is the primary site of clearance, patients with liver failure are at a high risk of drug accumulation and toxicity.

There is a potential for cross-sensitivity between Olanzapine and other thienobenzodiazepines or chemically related antipsychotics like clozapine. Patients who have had severe adverse reactions to clozapine should be monitored closely when starting Olanzapine, as they may share similar metabolic or allergic pathways.

> Important: Your healthcare provider will evaluate your complete medical history, including any history of 'fainting spells' or metabolic issues, before prescribing Olanzapine.

Olanzapine is classified as a medication that should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. According to the FDA, neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery. These symptoms can include agitation, hypertonia (increased muscle tone), hypotonia (decreased muscle tone), tremor, somnolence, and respiratory distress. There is a pregnancy registry (National Pregnancy Registry for Atypical Antipsychotics) to monitor outcomes in women exposed to these medications.

Olanzapine is excreted into human breast milk. Studies indicate that a nursing infant may receive approximately 2% of the maternal weight-adjusted dose. While this is relatively low, there are concerns regarding potential sedation, poor feeding, and developmental delays in the infant. Healthcare providers generally recommend monitoring the infant closely for these symptoms or considering alternative feeding methods if Olanzapine is necessary for the mother.

Olanzapine is FDA-approved for adolescents (ages 13-17) for schizophrenia and Bipolar I disorder. However, the safety profile in children is different than in adults. Adolescents are significantly more likely to experience profound weight gain and extreme elevations in liver enzymes and prolactin. Because of these risks, Olanzapine is typically not the first-line choice for pediatric patients unless other medications have failed.

In patients aged 65 and older, Olanzapine must be used with extreme caution. The risk of death is higher (see Black Box Warning), and the risk of falls due to orthostatic hypotension is significantly increased. Older adults also tend to have decreased hepatic clearance, meaning the drug stays in their system longer. Starting doses should always be low (e.g., 2.5 mg to 5 mg).

Renal impairment does not significantly affect the pharmacokinetics of Olanzapine, as only a small fraction is excreted unchanged in the urine. No specific dose adjustment is usually required for patients with kidney disease or those on dialysis, although clinical monitoring for tolerability is always advised.

For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), a starting dose of 5 mg is recommended. The drug should be titrated slowly. In patients with severe hepatic failure, Olanzapine should be used with extreme caution, and regular liver function tests are mandatory.

> Important: Special populations require individualized medical assessment. Never share your medication with others, even if they have similar symptoms.

Olanzapine is a thienobenzodiazepine that acts as a multi-receptor antagonist. Its clinical efficacy is primarily attributed to its potent antagonism at Dopamine D2 receptors in the mesolimbic pathway and Serotonin 5-HT2A receptors in the prefrontal cortex. By blocking D2 receptors, it reduces the positive symptoms of schizophrenia (hallucinations/delusions). By blocking 5-HT2A receptors, it facilitates dopamine release in the mesocortical pathway, which is thought to improve negative symptoms (apathy/social withdrawal) and cognitive function. It also has high affinity for 5-HT2C, 5-HT3, 5-HT6, Dopamine D1, D3, D4, Histamine H1, and Alpha-1 adrenergic receptors.

Olanzapine exhibits a dose-response relationship for both its therapeutic effects and its side effects. The onset of action for acute agitation is rapid (within 15-45 minutes via IM injection), but the full antipsychotic or mood-stabilizing effects usually take 2 to 6 weeks to manifest. Tolerance to the sedative effects may develop over time, but tolerance to the antipsychotic effects does not typically occur, making it suitable for long-term maintenance therapy.

| Parameter | Value |

|---|---|

| Bioavailability | ~60% (due to first-pass metabolism) |

| Protein Binding | 93% (primarily Albumin) |

| Half-life | 21 - 54 hours (mean 33 hours) |

| Tmax | ~6 hours |

| Metabolism | Hepatic (CYP1A2, CYP2D6, Glucuronidation) |

| Excretion | Renal 57%, Fecal 30% |

• Molecular Formula: C17H20N4S
• Molecular Weight: 312.43 g/mol
• Solubility: Practically insoluble in water; soluble in n-phosphate buffer at pH 1.2.
• Structure: It consists of a thienobenzodiazepine core, which is structurally related to clozapine but lacks the agranulocytosis risk associated with clozapine's nitrogen arrangement.

Olanzapine is classified as an Atypical Antipsychotic (also known as a Second-Generation Antipsychotic or SGA). It is related to other medications in this class such as Quetiapine (Seroquel), Clozapine (Clozaril), and Risperidone (Risperdal).