Olza-5

Olanzapine.

Each film-coated tablet contains: Olanzapine 5 mg.

Pharmacology: The exact mechanism by which olanzapine exerts its antipsychotic effect is unknown. However, this effect may be mediated through a combination of dopamine and serotonin 5-HT₂ antagonism. Olanzapine is a selective monoaminergic antagonist with a strong affinity for serotonin 5-HT_2A and 5-HT_2C receptors and dopamine D₁, D₂, D₃, D₄ receptors. Olanzapine binds weakly to γ-aminobutyric acid type A (GABA_A), benzodiazepine (BZD), and β-adrenergic receptors. Olanzapine's high affinity binding to, and antagonism of, muscarinic M₁, M₂, M₃, M₄ and M₅ receptors may explain its anticholinergic effects. Olanzapine also binds with high affinity to histamine H₁ and α₁-adrenergic receptors. Antagonism of histamine H₁ and α₁-adrenergic receptors may be responsible for the occurrence of somnolence and orthostatic hypotension, respectively, seen with olanzapine use.
Pharmacokinetics: Absorption: Systemic - Well absorbed. Food effects none.
Distribution: Systemic - Vd: 1,000 L.
Metabolism: Systemic - Hepatic: via CYP1A2 and CYP2D6.
Excretion: Systemic - Fecal: 30%, Renal: 57%.
Elimination: Half-life: Systemic - 30 hrs (range 21 to 54 hrs).

Adult >18 years and Children 12-18 years: Schizophrenia, combination therapy for mania, preventing recurrence in bipolar disorder and monotherapy for mania. Use in children should be under specialist supervision.

Adults >18 years: Schizophrenia, Combination Therapy for Mania, Preventing Recurrence in Bipolar Disorder: 10 mg daily adjusted to usual range of 5-20 mg daily. Doses >10 mg daily only after reassessment. Maximum dose: 20 mg daily.
Children 12-18 years: Schizophrenia, Combination Therapy for Mania: Initially 5-10 mg daily adjusted to usual range of 5-20 mg daily. Doses >10 mg daily only after reassessment. Maximum dose: 20 mg daily.
Monotherapy for Mania: 15 mg daily adjusted to usual range of 5-20 mg daily. Doses >15 mg only after reassessment. Maximum dose: 20 mg daily.

Symptoms: Acute: During premarketing trials, 67 cases of acute overdosage with olanzapine were identified. The highest reported ingestion was 300 mg. The only symptoms reported in this patient were drowsiness and slurred speech. Among overdose patients who were evaluated in hospitals, none showed changes in laboratory analysis or electrocardiograms (ECG), and vital signs were usually within normal limits.
Treatment: Multiple drug involvement should be considered. There is no specific antidote to olanzapine.
To Decrease Absorption: Gastric lavage, after intubation if patient is unconscious, and administration of activated charcoal with a laxative should be considered. Activated charcoal has been shown to reduce absorption of olanzapine, and may be of use since olanzapine does not reach peak plasma levels for approximately 6 hrs following ingestion. The risk of aspiration with induction of emesis may be increased by possible obtundation, seizures, or dystonic reaction of the head and neck.
Specific Treatment: Hypotension and circulatory collapse may be treated with IV fluids and/or sympathomimetic agents. Because of olanzapine-induced α-blockade, sympathomimetics with β-agonist activity eg, epinephrine and dopamine, may worsen hypotension and should not be used.
Monitoring: Continuous ECG monitoring should be employed to detect possible arrhythmias. Close medical supervision should continue until patient recovers.
Supportive Care: Airway should be established and maintained to ensure adequate oxygenation and ventilation. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Note: Olanzapine is not removed by dialysis.

Specific contraindications have not been determined.

Neonates exposed to antipsychotic drugs during third semester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity. While in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Olanzapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Anticholinergic properties of olanzapine: Use with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma or history of paralytic ileus.
Body temperature elevation (eg, strenuous exercise, extreme heat exposure, dehydration, concomitant anticholinergic use): Increased risk of hyperthermia.
Cardiovascular or cerebrovascular disease or conditions that predispose patients to hypotension (eg, dehydration, hypovolemia, antihypertensive medications): increased risk of orthostatic hypotension associated with bradycardia, syncope and sinus pause.
Cognitive and motor impairment (sedation-related events) has been reported. Concomitant use of parenteral benzodiazepine and intramuscular olanzapine is not recommended. If considered, monitor for excessive sedation and cardiorespiratory depression is recommended.
Diabetes mellitus, preexisting or borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL): increased risk of hyperglycemia that may not resolve upon discontinuation. Monitoring is recommended.
Hyperglycemia, in some extreme cases associated with ketoacidosis or hyperosmolar coma or death, has been reported. Baseline and periodic monitoring is recommended.
Preexisting diseases or conditions affecting hemodynamic response among elderly patients especially in women: Increased risk of tardive dyskinesia. Treatment discontinuation should be considered.
Hepatic impairment, significant, preexisting conditions associated with limited hepatic functional reserve, or due to concomitant use of hepatotoxic drugs: may increase risk of hepatic impairment.
Hyperlipidemia, hypercholesterolemia and significant hypertriglyceridemia have been reported. Baseline and periodic monitoring is recommended.
Hyperprolactinemia may induce cascade of suppressed hypothalamic gonadotropin releasing hormone (GnRH), reduced pituitary gonadotropin, impaired gonadal steroidogenesis (male/female), and potentially decreased bone density (male/female, when longstanding and associated with hypogonadism).
Increased duration of therapy and/or higher cumulative doses: Increased risk of tardive dyskinesia that is potentially irreversible.
Leukopenia, neutropenia, agranulocytosis temporal relationship has been reported. Monitoring is recommended. Discontinue with significant declines.
Neuroleptic malignant syndrome, potentially fatal, has been reported in association with olanzapine therapy. Immediate discontinuation and supportive treatment are recommended.
Orthostatic hypotension, in some severe cases, has been reported.
Seizure disorder, history, or conditions that may lower seizure threshold (eg, Alzheimer's disease), may increase seizure risk.
Weight gain, some cases clinically significant, has been reported. Monitoring is recommended.
Use in Children: Adolescents 13-17 years: Higher tendency to gain more weight and experience worse hyperlipidemia compared with adults. Assess long-term risk and comprehensive treatment program prior to initiating olanzapine.
Use in the Elderly: Elderly patients with dementia-related psychosis (unapproved use) have increased risk of death. Most deaths were attributed to cardiovascular events (eg, heart failure or sudden death) or infections (eg, pneumonia).
Elderly patients, especially women have increased risk of tardive dyskinesia. Consider treatment discontinuation.

Unless otherwise noted, adverse events are reported for placebo-controlled trials in adult patients on monotherapy.
>10%: Central Nervous System: Somnolence (dose dependent: 20-39%; adolescents: 39-48%), extrapyramidal symptoms (dose dependent: <32%), dizziness (11-18%), headache (adolescents: 17%), fatigue (adolescents: 3-14%), insomnia (12%).
Endocrine and Metabolic: Increased prolactin (30%; adolescents: 17%).
Gastrointestinal: Weight gain (5-6%, has been reported as high as 40%; adolescents: 29-31%), increased appetite (3-6%; adolescents: 17-29%), xerostomia (dose dependent: 3-22%), constipation (9-11%), dyspepsia (7-11%).
Hepatic: ALT increased >3 x upper limit of normal (adolescents: 12%; adults: 5%).
Neuromuscular and Skeletal: Weakness (dose dependent: 8-20%).
Miscellaneous: Accidental injury (12%).
1% to 10%: Cardiovascular: Chest pain, hypertension, peripheral edema, postural hypotension, tachycardia.
Central Nervous System: Fever, personality changes, restlessness (adolescents).
Dermatologic: Bruising.
Endocrine and Metabolic: Breast-related events in adolescents (discharge, enlargement, galactorrhea, gynecomastia, lactation disorder), menstrual-related events (amenorrhea, hypomenorrhea, delayed menstruation, oligomenorrhea), sexual function-related events (anorgasmia, delayed ejaculation, erectile dysfunction, changes in libido, abnormal orgasm, sexual dysfunction).
Gastrointestinal: Abdominal pain (adolescents), diarrhea (adolescents), flatulence, nausea (dose dependent), vomiting.
Genitourinary: Incontinence, UTI.
Hepatic: Increased hepatic enzymes.
Neuromuscular and Skeletal: Abnormal gait, akathisia, articulation impairment, back pain, falling, hypertonia, joint/extremity pain, muscle stiffness (adolescents), tremor (dose dependent).
Ocular: Amblyopia.
Respiratory: Cough, epistaxis (adolescents), pharyngitis, respiratory tract infection (adolescents), rhinitis, sinusitis (adolescents).
<1% (limited to important life-threatening): Acidosis, agranulocytosis, anaphylactoid reaction, angioedema, apnea, atelectasis, atrial fibrillation, cerebrovascular accident, congestive heart failure, deafness, diabetes mellitus, diabetic ketoacidosis, diabetic coma, dystonia, encephalopathy, facial paralysis, glaucoma, heart arrest, heart failure, hemorrhage (eye, rectal, subarachnoid, vaginal), hepatitis, hypercholesterolemia, hyper-/hypoglycemia, hyper-/hypokalemia, hyperlipidemia, hyper-/hyponatremia, hypertriglyceridemia, hyperuricemia, hyper-/hypoventilation, hypoproteinemia, hypoxia, jaundice, ileus, ketosis, leukocytosis, (eosinophilia), leucopenia, liver damage (cholestatic or mixed), liver fatty deposit, lung edema, lymphadenopathy, myasthenia, myopathy, neuralgia, neuroleptic malignant syndrome, neutropenia, pancreatitis, paralysis, pulmonary embolus, rash, rhabdomyolysis, seizure, sudden death, suicide attempt, syncope, tardive dyskinesia, thrombocytopenia, transient ischemic attack, venous thrombotic events.

Metabolism/transport effects substrate of CYP1A2 (major), 2D6 (minor). Inhibits CYP1A2 (weak), 2C19 (weak), 2D6 (weak), 3A4 (weak).
Benzodiazepines, metoclopramide: Avoid concomitant use with olanzapine.
Alcohol (ethyl), anticholinergics, benzodiazepines, CNS depressants, methotrimeprazine, methylphenidate: Increased levels/toxicity/effects with olanzapine.
Acetylcholinesterases inhibitors (central), CYP1A2 inhibitors (moderate), CYP1A2 inhibitors (strong), droperidol, fluvoxamine, lamotrigine, lithium formulations, methotrimeprazine, methylphenidate, metoclopramide, pramlintide, tetrabenazine: Increased levels of olanzapine.
Amphetamines, anti-Parkinson's agents (dopamine agonist), quinagolide: Decreased levels/effects.
CYP1A2 inducers (strong), lithium formulations, peginterferon alfa-2b: decreased levels/effects of olanzapine.
Ethanol/Nutrition/Herb Interactions: Ethanol: Avoid ethanol (increased CNS depression).
Herb/Nutraceutical: Avoid dong quai, St. John's wort (may cause photosensitization); kava kava, gotu kola, valerian, St. John's wort (increased CNS depression).

Store at temperature not more than 30°C.

Antipsychotics

N05AH03 - olanzapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics

P₁S₁S₃