Olanzapine

Olanzapine is a second-generation antipsychotic used for schizophrenia, bipolar mania, relapse prevention in bipolar disorder and acute agitation. It is effective and widely available as a generic, but it causes the most weight gain and metabolic disturbance of the common antipsychotics, and it is sedating.

Classification. Second-generation antipsychotic, thienobenzodiazepine.

Mechanism. Antagonism of dopamine D2 and 5-HT2A receptors, with strong histamine H1, muscarinic and alpha-1 blockade, which explains sedation, weight gain and anticholinergic effects.

Pharmacokinetics. Well absorbed orally, unaffected by food; peak in 5 to 8 hours (15 to 45 minutes intramuscularly). Metabolised mainly by CYP1A2 and glucuronidation. Half-life about 30 hours. Smoking induces CYP1A2 and lowers levels by about 40%.

Schizophrenia, adults (oral).

• Start 10 mg once daily (5 mg in older adults or if frail).
• Titration: adjust in steps of 5 mg at intervals of at least 1 week.
• Usual 10 to 20 mg daily. Maximum 20 mg daily.
• Duration: at least 12 months after a first episode.

Bipolar mania, adults. Monotherapy 15 mg once daily (10 to 15 mg in some labels); with lithium or valproate 10 mg once daily. Range 5 to 20 mg daily. Relapse prevention 5 to 20 mg daily.

Acute agitation (intramuscular). 10 mg (5 mg in older adults); repeat after 2 hours if needed. Maximum 20 mg intramuscular in 24 hours in many regions (30 mg in others). Do not give within 1 hour of a parenteral benzodiazepine.

Long-acting injection (pamoate, intramuscular). Confirm oral tolerance first. Dose is set from the stabilised oral dose: 150 to 300 mg every 2 weeks or 300 to 405 mg every 4 weeks. Observe for at least 3 hours after each injection for post-injection delirium and sedation.

Adolescents aged 13 to 17 years. Start 2.5 to 5 mg daily, target 10 mg daily, maximum 20 mg daily.

Dose limits. Liver impairment, older adults, women, non-smokers, and use with fluvoxamine or ciprofloxacin: start 5 mg. Kidney impairment: no adjustment.

Contraindications. Hypersensitivity. Narrow-angle glaucoma and prostatic hypertrophy are cautions. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis.

Serious adverse effects. Marked weight gain, hyperglycaemia and diabetes, dyslipidaemia, neuroleptic malignant syndrome, tardive dyskinesia, venous thromboembolism, seizures, orthostatic hypotension, neutropenia (rare), hepatitis, drug reaction with eosinophilia (rare), post-injection delirium sedation syndrome with the pamoate.

Common adverse effects. Sedation, weight gain, increased appetite, dry mouth, constipation, dizziness, raised prolactin (mild), peripheral oedema.

Interactions. Fluvoxamine and ciprofloxacin raise levels; carbamazepine, rifampicin and smoking lower them. Stopping smoking can raise levels by 30 to 50%. Parenteral benzodiazepines add cardiorespiratory depression. Alcohol and sedatives add sedation. Anticholinergics add constipation and retention. Antihypertensives add hypotension. Levodopa is antagonised.

Common prescribing errors. Not monitoring weight and glucose; giving intramuscular olanzapine with an intramuscular benzodiazepine; forgetting the effect of smoking changes; using it for insomnia.

Special groups.

• Pregnancy: use only if benefit outweighs risk; gestational diabetes and large babies are reported; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: low to moderate transfer; monitor the infant for sedation and poor feeding.
• Children: licensed from 13 years; metabolic effects are larger.
• Older adults: start 5 mg; falls and mortality in dementia.
• Kidney impairment: no adjustment.
• Liver impairment: start 5 mg and titrate cautiously.

Formulations. Tablets 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg; orally disintegrating tablets; injection 10 mg vial; pamoate depot. Give once daily with or without food.

Baseline. Weight, BMI, waist, blood pressure, fasting glucose or HbA1c, lipids, prolactin if symptomatic, liver tests, and a baseline rating of extrapyramidal symptoms.

Monitoring. Weight and waist at baseline, 4, 8 and 12 weeks, then annually; fasting glucose or HbA1c and lipids at baseline, 12 weeks, then annually. Check extrapyramidal symptoms at each review and rate abnormal movements every 6 to 12 months. Check blood pressure lying and standing after dose changes. If weight rises by 7% or more of baseline, review the dose and consider a switch.

Stopping. Reduce gradually over several weeks to limit relapse and rebound symptoms.

Referral and escalation. Refer to psychiatry for first-episode psychosis, treatment resistance or severe metabolic change. Fever with rigidity, syncope or seizures needs emergency care.