Clozapine ๐
โ ๏ธ Clozapine can cause severe gastrointestinal hypomotility โ constipation, faecal impaction,
intestinal obstruction and paralytic ileus. This is rare but potentially fatal. Treat constipation as a
medical priority, not a minor side-effect.
โน๏ธ About
- ๐ Always confirm indication, dose, monitoring requirements, interactions and counselling in the
BNF clozapine monograph and local clozapine protocol.
- ๐ฉบ Specialist initiation only; ensure the patient is registered with a UK clozapine monitoring service.
- ๐ฉธ Baseline: FBC with differential/ANC, BP including postural BP, pulse, weight/BMI/waist, glucose/HbA1c, lipids and LFTs.
- โค๏ธ Consider baseline ECG and myocarditis monitoring, e.g. CRP/troponin, according to local protocol.
- ๐ฆ Counsel on neutropenia red flags: fever, flu-like symptoms, sore throat or mouth ulcers โ seek urgent assessment and blood count.
- ๐ฝ Ask about bowels at every review: frequency, stool consistency, abdominal pain, vomiting and bloating. Escalate urgently if red flags occur.
Mode of action
- ๐ง Atypical antipsychotic with broad receptor antagonism: relatively weak/fast-dissociating D2 blockade, 5-HT2A antagonism, plus ฮฑ1, histamine H1 and muscarinic effects.
- These receptor effects explain many adverse effects: sedation, weight gain, postural hypotension, hypersalivation and anticholinergic gastrointestinal hypomotility.
Indications
- ๐งฉ Main UK use: treatment-resistant schizophrenia under specialist care.
- ๐ง May be used at low dose for psychosis in Parkinsonโs disease under specialist supervision, with very cautious titration.
- ๐ก๏ธ Clozapine also has evidence for reducing suicidal behaviour in schizophrenia/schizoaffective disorder, but prescribing remains specialist-led.
Dose Parkinsonโs disease psychosis: specialist low-dose approach
- ๐ Start 12.5 mg at bedtime.
- โฌ๏ธ Increase by 12.5 mg increments, often no more than twice weekly initially; go slower if frail, elderly or autonomic symptoms are present.
- ๐ฏ Typical effective dose is often 25โ50 mg/day, usually at night; use the lowest effective dose.
- โ Doses above 50 mg/day in Parkinsonโs disease should be exceptional and specialist-directed.
Key prescribing advice
- ๐ฉธ Blood monitoring is non-negotiable: clozapine cannot be supplied without compliant FBC/ANC monitoring.
- ๐ฌ Smoking matters: cigarette smoke induces CYP1A2 and lowers clozapine levels. Sudden smoking cessation can raise levels and cause toxicity.
- โ Caffeine changes can also affect clozapine levels; advise consistent intake.
- ๐ง Seizure risk rises with higher dose, high plasma level and rapid titration; avoid abrupt dose increases.
- โฑ๏ธ If clozapine is interrupted for more than 48 hours: do not simply restart the previous dose. Re-titration is usually required, commonly from 12.5 mg once or twice on day 1, following local protocol.
- ๐ฆ Acute infection/inflammation can increase clozapine levels; consider toxicity if sedation, confusion, seizures, hypersalivation or tachycardia develop.
Haematology monitoring โ typical UK schedule
- ๐
Weekly FBC/ANC for the first 18 weeks, then fortnightly up to 1 year, then 4-weekly/monthly if stable.
- ๐
Continue blood monitoring for at least 4 weeks after stopping.
- ๐จ If significant neutropenia occurs, stop clozapine and follow the monitoring service/haematology pathway. Thresholds depend on the service and whether benign ethnic neutropenia applies.
- ๐ Benign ethnic neutropenia: initiation/continuation may be possible under agreed specialist criteria.
GI hypomotility / constipation prevention
- ๐งป Record baseline bowel habit and review regularly using a stool chart where possible.
- ๐ Start a proactive bowel plan according to local policy; many patients need a stimulant laxative ยฑ osmotic/softening agent.
- ๐ง Encourage fluids, fibre and mobility where feasible, but do not rely on lifestyle advice alone.
- ๐ Review constipating co-medicines: opioids, antimuscarinics, iron, calcium-channel blockers and other sedatives.
- ๐ Red flags needing urgent same-day assessment: severe or colicky abdominal pain, persistent vomiting, abdominal distension, absent bowel sounds, no stool/flatus, fever or signs of sepsis.
Cautions
- โค๏ธ Cardiac disease, myocarditis/cardiomyopathy history, persistent tachycardia, QTc concerns or significant cardiovascular risk.
- โก Seizure disorder, alcohol withdrawal risk, head injury or other causes of reduced seizure threshold.
- ๐ง Dementia, frailty, falls risk, sedation risk and autonomic dysfunction/postural hypotension.
- ๐ฌ Diabetes and metabolic risk: weight gain, dysglycaemia and dyslipidaemia.
- ๐๏ธ Glaucoma risk, prostatic symptoms or urinary retention due to anticholinergic effects.
Contraindications
- โ See BNF and the relevant clozapine monitoring service for the full list.
- โ Important examples include previous clozapine-associated agranulocytosis or severe granulocytopenia, uncontrolled epilepsy, severe cardiac/renal/hepatic disease, paralytic ileus, and situations where blood monitoring cannot be assured.
Interactions โ high-yield
- ๐ Full list: see BNF and local pharmacy advice.
- ๐ซ Avoid or use extreme caution with other drugs that can suppress bone marrow, especially carbamazepine.
- ๐งช CYP interactions: inhibitors such as fluvoxamine or ciprofloxacin can increase clozapine levels; inducers such as smoking can reduce levels.
- ๐ค Additive sedation, hypotension and respiratory risk with benzodiazepines, opioids, alcohol and other CNS depressants.
- ๐ฝ Avoid unnecessary anticholinergics because they may worsen clozapine-induced gastrointestinal hypomotility.
Notable adverse effects
- ๐ฆ Neutropenia/agranulocytosis โ potentially fatal; requires strict monitoring and urgent blood count if infection symptoms occur.
- ๐จ Myocarditis, often early, and cardiomyopathy, often later โ watch for chest pain, dyspnoea, persistent tachycardia, fever or flu-like illness.
- ๐ฝ Constipation/ileus from gastrointestinal hypomotility โ prevent, monitor and treat proactively.
- ๐ด Sedation, hypersalivation, postural hypotension, tachycardia, seizures, weight gain and metabolic syndrome.
โฑ๏ธ Missed Doses / 48-Hour Rule
- If clozapine is missed for ≤48 hours: it may usually be continued at the previous dose, but assess sedation, BP, pulse, infection, interacting drugs and reason for missed doses.
- If clozapine is missed for >48 hours: do not restart at the previous dose. Re-titrate, usually from 12.5 mg once or twice on day 1, following local clozapine monitoring service advice.
- Before restarting: check FBC/ANC monitoring status, last dose taken, physical observations, smoking status, infection/inflammation, interacting medicines and whether the patient needs inpatient re-titration.
- High-risk patients: elderly/frail patients, Parkinsonโs disease, cardiac disease, hypotension, dehydration, acute infection or high previous dose need slower re-titration and senior specialist advice.
References
