Clozapine is an antipsychotic reserved for treatment-resistant schizophrenia and for reducing the risk of recurrent suicidal behaviour in schizophrenia or schizoaffective disorder. It is highly effective but requires close monitoring: it can cause severe neutropenia (agranulocytosis), so regular blood tests are mandatory.
Also known as: Leponex, Clozaril
Combining Clozapine with Carbamazepine increases the risk of agranulocytosis and also lowers Clozapine concentrations.
Carbamazepine induces CYP1A2 and CYP3A4 and can halve clozapine concentrations, compromising the antipsychotic effect; in addition, both clozapine and carbamazepine are associated with blood dyscrasias (agranulocytosis/neutropenia), and coadministration is traditionally avoided because of the additive haematological risk. Choose an alternative antiepileptic (e.g. valproate, lamotrigine) in patients on clozapine; if unavoidable, monitor the blood count and clozapine levels.
Carbamazepine + clozapine: carbamazepine lowers clozapine levels (CYP1A2/3A4 induction) and both carry additive haematological risk. Avoid the combination.
Both can induce blood dyscrasias; in addition, Carbamazepine induces Clozapine metabolism, lowering its levels.
Regular blood counts (white cells and neutrophils) during combined use.
Fever, sore throat or sudden infection with neutropenia require discontinuation and immediate evaluation.
Avoid the combination whenever possible; if unavoidable, strictly monitor the blood count.
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb ; approved Carbamazepine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f3d91cd-a959-4e07-a51b-8a4e9ba9ece2 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Clozapine with Fluoxetine increases Clozapine concentrations, with a risk of toxicity.
Clozapine is metabolised by CYP1A2 and CYP2D6, and fluoxetine inhibits these enzymes: the clozapine label explicitly states that "fluoxetine, quinidine, duloxetine, terbinafine or sertraline can increase clozapine levels and lead to adverse reactions". Raised clozapine levels potentiate the dose-dependent effects: sedation, sialorrhoea, constipation, tachycardia, hypotension, seizures and, above all, agranulocytosis/neutropenia and myocarditis (serious reactions requiring blood count monitoring). The combination requires: monitoring clozapine plasma levels (or reducing the dose by 30–50% in clinical practice), watching sedation, anticholinergic symptoms and the blood count, and reassessing when fluoxetine is discontinued (levels fall).
Clozapine + fluoxetine: fluoxetine inhibits CYP1A2/2D6 and raises clozapine levels. Monitor levels and adverse effects.
Fluoxetine, a CYP2D6/3A4 inhibitor, reduces Clozapine metabolism, raising its serum levels.
Excessive sedation, drooling, seizures or fever require reassessment.
Sedation, seizures or signs of haematological dyscrasia require reassessment.
Monitor signs of Clozapine toxicity and consider reducing the dose; watch the blood count.
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Alcohol potentiates clozapine sedation, hypotension and respiratory depression and can worsen hepatotoxicity.
Avoid alcohol intake during treatment.
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb
Caffeine inhibits CYP1A2, the enzyme that metabolises clozapine, potentially raising its concentrations and adverse effects.
Keep caffeine intake consistent; abrupt changes can alter clozapine levels.
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb
Clozapine can cause agranulocytosis; patients with a history of agranulocytosis or blood dyscrasias are at increased risk.
Monitor the blood count according to the protocol (weekly for the first 18 weeks).
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb
Clozapine lowers the seizure threshold, with an increased risk of seizures in patients with epilepsy.
Use with caution, titrate slowly and consider lower doses.
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb
Clozapine crosses the placenta; data are limited and there is a risk of maternal agranulocytosis and neonatal effects.
Avoid in pregnancy; use only if severe psychosis does not respond to alternatives.
Present in breast milk; avoid breastfeeding during treatment.
No specific contraception required, but plan pregnancy with the psychiatrist.
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Atypical antipsychotic with affinity for multiple receptors (H1, alpha-1A, 5-HT6, 5-HT2A, M1, D4, 5-HT2C and D2), explaining the effect profile (sedation, orthostatic hypotension, weight gain, hypersalivation). Causes little or no prolactin elevation. Increases delta/theta EEG activity (dose-dependent seizure risk, ~3%).
The exact mechanism is unknown; efficacy in schizophrenia is proposed to be mediated by D2 and 5-HT2A antagonism, with lower extrapyramidal risk than typical antipsychotics.
Oral bioavailability equivalent to the solution (25/100 mg tablets); steady-state peak ~2.5 hours (1-6 h) after dosing; food does not affect absorption. Protein binding ~97%.
Almost completely metabolised before excretion (only traces unchanged in urine and faeces); substrate of multiple CYPs (CYP1A2, CYP2D6, CYP3A4). About 50% of the dose in urine and 30% in faeces. CYP1A2 inhibitors (fluvoxamine) raise levels ~3-fold.
Mean elimination half-life of 8 hours after a single 75 mg dose (range 4-12 h) and 12 hours at steady state (range 4-66 h) — possibly concentration-dependent pharmacokinetics.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
