Clozapine

Atypical antipsychotic – dibenzodiazepine

ATC code: N05AH02

Updated 27 May 2026 · Methodology

Indications

Treatment-resistant schizophrenia

First line

Drug of choice for treatment-resistant schizophrenia per NG181 (2014, 2024 update) and the Spanish SEP 2024. Used after failure of at least two sequential antipsychotic trials from different classes at adequate doses. Starting dose 12.5 mg at bedtime with slow titration to 300–450 mg daily in 2–3 doses. Works in 30–60% of resistant cases – the highest rate among antipsychotics. Also indicated for suicidal behavior in schizophrenia.

Sources

ICD-10: F20.9 · ICD-11: 6A20

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

Insomnia and sleep disorders

Not recommended

Clozapine is a last-line antipsychotic, not a sleep medication. It is prescribed only for treatment-resistant schizophrenia and for reducing suicide risk in schizophrenia or schizoaffective disorder ( 2020 guidelines). For insomnia, clozapine is not used: the risks far outweigh any sedative benefit. The drug can cause agranulocytosis (a sudden drop in neutrophils), myocarditis, cardiomyopathy, metabolic syndrome, orthostatic hypotension, and severe anticholinergic effects. Because of the agranulocytosis risk, the requires mandatory blood-count monitoring under the REMS program. If clozapine was prescribed for insomnia, consider seeking a second opinion immediately – this prescription is dangerous.

Sources

ICD-10: G47.0 · ICD-11: 7A00

How to read tiers A–F

AStrong evidence – first or second line in international guidelines
BRecommended in selected cases
CStudy data contradict each other
DBenefit not proven, no documented harm
FDocumented harm, or risk without benefit

Mechanism of action

An antagonist at dopamine D1, D2, D4, serotonin 5-HT2A, 5-HT2C, 5-HT3, muscarinic, histamine H1, and α1-adrenoceptors. The unique profile with predominant D4 affinity and low D2 affinity explains minimal extrapyramidal effects. Effective in 30–60% of treatment-resistant schizophrenia previously unresponsive to other antipsychotics. Also reduces suicide risk in schizophrenia (InterSePT 2003). CYP1A2-metabolized; smoking halves the concentration.

Safety

Boxed warning

FDA five boxed warnings: severe neutropenia with fatal infection risk; orthostatic hypotension and syncope during titration; seizures at high doses; myocarditis and cardiomyopathy; increased mortality in older adults with dementia. Used only within a mandatory blood-monitoring program.

Contraindications

Clozapine hypersensitivity
History of agranulocytosis or severe neutropenia on clozapine
Bone marrow suppression
Active myeloproliferative disease, myelodysplastic syndromes
Paralytic ileus
Uncontrolled epilepsy
Severe cardiac, hepatic, or renal disease
Pregnancy – with caution

Serious adverse effects

Severe neutropenia and agranulocytosis (1% of patients, fatal infection risk)
Myocarditis and cardiomyopathy
Seizures (dose-dependent, at over 600 mg)
Thromboembolic events
Paralytic ileus and intestinal obstruction
Type 2 diabetes, ketoacidosis
Neuroleptic malignant syndrome

Common adverse effects

Hypersalivation (especially nocturnal)
Drowsiness and sedation
Weight gain (often over 10 kg)
Tachycardia
Constipation (paralytic ileus risk)
Orthostatic hypotension
Hyperglycemia

Pregnancy: can you take Clozapine?

AEMPS summary of product characteristics (section 4.6): only limited clinical data on pregnancies exposed to clozapine are available, and animal studies do not indicate direct or indirect harmful effects on pregnancy, embryo-fetal development, parturition or postnatal development. Caution is advised when prescribing clozapine to pregnant women. Newborns exposed to antipsychotics, including clozapine, during the third trimester are at risk of extrapyramidal or withdrawal symptoms that may vary in severity and duration after birth; agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorders have been reported. These newborns should be monitored carefully.

Breastfeeding: can you take Clozapine?

Milk concentrations are high; infant sedation and agranulocytosis are possible. Not used during lactation.

Calculate RID Full profile on NIH LactMed ↗

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

Practical notes

Monitoring

Mandatory monitoring program per REMS and : CBC with neutrophil count weekly for the first 6 months, every 2 weeks from 6–12 months, then monthly after the first year. Discontinue at neutrophils under 1500/μL. Monitor ECG (myocarditis, cardiomyopathy), weight, glycemia, lipid profile. In smokers and with smoking status changes, clozapine levels shift significantly – dose adjustment is needed.

Drug–drug interactions

3 pairs found. Sorted from critical to minor.

CriticalMetamizole sodiumAnalgesics and antipyretics. Pyrazolones

Mechanism

Both clozapine and metamizole cause agranulocytosis, a sharp fall in neutrophils that can lead to severe and fatal infection (both labels). With metamizole, the reaction does not depend on the dose, can start at any time during treatment or shortly after stopping, and can occur in people who took it before without problems (metamizole label). Metamizole is a pyrazolone analgesic. Pyrazolone analgesics are on the clozapine label's list of bone marrow suppressants, which increase the risk and severity of bone marrow suppression when combined with clozapine. Metamizole also lowers fever, and fever is exactly the sign that calls for an urgent blood count in a patient taking clozapine. Metamizole induces the enzyme CYP3A4 (metamizole label), and cytochrome P450 inducers can lower clozapine levels (clozapine label), but neither label addresses this pair directly.

Symptoms

Agranulocytosis starts with fever, chills, sore throat and painful sores on the lining of the mouth, nose, throat, genital or anal area (metamizole label). In a patient taking clozapine, any sign of infection or a flu-like illness is a warning sign (clozapine label). Metamizole lowers fever, so some early signs may go unnoticed (metamizole label). The full blood count shows a fall in the absolute neutrophil count.

Management

The combination is contraindicated (Spanish clozapine label, sections 4.3 and 4.5). This label rules out starting clozapine together with substances known to have a substantial potential to cause agranulocytosis. It also rules out using clozapine with bone marrow suppressants, a list that includes pyrazolone analgesics. The Spanish medicines agency (AEMPS) advises taking a careful history before prescribing metamizole and not giving it to patients who take medicines that can cause agranulocytosis (AEMPS safety note 15/2018). Metamizole is therefore not an option for pain or fever in a patient taking clozapine. If the patient is already taking both, consider checking the absolute neutrophil count (ANC) more often than the standard schedule (US clozapine label, ). If fever, chills, sore throat or mouth ulcers appear, order a full blood count with differential and stop metamizole at once, without waiting for the result (metamizole label). At a temperature of 38.5 °C or higher, interrupt clozapine and obtain an ANC (US clozapine label, FDA). If the ANC falls below 1000/mm³, stop clozapine immediately, repeat the count daily and do not re-expose the patient to clozapine (Spanish clozapine label).

Sources

Pair details →Metamizole sodium →

MajorTramadolOther opioids

Mechanism

Tramadol and clozapine both depress the central nervous system, and together they raise the risk of profound sedation, respiratory depression, coma and death (tramadol label). Both lower the seizure threshold: tramadol can cause seizures even at recommended doses and adds to the seizure potential of antipsychotics, while the seizure risk of clozapine rises with the dose (tramadol and clozapine labels). Clozapine slows gut motility through its potent anticholinergic effect and tramadol also reduces motility, so together they increase the risk of severe constipation and bowel obstruction (US clozapine and tramadol labels). The liver enzyme CYP2D6 converts tramadol to its active metabolite. The US clozapine label says clozapine can raise levels of drugs broken down by CYP2D6, while the Spanish clozapine label reports no clinically relevant interactions with such drugs. Clozapine is not on the serotonergic drug lists in the tramadol labels, and no document describes serotonin syndrome for this pair.

Symptoms

Central nervous system depression shows as unusual drowsiness, confusion, pinpoint pupils, slow and shallow breathing, and coma in severe cases (tramadol label). Seizures present as sudden loss of consciousness with convulsions and are more likely at higher doses of either drug. Constipation, abdominal distension or pain, nausea and vomiting point to slowed gut motility that can progress to obstruction (US clozapine label). Both drugs can lower blood pressure, causing dizziness or fainting on standing up (clozapine and tramadol labels).

Management

Under the US tramadol label (), combine tramadol with antipsychotics only when other pain treatment options are inadequate. Use the lowest effective tramadol dose and the shortest duration of combined use (Spanish tramadol label). When adding tramadol for a patient who already takes clozapine, start tramadol at a lower dose than usual and titrate to response (US tramadol and clozapine labels). Keep tramadol at or below 400 mg a day, since the seizure risk rises above that dose (tramadol label). Uncontrolled epilepsy contraindicates both tramadol and clozapine (both labels). If seizures occur, reduce the clozapine dose and start anticonvulsant treatment if needed (clozapine label). Warn the patient and carers about drowsiness and signs of respiratory depression, and advise against driving or operating machinery (clozapine and tramadol labels). Check bowel function often, treat constipation promptly and consider preventive laxatives in high-risk patients (US clozapine label).

Sources

Pair details →Tramadol →

ModerateValproic acidAntiepileptics. Fatty acid derivatives

Mechanism

The clozapine SmPC describes the interaction as pharmacodynamic and does not name its mechanism. Clozapine itself lowers the seizure threshold, and the seizure risk rises with the dose (Clozaril label, ). It also causes neutropenia and myocarditis. With valproic acid added, the SmPCs report rare but serious seizures, including in people without epilepsy, and isolated cases of delirium. They also report a higher risk of clozapine-induced neutropenia and myocarditis (clozapine and valproate SmPCs). The drugs do not change each other's blood levels: a study in 11 patients with psychosis found no pharmacokinetic interaction (valproic acid label, FDA).

Symptoms

A seizure, including in a person without epilepsy, confusion and delirium (clozapine SmPC). Signs of neutropenia: fever, sore throat, mouth or throat ulcers, flu-like symptoms, any infection (clozapine SmPC). Signs of myocarditis, most often in the first two months of clozapine treatment: persistent resting tachycardia, palpitations, arrhythmia, chest pain, shortness of breath, rapid breathing, unexplained fatigue, flu-like symptoms (clozapine SmPC).

Management

The SmPCs do not forbid the combination: valproate is given with clozapine under close monitoring of both treatments (clozapine and valproate SmPCs). On clozapine the absolute neutrophil count (ANC) is checked weekly for the first 18 weeks, then monthly to the end of the first year. Extra counts are taken after valproic acid is added, especially in the initial period (clozapine SmPC). With an ANC of 1000–1499/mm3 clozapine continues with counts twice a week until the count stabilises; below 1000/mm3 clozapine is stopped at once and never restarted (clozapine SmPC). With fever, sore throat or any infection the ANC is checked immediately (clozapine SmPC). Before valproate starts, a full blood count with platelets and coagulation tests is done (valproate SmPC). With persistent resting tachycardia, chest pain, shortness of breath or flu-like symptoms clozapine is stopped promptly and the patient is referred to a cardiologist. After myocarditis clozapine is not restarted (clozapine SmPC). After a seizure the clozapine dose is reduced and anticonvulsant treatment is started if needed (clozapine SmPC). The seizure risk rises with the dose, so clozapine is started low and increased slowly (Clozaril label, ). No dose adjustment for blood levels is needed, because no pharmacokinetic interaction was found (valproic acid label, FDA).

Sources

Pair details →Valproic acid →

Label mentions88 mentions

Verbatim lines from the interaction sections, in the language of the label

From this drug’s label

Majorantineoplásicosclass named in the label
«Comentarios: Supresores de la médula ósea (p.ej., carbamazepina, cloranfenicol, sulfonamidas (p.ej., cotrimoxazol), analgésicos pirazolónicos (p.ej., fenilbutazona), penicilamina, agentes citotóxicos…»
AEMPS, section 4.5 · Open on CIMA
MajorCarbamazepine
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inductoras de los enzimas del citocromo P450 puede disminuir los niveles plasmáticos de…»
AEMPS, section 4.5 · Open on CIMA
MajorChloramphenicol
«Comentarios: Supresores de la médula ósea (p.ej., carbamazepina, cloranfenicol, sulfonamidas (p.ej., cotrimoxazol), analgésicos pirazolónicos (p.ej., fenilbutazona), penicilamina, agentes citotóxicos…»
AEMPS, section 4.5 · Open on CIMA
MajorCiprofloxacin
«Comentarios: Sustancias que inhiben el CYP1A2 p. ej. fluvoxamina, cafeína, ciprofloxacino, perazina o anticonceptivos hormonales (CYP1A2, CYP3A4 y CYP2C19)»
AEMPS, section 4.5 · Open on CIMA
MajorCiprofloxacin
«Potential for Other Drugs to Affect Clozapine: Concomitant use of clozapine and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the…»
FDA, section 7 · Open on DailyMed
MajorCo-trimoxazole
«Comentarios: Supresores de la médula ósea (p.ej., carbamazepina, cloranfenicol, sulfonamidas (p.ej., cotrimoxazol), analgésicos pirazolónicos (p.ej., fenilbutazona), penicilamina, agentes citotóxicos…»
AEMPS, section 4.5 · Open on CIMA
MajorCYP1A2 inhibitorsclass named in the label
«Potential for Other Drugs to Affect Clozapine: Concomitant use of clozapine and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the…»
FDA, section 7 · Open on DailyMed
MajorDiphenhydramine
«Potential for Other Drugs to Affect Clozapine: Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine…»
FDA, section 7 · Open on DailyMed
MajorFluvoxamine
«Potential for Other Drugs to Affect Clozapine: Concomitant use of clozapine and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the…»
FDA, section 7 · Open on DailyMed
MajorOmeprazole
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inductoras de los enzimas del citocromo P450 puede disminuir los niveles plasmáticos de…»
AEMPS, section 4.5 · Open on CIMA
MajorPhenytoin
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inductoras de los enzimas del citocromo P450 puede disminuir los niveles plasmáticos de…»
AEMPS, section 4.5 · Open on CIMA
MajorPhenytoin
«Potential for Other Drugs to Affect Clozapine: Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness…»
FDA, section 7 · Open on DailyMed
MajorRifampicin
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inductoras de los enzimas del citocromo P450 puede disminuir los niveles plasmáticos de…»
AEMPS, section 4.5 · Open on CIMA
ModerateAmiodarone
«Potential for Other Drugs to Affect Clozapine: Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT…»
FDA, section 7 · Open on DailyMed
Moderateantiarrhythmicsclass named in the label
«Potential for Clozapine to Affect Other Drugs: Concomitant use of clozapine with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering…»
FDA, section 7 · Open on DailyMed
Moderateanticonceptivos hormonalesclass named in the label
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inhibidores de la actividad de algunos de los isoenzimas del citocromo P450 puede aumentar los…»
AEMPS, section 4.5 · Open on CIMA
Moderateantifúngicos azólicosclass named in the label
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inhibidores de la actividad de algunos de los isoenzimas del citocromo P450 puede aumentar los…»
AEMPS, section 4.5 · Open on CIMA
Moderateantihistamínicosclass named in the label
«Precauciones que incluyen ajuste de dosis: Clozapina puede aumentar los efectos centrales de los depresores del SNC tales como narcóticos, antihistamínicos y benzodiazepinas. Se aconseja especial…»
AEMPS, section 4.5 · Open on CIMA
Moderatebenzodiazepinasclass named in the label
«Precauciones que incluyen ajuste de dosis: Clozapina puede aumentar los efectos centrales de los depresores del SNC tales como narcóticos, antihistamínicos y benzodiazepinas. Se aconseja especial…»
AEMPS, section 4.5 · Open on CIMA
ModerateBupropion
«Potential for Other Drugs to Affect Clozapine: Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine…»
FDA, section 7 · Open on DailyMed
ModerateCaffeine
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inhibidores de la actividad de algunos de los isoenzimas del citocromo P450 puede aumentar los…»
AEMPS, section 4.5 · Open on CIMA
ModerateCaffeine
«Potential for Other Drugs to Affect Clozapine: Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when clozapine is coadministered with these…»
FDA, section 7 · Open on DailyMed
ModerateCarbamazepine
«DRUG INTERACTIONS: Discontinuation of CYP1A2 or CYP3A4 Inducers : Consider reducing clozapine dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are…»
FDA, section 7 · Open on DailyMed
ModerateChlorpromazine
«Potential for Other Drugs to Affect Clozapine: Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT…»
FDA, section 7 · Open on DailyMed
ModerateCitalopram
«Precauciones que incluyen ajuste de dosis: Se han comunicado casos de interacción entre citalopram y clozapina, que puede aumentar el riesgo de reacciones adversas asociadas con clozapina. La…»
AEMPS, section 4.5 · Open on CIMA
ModerateCYP3A4 inducersclass named in the label
«DRUG INTERACTIONS: Concomitant use of Strong CYP3A4 Inducers is not recommended. ( 2.7 , 7.1 )»
FDA, section 7 · Open on DailyMed
ModerateCYP3A4 inhibitorsclass named in the label
«Potential for Other Drugs to Affect Clozapine: Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine…»
FDA, section 7 · Open on DailyMed
ModerateDigoxin
«Comentarios: Sustancias con elevada unión a proteínas (p.ej., warfarina, digoxina)»
AEMPS, section 4.5 · Open on CIMA
ModerateDroperidol
«Potential for Other Drugs to Affect Clozapine: Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT…»
FDA, section 7 · Open on DailyMed
ModerateDuloxetine
«Potential for Other Drugs to Affect Clozapine: Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine…»
FDA, section 7 · Open on DailyMed
ModerateErythromycin
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inhibidores de la actividad de algunos de los isoenzimas del citocromo P450 puede aumentar los…»
AEMPS, section 4.5 · Open on CIMA
ModerateErythromycin
«Potential for Other Drugs to Affect Clozapine: Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine…»
FDA, section 7 · Open on DailyMed
ModerateEscitalopram
«Potential for Other Drugs to Affect Clozapine: Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine…»
FDA, section 7 · Open on DailyMed
ModerateFlecainide
«Potential for Clozapine to Affect Other Drugs: Concomitant use of clozapine with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering…»
FDA, section 7 · Open on DailyMed

From other drugs’ labels

CriticalRitonavir
«Antipsicóticos/Neurolépticos: La coadministración con ritonavir es probable que produzca como resultado un aumento de las concentraciones plasmáticas de clozapina o pimozida y por tanto está…»
AEMPS, section 4.5 · Open on CIMA
MajorDeferasirox
«Interacción con teofilina y otros medicamentos que se metabolizan por CYP1A2: En un estudio con voluntarios sanos, la administración concomitante de deferasirox como un inhibidor del CYP1A2 (a dosis…»
AEMPS, section 4.5 · Open on CIMA
ModerateAmisulpride
«Clozapina: la administración conjunta de amisulprida con clozapina puede aumentar los niveles plasmáticos de amisulprida.»
AEMPS, section 4.5 · Open on CIMA
ModerateCiprofloxacin
«Citocromo P450: Ciprofloxacino inhibe el CYP1A2 y, por lo tanto, puede causar un aumento de la concentración sérica de fármacos que se metabolizan por esta vía, cuando se administran…»
AEMPS, section 4.4 · Open on CIMA
ModerateCiprofloxacin
«DRUG INTERACTIONS: Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration…»
FDA, section 7 · Open on DailyMed
ModerateFluoxetine
«Hemorragia: Los ISRS/IRSN pueden aumentar el riesgo de hemorragia posparto (ver secciones 4.6, 4.8). Se han comunicado raramente otras manifestaciones hemorrágicas (p.ej. hemorragias ginecológicas…»
AEMPS, section 4.4 · Open on CIMA

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Frequently asked

What is Clozapine used for?

Clozapine is evaluated for the following indications with varying evidence strength: Treatment-resistant schizophrenia (evidence tier A), Insomnia and sleep disorders (evidence tier F). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Clozapine?

Common side effects of Clozapine (≥ 1 in 100): Hypersalivation (especially nocturnal), Drowsiness and sedation, Weight gain (often over 10 kg), Tachycardia, Constipation (paralytic ileus risk), Orthostatic hypotension. See the Safety section for uncommon and serious reactions.

Is Clozapine safe during pregnancy?

Is Clozapine compatible with breastfeeding?

Milk concentrations are high; infant sedation and agranulocytosis are possible. Not used during lactation.

Who should not take Clozapine?

Clozapine is contraindicated in: Clozapine hypersensitivity; History of agranulocytosis or severe neutropenia on clozapine; Bone marrow suppression; Active myeloproliferative disease, myelodysplastic syndromes; Paralytic ileus. Full list in the Safety section.

Does Clozapine carry an FDA boxed warning?

Official sources

Direct links to regulator labels. Open in a new tab.

AEMPS / CIMALabel dated 05/26/2026
FDA / DailyMedLabel dated 05/11/2026

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