Atypical antipsychotic – thienobenzodiazepine
Updated · Methodology
First line
First-line in acute mania and maintenance of bipolar I disorder per CANMAT 2018. Dose 10–20 mg daily. Combined with fluoxetine (Symbyax), -approved for bipolar depression and treatment-resistant depression.
Sources
ICD-10: F31 · ICD-11: 6A60
First line
First-line for schizophrenia and schizoaffective disorder per 2020 and NG178 (2020). Starting dose 5–10 mg once daily at bedtime, titrated to 10–20 mg. Among the most effective atypical antipsychotics (Huhn 2019), but choice is individualized due to metabolic adverse effects. In patients at metabolic syndrome risk, aripiprazole is preferred.
Sources
ICD-10: F20 · ICD-11: 6A20
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Off-label low-dose olanzapine (2.5–5 mg at bedtime) for insomnia is common due to marked sedation via H1 blockade. 2017 does not recommend this use – evidence is absent, and the risk of metabolic disturbance, 5–10 kg weight gain over 6 months, type 2 diabetes, and tardive dyskinesia with prolonged use is not justified by the symptomatic effect. First-line for chronic insomnia is cognitive-behavioral therapy for insomnia (CBT-I). When pharmacotherapy is needed, melatonin or a sedating antidepressant are preferred.
Off-label use, common in Spain, Russia, and Latin America.
Sources
ICD-10: G47.0 · ICD-11: 7A00
An antagonist at dopamine D1, D2, D4, serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, muscarinic M1–M5, histamine H1, and α1-adrenoceptors. The broad receptor profile drives strong antipsychotic effect but also high metabolic disturbance and weight gain rates (among the highest in atypical antipsychotics). The Huhn 2019 network meta-analysis showed one of the highest efficacies. CYP1A2-metabolized.
Boxed warning
FDA boxed warning: increased mortality in elderly patients with dementia on atypical antipsychotics. The Zyprexa Relprevv long-acting form carries post-injection delirium/sedation syndrome (PDSS) risk.
T3 use carries neonatal extrapyramidal and withdrawal risk. In pregnant psychotic patients, decisions are made with the psychiatrist.
Milk concentrations are low. Use during lactation cautiously with monitoring of infant sedation and weight gain.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
1 pair found. Sorted from critical to minor.
Mechanism
Fluvoxamine is a potent inhibitor of CYP1A2, the liver enzyme that mainly clears olanzapine (fluvoxamine and olanzapine labels). With fluvoxamine, mean peak olanzapine concentration (Cmax) rose by 54% in female non-smokers and by 77% in male smokers, and the area under the concentration-time curve (AUC) by 52% and 108% (olanzapine label).
Symptoms
Olanzapine adverse effects become stronger: somnolence, dizziness, orthostatic hypotension (a drop in blood pressure on standing), increased appetite and weight gain with longer use.
Management
The pair is not banned. Drugs cleared through CYP1A2 are started at, or brought down to, the lower end of their dose range when given with fluvoxamine; their effects and adverse reactions are then monitored and the dose is lowered further if needed (fluvoxamine SmPC). If the patient already takes fluvoxamine, olanzapine is started at a lower dose; if fluvoxamine is added to olanzapine, a lower olanzapine dose is considered (olanzapine SmPC). The US Food and Drug Administration () olanzapine label also advises lower olanzapine doses with fluvoxamine.
Sources
Verbatim lines from the interaction sections, in the language of the label
«Potential for Other Drugs to Affect Olanzapine: Fluvoxamine : Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following…»FDA, section 7 · Open on DailyMed
«Potential for Other Drugs to Affect Olanzapine: Fluvoxamine : Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following…»FDA, section 7 · Open on DailyMed
«Neutropenia: Se deben tomar precauciones en pacientes que presentan recuentos bajos de leucocitos y/AEMPS, section 4.4 · Open on CIMA
«Inducción del CYP1A2: El tabaco y la carbamazepina pueden inducir el metabolismo de la olanzapina, lo que puede producir una reducción de las concentraciones de olanzapina. Tan solo se ha observado…»AEMPS, section 4.5 · Open on CIMA
«Inhibición del CYP1A2: Se ha demostrado que la fluvoxamina, un inhibidor específico del CYP1A2, inhibe significativamente el metabolismo de la olanzapina. El incremento medio de la C máx de…»AEMPS, section 4.5 · Open on CIMA
«Inhibición del CYP1A2: Se ha demostrado que la fluvoxamina, un inhibidor específico del CYP1A2, inhibe significativamente el metabolismo de la olanzapina. El incremento medio de la C máx de…»AEMPS, section 4.5 · Open on CIMA
«Intervalo QTc: Se debe tener precaución cuando olanzapina se administre concomitantemente junto con medicamentos que prolongan el intervalo QTc (ver sección 4.4).»AEMPS, section 4.5 · Open on CIMA
«Potential for Other Drugs to Affect Olanzapine: Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of…»FDA, section 7 · Open on DailyMed
«Disminución de la biodisponibilidad: No se ha observado que la fluoxetina (un inhibidor del CYP2D6), dosis únicas de antiácidos (aluminio, magnesio) o la cimetidina afecten de forma significativa la…»AEMPS, section 4.5 · Open on CIMA
«Riesgo de que la olanzapina afecte a otros medicamentos: La olanzapina no inhibe los principales isoenzimas del CYP450 in vitro (p.ej. 1A2, 2D6, 2C9, 2C19, 3A4). De modo que no se espera ninguna…»AEMPS, section 4.5 · Open on CIMA
«Psicosis y/AEMPS, section 4.4 · Open on CIMA
«DRUG INTERACTIONS: Carbamazepine: Increased clearance of olanzapine ( 7.1)»FDA, section 7 · Open on DailyMed
«Riesgo de que la olanzapina afecte a otros medicamentos: La olanzapina no inhibe los principales isoenzimas del CYP450 in vitro (p.ej. 1A2, 2D6, 2C9, 2C19, 3A4). De modo que no se espera ninguna…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Diazepam: May potentiate orthostatic hypotension ( 7.1, 7.2 )»FDA, section 7 · Open on DailyMed
«Potential for Other Drugs to Affect Olanzapine: Alcohol — Ethanol (45 mg/FDA, section 7 · Open on DailyMed
«Disminución de la biodisponibilidad: No se ha observado que la fluoxetina (un inhibidor del CYP2D6), dosis únicas de antiácidos (aluminio, magnesio) o la cimetidina afecten de forma significativa la…»AEMPS, section 4.5 · Open on CIMA
«Riesgo de que la olanzapina afecte a otros medicamentos: La olanzapina no mostró interacción cuando se administró conjuntamente con litio o biperideno.»AEMPS, section 4.5 · Open on CIMA
«Potential for Other Drugs to Affect Olanzapine: Inducers of CYP1A2 or Glucuronyl Transferase — Omeprazole and rifampin, may cause an increase in olanzapine clearance.»FDA, section 7 · Open on DailyMed
«Riesgo de que la olanzapina afecte a otros medicamentos: La olanzapina no inhibe los principales isoenzimas del CYP450 in vitro (p.ej. 1A2, 2D6, 2C9, 2C19, 3A4). De modo que no se espera ninguna…»AEMPS, section 4.5 · Open on CIMA
«Potential for Olanzapine to Affect Other Drugs: Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.»FDA, section 7 · Open on DailyMed
«Riesgo de que la olanzapina afecte a otros medicamentos: La olanzapina no inhibe los principales isoenzimas del CYP450 in vitro (p.ej. 1A2, 2D6, 2C9, 2C19, 3A4). De modo que no se espera ninguna…»AEMPS, section 4.5 · Open on CIMA
«Potential for Other Drugs to Affect Olanzapine: Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions (7.2 ) ].»FDA, section 7 · Open on DailyMed
«Interacción farmacodinámica fármaco-fármaco: Se han producido efectos acumulativos de olanzapina y diazepam sobre la sedación e hipotensión en ausencia de interacción farmacocinética. El uso…»AEMPS, section 4.5 · Open on CIMA
«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
«Drugs Affecting Glucose Metabolism: A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening…»FDA, section 7 · Open on DailyMed
«Interacciones que disminuyen los niveles de litio: Antipsicóticos típicos y atípicos : se han reportado casos de reacciones neurotóxicas en pacientes tratados tanto con litio como con un…»AEMPS, section 4.5 · Open on CIMA
«Fármacos que pueden aumentar los niveles plasmáticos de la carbamazepina: Antipsicóticos: loxapina, olanzapina, quetiapina.»AEMPS, section 4.5 · Open on CIMA
«Medicamentos con estrecho margen terapéutico: tricíclicos (p. ej., clomipramina, imipramina, amitriptilina) y neurolépticos (p. ej., clozapina, olanzapina, quetiapina) que se metabolizan básicamente…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines…»FDA, section 7 · Open on DailyMed
«Entre las sustancias que pueden reducir el efecto hipoglucemiante se incluyen los corticosteroides, el danazol, el diazóxido, los diuréticos, el glucagón, la isoniazida, los estrógenos y los…»AEMPS, section 4.5 · Open on CIMA
«Las sustancias que podrían disminuir la actividad reductora del nivel de glucosa en sangre incluyen corticoides, danazol, diazóxido, diuréticos, glucagón, isoniazida, derivados de la fenotiazina…»AEMPS, section 4.5 · Open on CIMA
«Fármacos que tienen poco o ningún efecto en la concentración de lamotrigina: Olanzapina»AEMPS, section 4.5 · Open on CIMA
«La concentración plasmática de otros productos metabolizados en parte por CYP1A2, por ejemplo; cafeína, imipramina, olanzapina, clomipramina y fluvoxamina pueden aumentar cuando se deja de fumar.»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Examples: Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral…»FDA, section 7 · Open on DailyMed
«Effect of Other Drugs on EMSAM: No dose adjustment for EMSAM is needed when EMSAM is used concomitantly with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and CYP3A4…»FDA, section 7 · Open on DailyMed
«Olanzapina: Ácido valproico puede disminuir las concentraciones plasmáticas de olanzapina.»AEMPS, section 4.5 · Open on CIMA
«Effects of Valproate on Other Drugs: Olanzapine No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg…»FDA, section 7 · Open on DailyMed
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Olanzapine is evaluated for the following indications with varying evidence strength: Schizophrenia (evidence tier A), Bipolar disorder maintenance (evidence tier A), Insomnia and sleep disorders (evidence tier D). See the full indication matrix with dosing and citations above on this page.
Common side effects of Olanzapine (≥ 1 in 100): Weight gain (often 5–10 kg over 6 months), Drowsiness and sedation, Hyperlipidemia, hyperglycemia, Dry mouth, Constipation, Orthostatic hypotension. See the Safety section for uncommon and serious reactions.
T3 use carries neonatal extrapyramidal and withdrawal risk. In pregnant psychotic patients, decisions are made with the psychiatrist.
Milk concentrations are low. Use during lactation cautiously with monitoring of infant sedation and weight gain.
Olanzapine is contraindicated in: Olanzapine hypersensitivity; Angle-closure glaucoma; Dementia in older adults; Parkinson's disease, Lewy body dementia; Pregnancy (except life-saving indications). Full list in the Safety section.
FDA boxed warning: increased mortality in elderly patients with dementia on atypical antipsychotics. The Zyprexa Relprevv long-acting form carries post-injection delirium/sedation syndrome (PDSS) risk.
Direct links to regulator labels. Open in a new tab.
Paliperidone, Passionflower (Passiflora incarnata, aerial parts), Phenazepam, Phenibut, Pimozide, Zolpidem, Chlorpromazine, Haloperidol