What is clozapine, and what is it used for?

Clozapine is a second generation atypical antipsychotic medication used for treatment-resistant schizophrenia and to reduce the risk of suicidal behavior in patients with schizophrenia.

Antipsychotic medications are essential for treating delusion and hallucination, the positive symptoms of schizophrenia. Clozapine is not commonly used as a first-line therapy because of its adverse effects, however, the advantages of clozapine include the following:

• Reduces suicidal behavior even as first-line therapy in patients with non-treatment-resistant schizophrenia and schizoaffective disorder.
• Improves cognition and thereby, quality of life in patients with schizophrenia.
• Decreases the incidence of schizophrenia relapse.
• Has lower risk compared to other antipsychotic drugs for drug-related movement disorders known as extrapyramidal symptoms and tardive dyskinesia, which results from long-term use of antipsychotic drugs.

Clozapine reduces the symptoms of schizophrenia by modifying the activity of dopamine and serotonin, two key chemicals (neurotransmitters) in the brain that appear to be involved in schizophrenia. Dopamine has many functions including regulation of movement, memory, motivation and pleasure, while serotonin’s functions include regulation of mood, emotions, sleep cycle, and digestion.

Imbalance in the neurotransmitter levels and/or abnormal neurotransmission play a major role in psychiatric disorders. Overactivity of dopamine in certain pathways of the brain leads to positive symptoms of schizophrenia such as hallucinations, delusions, and abnormal activity of serotonin is responsible for negative symptoms such as apathy, lack of pleasure, and emotions. 

Clozapine reduces both positive and negative symptoms of schizophrenia by blocking dopamine D2 and D4 receptors and serotonin 5-HT2A receptors in nerve cells (neurons). Unlike most other antipsychotics, clozapine binds only transiently to D2 and has a stronger affinity for D4, which is the reason for lower risk for extrapyramidal symptoms. Clozapine also has antagonistic effects on many other neurotransmitters which cause its adverse effects.

What are the side effects of clozapine?

Common side effects of clozapine include:

Less common side effects of clozapine include:

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug.

Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

What are the dosages of clozapine?

Tablet

• 25 mg
• 50 mg
• 100 mg
• 200 mg

Oral Suspension (Versacloz)

Adult:

Schizophrenia

Indicated for reducing risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder in patients who are judged to be at chronic risk to re-experience suicidal behavior

Also indicated for treatment-resistant schizophrenia in patients who fail to respond adequately to standard antipsychotic treatment

• 12.5 mg orally once daily or every 12 hours initially; increase in increments of 25-50 mg/day, if well tolerated, to achieve target dosage of 300-450 mg/day (administered in divided doses) by end of 2 weeks
• Subsequently, may increase dose once or twice weekly in increments of up to 100 mg; not to exceed 900 mg/day
• Maintenance: Generally, patients who respond should continue maintenance treatment on their effective dose beyond the acute episode

Re-initiation of therapy

• If therapy interrupted for 48 hours or longer, must reinitiate dose at 12.5 mg once a day or twice a day to minimize risk of hypotension, bradycardia, and syncope; if dose well tolerated, may increase more rapidly than with initial titration, unless cardiopulmonary arrest occurred during initial titration, then titrate with extreme caution

Discontinuation of therapy

• Method of treatment discontinuation depends on patient’s last absolute neutrophil count (ANC)
• Reduce dose gradually over a period of 1-2 weeks if termination not related to neutropenia; taper gradually to avoid withdrawal symptoms and minimize risk of relapse; for schizophrenia, guidelines recommend gradual taper over 6-24 months (American Psychiatric Association guidelines recommend reducing dose 10% each month)
• For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continue existing ANC monitoring until ANC is 1500/mm3 or greater
• If benign patient has benign ethnic neutropenia (BEN); monitor until ANC is 1000/mm3 or greater, or above baseline
• Additional ANC monitoring required for onset of fever during the 2 weeks after discontinuation
• Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea)

Dosage Modifications

Coadministration with CYP inhibitors

• Strong CYP1A2 inhibitors: Use one-third clozapine dose
• Moderate or weak CYP1A2 inhibitors: Monitor for adverse reactions; consider reducing clozapine dose if needed
• CYP2D6 or CYP3A4 inhibitors: Monitor for adverse reactions; consider reducing clozapine dose if needed
• CYP2D6 poor metabolizers: Clozapine dose reduction may be needed

Coadministration with CYP inducers

• Strong CYP3A4 inducers: Coadministration not recommended; if the inducer is necessary, clozapine dose may need to be increased
• Moderate or weak CYP1A2 or CYP3A4 inducers: Monitor for decreased effectiveness; consider increasing clozapine dose if necessary

Renal or hepatic impairment

• Dose reduction may be necessary with significant renal or hepatic impairment

Dosing Considerations

• Required laboratory monitoring
• Before initiating, obtain complete blood count (CBC) with differential for baseline ANC; to continue treatment, ANC must be monitored regularly
• In order to initiate treatment, ANC must be 1500/mm3 or greater for the general population and 1000/mm3 or greater for patients with documented benign ethnic neutropenia

Geriatric:

Lower initial dosage of 12.5-25 mg/day indicated; may be titrated more slowly than in younger adults

Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to orthostatic hypotension and tachycardia; anticholinergic effects are also common (constipation, confusion, urinary retention)

Pediatric:

• Safety and efficacy not established.

Overdose

• The most common symptoms of clozapine overdose include sedation, delirium, coma, rapid heart rate, low blood pressure, respiratory depression or failure, and excessive salivation. There have been reports of aspiration pneumonia, irregular heart rhythms, seizure, and death with severe overdose.
• There are no specific antidotes for clozapine. Overdose is treated with symptomatic and supportive care including respiratory support and monitoring of heart function and other vital signs.
• In case of overdose, immediately seek medical help or contact Poison Control.

What drugs interact with clozapine?

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe Interactions of clozapine include:
  • amisulpride
  • dronedarone
  • eliglustat
  • flibanserin
  • irinotecan
  • irinotecan liposomal
  • lomitapide
  • lonafarnib
  • nirmatrelvir
  • nirmatrelvir/ritonavir
  • saquinavir
  • thioridazine
• Clozapine has serious interactions with at least 146 different drugs.
• Clozapine has moderate interactions with at least 439 different drugs.
• Mild Interactions of clozapine include:

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

Pregnancy and breastfeeding

• Animal reproductive studies do not show impairment of fertility or fetal harm with the use of clozapine during pregnancy. There are, however, no adequate or well-controlled studies of clozapine in pregnant women. Clozapine should be used during pregnancy only if clearly needed.
• There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics during pregnancy.
• Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms) and/or withdrawal symptoms in newborns following delivery.
• Clozapine is present in breast milk. A decision to discontinue the drug or nursing should be made after considering potential adverse effects on the baby and the nursing mother’s need for therapy.
• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy. Health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/.

What else should I know about clozapine?

• Take clozapine exactly as prescribed. Do not miss your doses. In case you miss doses for more than 2 days, consult your physician before restarting your medication.
• Report immediately to your physician if you develop flu-like illness, fever, lethargy, weakness or infections.
• Clozapine is associated with risks of drowsiness and seizure. Avoid potentially hazardous activities such as driving or operating heavy machinery while on therapy.
• Consult your physician immediately if you feel faint or have any heart-related symptoms.