Clozapine (US brand names Clozaril®, Fazaclo® ODT, Versacloz®, and generic) is a second-generation (“atypical”) antipsychotic.
On this page, we present some basic information about this medication. Other articles on this website with more advanced information and tips related to this medication are linked to under Related Pages below.
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Mechanism of Action/ Pharmacodynamics
Clozapine is an antagonist at dopamine D2 and the serotonin 2A (5-HT2A) receptors.
It is also an antagonist at:
– All the other dopaminergic receptors D1 through D5.
– Some other serotonergic receptors: 5-HT1A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7.
– Adrenergic alpha-1A, cholinergic M1, and histaminergic H1 receptors.
Clozapine is metabolized by cytochrome P450 1A2, 2D6, and 3A4.
Warnings and Precautions
1. Gastrointestinal hypomotility may occur with the use of clozapine which may be associated with constipation and in severe cases with intestinal obstruction, fecal impaction, megacolon, and intestinal ischemia or infarction.
Recommendation: Close monitoring and treatment are recommended if constipation develops in a patient.
2. Eosinophilia (eosinophil count of >700/µL) with organ involvement is seen in some cases which may lead to myocarditis, pancreatitis, hepatitis, colitis, and nephritis.
Recommendation: Discontinue treatment if there is organ involvement due to eosinophilia.
3. QT prolongation may occur with clozapine treatment.
Recommendations: Before starting treatment with clozapine, a careful history and physical examination, and a baseline ECG are recommended.
If symptoms of torsades de pointes or other arrhythmias develop, immediate cardiac evaluation and discontinuation of clozapine are recommended.
4. Baseline evaluation (weight, fasting blood sugar, and lipid panel) may be needed before starting clozapine. And, monitoring of metabolic changes such as hyperglycemia, dyslipidemia, and weight gain is recommended.
5. It is recommended to monitor for hepatotoxicity as it can be fatal in some cases.
6. If neuroleptic malignant syndrome (NMS) develops, discontinue treatment.
7. If a fever develops, immediately evaluate for an infection and for neutropenia.
8. Avoid concomitant use with anticholinergic drugs. Be cautious while prescribing in patients with prior history of constipation, urinary retention, benign prostatic hypertrophy, and other conditions that may worsen with anticholinergic treatment.
9. Advise caution while operating machinery or driving.
Potential side effects
Please see THIS PAGE for a handout listing both the common and less common side effects of this medication along with the percentages of patients who report them.
Potential drug interactions
1. Reduce clozapine dose to 1/3rd when using concomitantly with strong CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, enoxacin, etc.
2. It is not recommended to use clozapine with strong CYP3A4 inducers (carbamazepine, phenytoin, St. John’s wort, and rifampin).
3. Clozapine dose reduction is recommended when CYP1A2 inducers (tobacco smoke) or CYP3A4 inducers are discontinued.
4. Anticholinergic toxicity may occur if clozapine is used concomitantly with anticholinergic drugs.
Starting: 12.5 mg once or twice daily, with or without food
Titration: Increase the total daily dosage in increments of 25 mg to 50 mg per day
Target: 300 – 450 mg per day, in divided doses, by the end of 2 weeks
Subsequent increases: Increments of 100 mg or less, once or twice weekly
Maximum: 900 mg daily
1. Clozapine can cause severe neutropenia. As a result, clozapine is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program (see Related Pages below). Prior to initiating treatment with clozapine, a baseline ANC must be obtained. The baseline ANC must be at least 1500/µL for the general population, and at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly.
2. Dose adjustments may be necessary in patients with concomitant use of:
Strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin): Use 1/3rd dose of clozapine
Moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine): Monitor for side effects and consider reducing the dose of clozapine if necessary.
CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); Monitor for side effects and consider reducing the dose of clozapine if necessary.
Strong CYP3A4 inducers (carbamazepine, phenytoin, St. John’s wort, and rifampin): Concomitant use of clozapine is not recommended. If necessary, consider increasing the clozapine dose. Also, consider reducing the clozapine dosage when discontinuing coadministered enzyme inducers.
Moderate or weak CYP1A2 (tobacco smoking) or CYP3A4 inducers: Monitor for decreased effectiveness. Consider increasing the clozapine dose if necessary.
3. Seizures have occurred with clozapine treatment. The risk is dose-related. Use caution when administering clozapine to patients with a history of seizures or other predisposing risk factors for seizure.
Dosage forms and strengths
Oral tablet (Clozaril® and generic): 25 mg (scored) and 100 mg (scored). Generic also available in 12.5 mg, 50 mg, and 200 mg strengths.
Orally-disintegrating tablet (Fazaclo® ODT and generic): 12.5 mg, 25 mg, 100 mg, 150 mg, and 200 mg
Oral suspension (Versacloz®): 50 mg/mL
Important! Please refer to the full Prescribing Information (see link below) before prescribing this medication.
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