Clozapine Dosage

This dosage information may not include all the information needed to use Clozapine safely and effectively. See additional information for Clozapine.

The information at Drugs.com is not a substitute for medical advice. ALWAYS consult your doctor or pharmacist.

Usual Adult Dose for:

Additional dosage information:

Usual Adult Dose for Schizophrenia

Treatment resistant schizophrenia:
Initial dose: 12.5 mg orally once or twice a day.
Maintenance dose: If the first dose is well- tolerated, dosages may then be titrated in daily increments of 25 mg to 50 mg for approximately two weeks until a daily dose of 300 to 450 mg is achieved. If, after the initial titration, a larger dose is necessary a slower increase in dose, not to exceed a 100 mg increment once or twice a week, may be initiated. Cautious titration and a divided dosage schedule may minimize the risks of hypotension, seizure, and sedation in the patient. However, sedation following daytime doses may necessitate administration of most or all of the daily dose at bedtime.
Maximum dose: 900 mg per day.

Reduction of the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder:
Initial dose: 12.5 mg orally once or twice a day.
Maintenance dose: If the first dose is well- tolerated, dosages may then be titrated in daily increments of 25 mg to 50 mg for approximately two weeks until a daily dose of 300 to 450 mg is achieved. If, after the initial titration, a larger dose is necessary a slower increase in dose, not to exceed a 100 mg increment once or twice a week, may be initiated. Cautious titration and a divided dosage schedule may minimize the risks of hypotension, seizure, and sedation in the patient. However, sedation following daytime doses may necessitate administration of most or all of the daily dose at bedtime.
Maximum dose: 900 mg per day.

Renal Dose Adjustments

Clozapine should be used with caution in patients with renal dysfunction.

Liver Dose Adjustments

Clozapine should be used with caution in patients with hepatic disease and/or dysfunction. Because clozapine is metabolized in the liver, use in patients with frank hepatic failure is not recommended.

Dose Adjustments

Dosage may be increased in daily increments of 25 to 50 mg for 2 weeks. Subsequent adjustments can be made once or twice a week at no more than 100 mg increments.

Patients undergoing smoking cessation may require a reduction in clozapine dosage. CYP450 1A2, the primary isoenzyme involved in the metabolism of clozapine, is inducible by smoking; therefore, an elevation in plasma clozapine levels may occur as a result of smoking cessation.

Precautions

Clozapine is not approved by the FDA for use in the treatment of patients with dementia- related psychosis.

Some clinicians recommend that the first dose of clozapine be given in a setting where access to personnel and equipment necessary for cardiopulmonary resuscitation are immediately available for the first several hours after the dose.

Abrupt discontinuation of clozapine therapy is generally not recommended. For planned termination of therapy, gradual dose reductions over one to two weeks are recommended. If termination of clozapine therapy has occurred (even after two days of missed doses), therapy, if needed and appropriate, should be reinstituted with 12.5 mg of clozapine once or twice daily. Dosages should then be titrated upward according to the patient's response. If clozapine therapy must be discontinued abruptly for medical reasons (like agranulocytosis) the patient should be observed closely for recurrence of psychotic symptoms and occurrence of other problems. In addition, any patient reinstituted on clozapine who previously experienced respiratory or cardiac arrest with initial dosing of clozapine should be re- titrated with extreme caution even after 24 hours of discontinuation.

The safety of clozapine when used chronically for treatment resistant schizophrenia, without the risk of recurrent suicide, has not been determined. Therapy should be continued only in patients who respond to clozapine and at the lowest level necessary to maintain response. Periodic reevaluation of the need for continued clozapine therapy is recommended.

Clozapine is often necessary for a minimum duration of 2 years in patients with schizophrenia or schizoaffective disorder treated for reduction of the risk of recurrent suicide. After this 2- year period, a periodic reassessment of the patient's risk for suicidal behavior should be made and clozapine continued or discontinued based on these findings.

Due to the significant risk of agranulocytosis, clozapine should be reserved for use only in FDA approved indications. Clozapine is only available through a distributing system that ensures monitoring of white blood cell (WBC) count and absolute neutrophil count (ANC) according to a prescribed schedule prior to the dispensing of the next supply of medication.

A baseline WBC count and an ANC must be obtained prior to initiating clozapine therapy, and every week for the first 6 months. If adequate WBC count (at least 3500/mm3) and ANC (at least 2000/mm3) have been maintained during the first 6 months of continuous therapy, monitoring may be reduced to every 2 weeks for next 6 months. Thereafter, monitoring may be reduced to every 4 weeks ad infinitum, if adequate WBC count and ANC have been maintained during the second 6 months of continuous therapy.

Inadequate WBC count and ANC experienced during course of continuous therapy are to be monitored as follows:
If immature forms are present - repeat WBC count and ANC.

If substantial drop in WBC or ANC (single drop or cumulative drop) within 3 weeks of a WBC count of at least 3000/mm3 or ANC of at least 1500/mm3 - repeat WBC count and ANC. If repeat values yield a WBC of at least 3000/mm3 but not greater than 3500/mm3 and ANC less than 2000/mm3 - monitor twice weekly.

If mild leukopenia and/or mild granulocytopenia (WBC at least 3000/mm3 and less than 3500/mm3 and/or ANC at least 1500/mm3 and less than 2000/mm3) - twice weekly until WBC greater than 3500/mm3 and ANC greater than 2000/mm3, then return to previous monitoring frequency.

If moderate leukopenia and/or moderate granulocytopenia (WBC at least 2000/mm3 and less than 3000/mm3 and/or ANC at least 1000/mm3 and less than 1500 mm3) - interrupt therapy and monitor daily until WBC is greater than 3000/mm3 and ANC is greater than 1500/mm3, then twice weekly until WBC greater than 3500/mm3 and ANC greater than 2000/mm3. At this point may rechallenge. If rechallenged, monitor weekly for 1 year, then every 2 weeks for 6 months, then every 4 weeks ad infinitum.

If severe leukopenia and/or severe granulocytopenia (WBC less than 2000/mm3 and/or ANC less than 1000/mm3) - discontinue treatment, do not rechallenge, and for at least four weeks from day of discontinuation monitor as follows: daily until WBC greater than 3000/mm3 and ANC greater than 1500/mm3, then twice weekly until WBC greater than 3500/mm3 and ANC greater than 2000/mm3, then weekly after WBC greater than 3500/mm3.

Agranulocytosis (ANC less than or equal to 500/mm3) - discontinue treatment, do not rechallenge, and monitor until normal and for at least four weeks from day of discontinuation as follows: daily until WBC greater than 3000/mm3 and ANC greater than 1500/mm3, then twice weekly until WBC greater than 3500/mm3 and ANC greater than 2000/mm3, then weekly after WBC greater than 3500/mm3.

If there is a break in therapy, WBC count and ANC should be monitored as follows:

Therapy less than 6 months prior to break:

No abnormal blood event (WBC at least 3500/mm3 and ANC at least 2000/mm3) and a break of greater than 3 days and less than or equal to 1 month - do not reset monitoring schedule.

No abnormal blood event (WBC at least 3500/mm3 and ANC at least 2000/mm3) and a break greater than 1 month - monitor weekly for 6 months.

An abnormal blood event (WBC less than 3500/mm3 or ANC less than 2000/mm3) and rechallengeable - weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months and then every 4 weeks ad infinitum.

Therapy greater than 6 months and less than or equal to 12 months prior to break:

No abnormal blood event (WBC at least 3500/mm3 and ANC at least 2000/mm3) and a break of greater than 3 days and less than or equal to 1 month - weekly for 6 weeks, then return to every 2 weeks for 6 months.

No abnormal blood event (WBC at least 3500/mm3 and ANC at least 2000/mm3) and a break of greater than 1 month - weekly for 6 months, then every 2 weeks for 6 months.

An abnormal blood event (WBC less than 3500/mm3 or ANC less than 2000/mm3) and rechallengeable - weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months and then every 4 weeks ad infinitum.

Therapy greater than 12 months duration prior to break:

No abnormal blood event (WBC at least 3500/mm3 and ANC at least 2000/mm3) and a break of greater than 3 days and less than or equal to 1 month duration - weekly for 6 weeks, then return to every 4 weeks.

No abnormal blood event (WBC at least 3500/mm3 and ANC at least 2000/mm3) and break of greater than 1 month - weekly for 6 months, then every 2 weeks for 6 months, then return to every 4 weeks.

An abnormal blood event (WBC less than 3500/mm3 and ANC less than 2000/mm3) and rechallengeable - weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months and then every 4 weeks ad infinitum.

Individuals with a fall in total WBC count to below 2000/mm3 or ANC below 1000/mm3 may not be rechallenged. In addition, individuals with an initial episode of moderate leukopenia (WBC of at least 2000/mm3 and less than 3000/mm3) have up to a 12- fold increased risk of having a subsequent episode of agranulocytosis upon rechallenge compared to the full cohort of patients treated with clozapine. Therefore, even though an individual with moderate leukopenia who meets all criteria may be rechallenged clinicians are advised to consider the benefit of clozapine therapy versus the increased risk of agranulocytosis. To reduce the chances of rechallenge occurring in these patient populations a report should be filed with the Clozapine National Registry (CNR - phone 1-800-448-5938), a single, national, confidential database.

After discontinuation of clozapine therapy, regardless of reason, WBC count and ANC must be monitored weekly for at least four weeks from the day of discontinuation or until WBC count is at least 3500/mm3 and ANC is greater than 2000/mm3.

Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat, or any other signs of infection. A WBC count and ANC should be performed on such patients immediately.

Clozapine has been associated with the development of eosinophilia. Clozapine therapy should be interrupted if total eosinophilia count is greater than 4000/mm3 and may be resumed when the eosinophilia count is less than 3000/mm3.

To rule out possible hepatitis, liver function tests should be performed on any patient who develops nausea, vomiting, and/or anorexia during clozapine therapy. Clozapine therapy should be discontinued if the elevation of these values is clinically relevant or if symptoms of jaundice occur.

Dose selection should be made with caution in the elderly.

Safety and effectiveness have not been established in pediatric patients (less than 18 years of age).

Dialysis

Data not available

Other Comments

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for clozapine oral suspension marketed as Versacloz (TM). It includes elements to assure safe use, and an implementation system. Additional information is available at
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

Although controversial and still subject to debate, a beneficial therapeutic response has been associated with a threshold clozapine plasma concentration of 350 to 420 ng/mL. However, studies have suggested that the clinical response to clozapine is not mediated by differences in serum concentrations. The therapeutic range provided here is intended to complement the normal process of clinical evaluation and not replace it.

Studies have shown that patients receiving clozapine are at an increased risk of developing metabolic syndrome, hyperglycemia, and diabetes mellitus. Therefore, it has been recommended that patients receive regular monitoring of body mass index, lipid levels, fasting blood glucose levels, and blood pressure.

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