Usual Adult Dose for Schizophrenia

Initial dose: 12.5 mg orally once or twice a day
Titration and Maintenance dose: May increase total daily dose in increments of 25 mg to 50 mg per day to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of week 2. Subsequent dose increases can be in increments of up to 100 mg once or twice weekly.
Maximum dose: 900 mg per day

Comments:

• The absolute neutrophil count (ANC) must be 1500/microL or greater for the general population and at least 1000/microL for patients with documented Benign Ethnic Neutropenia (BEN) prior to initiating treatment; to continue therapy, the ANC must be monitored regularly.
• A low starting dose, gradual titration, and divided doses are necessary to minimize the risk of orthostatic hypotension, bradycardia, and syncope.
• When therapy is interrupted for 2 or more days, re-initiate with 12.5 mg once or twice a day; based on tolerability, a dose that is restarted may be increased to a previously therapeutic dose more quickly than it was for initial treatment.

• For the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment
• To reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder, who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state

Renal Dose Adjustments

Significant renal dysfunction: Dose reduction may be necessary.

Liver Dose Adjustments

Significant liver dysfunction: Dose reduction may be necessary.

Dose Adjustments

Elderly Patients: Dosing should be conservative taking into account the greater frequency of decreased renal, hepatic, or cardiac function, as well as other concomitant disease and other drug therapy.

CYP450 2D6 Poor Metabolizers: Dose reductions may be necessary.

Drug Discontinuation:

• Planned Discontinuation: Reduce the dose gradually over a period of 1 to 2 weeks.
• Abrupt Discontinuation Due to Moderate or Severe Neutropenia: ANC monitoring should continue per Clozapine REMS program requirements.
• Abrupt Discontinuation NOT Related to Neutropenia: Continue ANC monitoring until ANC is at least 1500/microliter (microL) (general population) or at least 1000/microL (patients with Benign Ethnic Neutropenia [BEN]).
• Patients with a fever (e.g., 38.5C or higher): Continue ANC monitoring for an additional 2 weeks after discontinuation.
• Upon discontinuation, monitor all patients for recurrence of psychotic symptoms, and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.

• Upon initiating therapy or adding a strong CYP450 1A2 inhibitor to clozapine therapy: Reduce clozapine dose to one-third.
• When discontinuing a strong CYP450 1A2 inhibitor and continuing clozapine: Increase clozapine dose based on clinical response.

• Upon initiating clozapine therapy or adding a moderate or weak CYP450 1A2 inhibitor, a CYP450 2D6 inhibitor or a CYP450 3A4 inhibitor to clozapine therapy: Monitor for adverse reactions and reduce clozapine dose if needed.
• When discontinuing a moderate or weak CYP450 1A2 inhibitor or a CYP450 2D6 or 3A4 inhibitor, and continuing clozapine: Monitor for lack of effectiveness and consider increasing clozapine dose if necessary.

• Concomitant use of clozapine is not recommended, however, if a strong CYP450 3A4 inducer is necessary, a dose increase of clozapine dose may be needed. Monitor for decreased effectiveness.
• When discontinuing a strong CYP450 3A4 inducer and continuing clozapine: Reduce clozapine dose based on clinical response.

• Upon initiating clozapine therapy or adding a moderate or weak CYP450 1A2 or CYP450 3A4 inducer to clozapine therapy: Monitor for decreased effectiveness and consider increasing clozapine dose if needed.
• When discontinuing a moderate or weak CYP450 1A2 or CYP450 3A4 inducer and continuing clozapine: Monitor for adverse reactions and consider reducing the clozapine dose if needed.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for DRUG and/or SHARED SYSTEM. It includes elements to assure safe use and an implementation system. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS:
SEVERE NEUTROPENIA:

• Treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500 per microliter (microL). Severe neutropenia can lead to serious infection and death.
• Prior to initiating treatment, a baseline ANC must be at least 1500 per microL for the general population; and must be at least 1000 per microL for patients with documented Benign Ethnic Neutropenia (BEN).
• During treatment, patients must have regular ANC monitoring.
• Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, or sore throat).
• Because of the risk of severe neutropenia, this drug is only available through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.

• Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with treatment.
• The risk is highest during the initial titration period, particularly with rapid dose escalation.
• These reactions can occur with the first dose, with doses as low as 12.5 mg per day.
• Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages.
• Use cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications).

• Seizures have occurred with treatment. The risk is dose-related.
• Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing.
• Use caution when administering to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse).
• Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others.

• Fatal myocarditis and cardiomyopathy have occurred with treatment.
• Discontinue this drug and obtain a cardiac evaluation upon suspicion of these reactions.
• Generally, patients with drug-related myocarditis or cardiomyopathy should not be rechallenged.
• Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur.

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
• This drug is not approved for use in patients with dementia-related psychosis.

Dialysis

Data not available

Other Comments

Administration advice:
Oral Tablets:

• May be taken with or without food.
• If a dose is missed for more than 2 days; patients should be restarted at 12.5 mg once or twice a day.

• Do not remove from blister until time of use; peel foil from blister and remove tablet; do not push tablet through foil as it may damage tablet.
• Place tablet in mouth and allow to disintegrate; swallow with saliva; ODTs do not require additional water and may be chewed.

• Some experts recommend: Shake the bottle for 90 seconds 24 hours prior to first use to ensure any sedimentation occurring during storage has been re-suspended.
• Prior to use, shake bottle for 10 seconds; on first use, remove cap and press syringe adaptor into bottle opening.
• Fill oral syringe with air; insert syringe into bottle neck adapter and push air into bottle.
• Draw out prescribed dose into oral syringe; administer dose directly from the oral syringe into the mouth.
• Measured dose should be used immediately; do not store suspension in the syringe.
• Syringe should be washed with warm water after each use; the bottle cap may be closed without removing the syringe adaptor.

• Do not refrigerate or freeze; protect from light.
• Stable for 100 days after initial bottle opening.

• Tablets must remain in original package until ready for use.

• Because of the risk of severe neutropenia, this drug is available only through a restricted program; the CLOZAPINE REMS program. Information is available at www.clozapinerems.com or 1-844-267-8678.

• Obtain baseline CBC to include the ANC value; to initiate therapy ANC must be at least 1500/microL for the general population and at least 1000/microL for patients with documented Benign Ethnic Neutropenia (BEN). Thereafter, ANC testing and monitoring requirements must be followed per CLOZAPINE REMS Program.
• Electrolytes should be monitored to decrease the risk of QT prolongation
• Monitor cardiac status
• Monitor for increases in blood sugar, weight, and lipids
• Monitor for clinical worsening and suicidality

• Patients should be informed of the significant risk of developing agranulocytosis and that their participation in the CLOZAPINE REMS Program is designed to reduce this risk; patients will need to immediately report symptoms consistent with severe neutropenia or infection (e.g. fever, weakness, lethargy, or sore throat).
• Patients should be informed of the risk of orthostatic hypotension, bradycardia, and syncope, as well as the risk of QT interval prolongation; patients should discuss with their physician any new medications or use of over-the-counter medications or alcohol.
• This drug may impair judgment, thinking, or motor skills, and carries a risk of seizures; patients should be cautioned about engaging in activities that could cause serious risk to self or others if a sudden loss of consciousness were to occur.
• Patients should be advised to contact their health care professional if they miss taking their drug for more than 2 days.
• Advise patient to speak to physician or health care professional if pregnant, intend to become pregnant, or are breastfeeding.