Clozapine

Clozapine is an antipsychotic medication that is used to treat severe schizophrenia symptoms in people who have not responded to other medications. It is also used to help reduce the risk of suicidal behavior in people with schizophrenia or similar disorders.

Clozapine is available under the following different brand names: Clozaril, FazaClo ODT, and Versacloz.

Dosages of Clozapine:

Dosage Forms and Strengths

Tablet

• 25 mg
• 50 mg
• 100 mg
• 200 mg

Tablet, orally disintegrating (FazaClo ODT)

• 12.5 mg
• 25 mg
• 100 mg
• 150 mg
• 200 mg

Oral suspension (Versacloz)

• 50 mg/mL

Dosage Considerations – Should be Given as Follows:

Schizophrenia

• Indicated for reducing the 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; increased daily in increments of 25-50 mg/day, if well-tolerated, to achieve target dosage of 300-450 mg/day by end of 2 weeks
• On occasion, may have to be increased to 600-900 mg/day to obtain an acceptable response
• Maintenance: Generally, patients who respond should continue maintenance treatment on their effective dose beyond the acute episode

Dosing Modifications

• 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
• Strong CYP3A4 inducers: Co-administration 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; consider reducing dose if CYP1A2 or CYP3A4 inducers are discontinued
• CYP2D6 poor metabolizers: Clozapine dose reduction may be needed
• Significant renal or hepatic impairment: Clozapine dose reduction may be needed

Dosing Considerations

Required laboratory monitoring

• Prior to initiating, obtain complete blood count (CBC) with differential, to continue treatment, absolute neutrophil count (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
• See prescribing information for detailed monitoring requirements, including those for patients with benign ethnic neutropenia

Pediatric: Safety and efficacy not established

Geriatric: A 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)

Side effects of clozapine include:

• Low blood pressure (hypotension)
• Fast heart rate
• Fever, sedation, seizures (with high doses)
• Appetite increased
• Constipation
• Heartburn
• Nausea
• Increased hunger
• Excess salivation/drooling (especially at night)
• Vomiting
• Weight gain
• Sleep problems
• Increased sweating
• Dry mouth
• Blurred vision
• Drowsiness
• Spinning sensation
• Headache

Less common side effects of clozapine include:

• Delirium
• Depression
• Dizziness
• Extrapyramidal symptoms (EPS), such as tremor, restlessness, rigidity, restlessness
• Fatigue
• Headache
• High blood sugar (hyperglycemia), potential for new-onset diabetes
• Impotence
• Increased urination
• Insomnia
• Involuntary urination, especially at night
• Low white blood cell and platelet counts (leukopenia, neutropenia, thrombocytosis)
• Menstrual cramps
• Seizures (with low doses)
• Shortness of breath
• Slurred speech
• Weakness
• Wheezing

Rare side effects of clozapine include:

• Agranulocytosis
• Amnesia
• Anemia
• Change in libido
• Hallucinations
• Increased platelet count
• Leukocytosis
• Myocarditis
• Neuroleptic malignant syndrome (NMS)
• Parkinsonian syndrome
• Periodic cataplexy

Postmarketing side effects of clozapine reported include:

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

Severe Interactions of clozapine include:

• eliglustat
• flibanserin
• irinotecan
• irinotecan liposomal
• lomitapide

Clozapine has serious interactions with at least 48 different drugs.

Clozapine has moderate interactions with at least 371 different drugs.

Mild Interactions of clozapine include:

• bendroflumethiazide
• bumetanide
• chlorothiazide
• chlorthalidone
• cyclopenthiazide
• desmopressin
• ethacrynic acid
• eucalyptus
• furosemide
• hydrochlorothiazide
• indapamide
• methyclothiazide
• metolazone
• noni juice
• sage
• torsemide

Clozapine has moderate interactions with at least 108 different drugs.

Mild Interactions of clozapine include:

• azithromycin
• brimonidine
• chasteberry
• cilostazol
• divalproex sodium
• ethanol
• eucalyptus
• sage
• valproic acid

This information does not contain all possible interactions or adverse effects. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns or for more information about this medicine.

Warnings

Agranulocytosis

• Available only through a restricted program called the Clozapine REMS
• Severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/mm³, has been reported
• Severe neutropenia can lead to serious infection and death
• Prior to initiating treatment, a baseline ANC must be 1500/mm³ or greater for the general population and 1000/mm³ or greater for patients with documented benign ethnic neutropenia
• Regularly monitor ANC during treatment
• Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, sore throat)

Seizures

• Caution with history of seizure or other factors predisposing to seizure
• Risk is dose-related

Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence

• Fatal myocarditis and cardiomyopathy reported; discontinue and obtain cardiac evaluation if suspected
• Measuring brain NP levels may offer a means of monitoring to detect early, asymptomatic myocarditis
• Do not re-challenge patients with history of clozapine-associated myocarditis or cardiomyopathy

Orthostatic hypotension, bradycardia, syncope

• Dizziness upon standing (orthostatic hypotension), slow heart rate (bradycardia), fainting (syncope), and cardiac arrest may occur
• Risk is highest during initial titration period, particularly with rapid dose escalation
• May occur with the first dose, and with doses as low as 12.5 mg/day
• Caution with history of cardiovascular or cerebrovascular disease or conditions predisposing to low blood pressure (hypotension)

Increased mortality in elderly with dementia-related psychosis

• Not approved for dementia-related psychosis; patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials; deaths in these trials appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature

This medication contains clozapine. Do not take Clozaril, FazaClo ODT, or Versacloz if you are allergic to clozapine or any ingredients contained in this drug.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• Hypersensitivity (e.g., photosensitivity, vasculitis, erythema multiforme, Stevens-Johnson syndrome)

Effects of Drug Abuse

• None

Short-Term Effects

• Short-Term Effects
• May cause anticholinergic effects (e.g., dry mouth, urinary retention, constipation)
• See "What Are Side Effects Associated with Using Clozapine?"

Long-Term Effects

• Significant weight gain has occurred; monitor weight gain.
• May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy
• See "What Are Side Effects Associated with Using Clozapine?"

Cautions

• Only available through a restricted access program because of risk for neutropenia (i.e., low ANC); patients must be registered, prescriber must enroll and complete training, and pharmacies dispensing clozapine must be certified and complete training
• Severe neutropenia (ANC less than 500/mm³) occurs in a small percentage of patients and is associated with increased risk of serious and potentially fatal infections; risk is greatest during the first 18 weeks of treatment and then declines; see prescribing information for detailed information regarding monitoring ANC, including patients with benign ethnic neutropenia
• Benign transient elevation of temperature reported, peaking within first 3 weeks of treatment (rule out agranulocytosis, infection, NMS)
• Increased risk of seizures
• Risk of potentially fatal myocarditis
• Increased risk of cerebrovascular adverse events reported with some atypical antipsychotics (mechanism unknown)
• Increased risk of hyperglycemia and diabetes; in some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with esophageal dysmotility, ketoacidosis, hyperosmolar coma, or death; monitor blood glucose of high-risk patients
• FDA warning regarding off-label use for dementia in elderly
• May cause anticholinergic effects (e.g., dry mouth, urinary retention, constipation)
• Possible QT prolongation; use with caution in patients with history of long QT syndrome or other conditions that may increase risk (e.g., hypokalemia, hypomagnesemia)
• Possible increased serum levels and toxicity in patients with reduced activity of CYP isoenzymes 1A2, 2D6, or 3A4
• Co-administration with other drugs that prolong QT interval or drugs that inhibit metabolism of clozapine (e.g., inhibitors of CYP isoenzymes 1A2, 2D6, and 3A4)
• Postmarketing analysis has suggested an increased incidence of myocarditis that is particularly prevalent within first month of treatment; accordingly, do not stop medication abruptly, and perform WBC testing every 2 weeks for duration of therapy
• Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis) if eosinophilia occurs
• Monitor glucose regularly in patients with diabetes or at risk for diabetes
• Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics
• Significant weight gain has occurred; monitor weight gain
• Immediately discontinue and monitor closely if neuroleptic malignant syndrome occurs; assess for co-morbid conditions
• Evaluate for infections, agranulocytosis, and neuroleptic malignant syndrome if fever occurs
• Consider pulmonary embolism if respiratory distress, chest pain, or deep vein thrombosis occur
• Use with caution in history of narrow glaucoma or concomitant use with other anticholinergic drugs
• Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis reported in post marketing studies; monitor for appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy; perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine
• May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Pregnancy and Lactation