Dosing and uses of Clozaril, Fazaclo ODT (clozapine)
Adult dosage forms and strengths
tablet
- 25mg
- 50mg
- 100mg
- 200mg
tablet, orally disintegrating (FazaClo ODT)
- 12.5mg
- 25mg
- 100mg
- 150mg
- 200mg
oral suspension (Versacloz)
- 50mg/mL
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 PO once daily or q12hr 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 acceptable response
Maintenance: Generally, patients who respond should continue maintenance treatment on their effective dose beyond the acute episode
Dosage 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: 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; 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 CBC with differential, to continue treatment, ANC must be monitored regularly
- In order to initiate treatment, ANC must be ≥1500/mm³ for the general population and ≥1000/mm³ for patients with documented benign ethnic neutropenia
- See prescribing information for detailed monitoring requirements, including those for patients with benign ethnic neutropenia
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
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)
Clozaril, Fazaclo ODT (clozapine) adverse (side) effects
Frequency not defined
Common
- Hypotension, tachycardia
- Fever, sedation, seizures (with high doses)
- Appetite increase
- Constipation
- Heartburn
- Nausea
- Polyphagia
- Sialorrhea
- Vomiting
- Weight gain
Less common
- Extrapyramidal symptoms (EPS), such as tremor, restlessness, rigidity, akathisia
- Dizziness
- Headache
- Insomnia
- Delirium
- Depression
- Fatigue
- Weakness
- Slurred speech
- Seizures (with low doses)
- Hyperglycemia, potential for new-onset diabetes
- Leukopenia, neutropenia, thrombocytosis
- Shortness of breath, wheezing
- Polyuria, enuresis, impotence, dysmenorrhea
Rare
- Myocarditis
- Amnesia, hallucinations
- Parkinsonian syndrome
- Periodic cataplexy
- Neuroleptic malignant syndrome (NMS)
- Anemia
- Leukocytosis
- Increased platelet count
- Agranulocytosis
- Change in libido
Postmarketing Reports
Skin: Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome, skin pigmentation disorder
Musculoskeletal system: Myasthenic syndrome, rhabdomyolysis, systemic lupus erythematosus
Respiratory system: Aspiration, pleural effusion, pneumonia and lower respiratory tract infection (LRTI), which may be fataL
Central nervous system: Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions
Cardiovascular: Atrial or ventricular tachycardia or fibrillation, periorbital edema, myocardial infarction, cardiac arrest, QT prolongation, Torsades de pointes, hypertension
Gastrointestinal system: Acute pancreatitis, dysphagia, salivary gland swelling, colitis, hypersalivation, dry mouth
Hepatobiliary: Hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure
Urogenital: Renal failure, nocturnal enuresis, acute interstitial nephritis, priapism, retrogate ejaculation
Hemic and lymphatic system: DVT; elevated hemoglobin/hematocrit, ESR; sepsis, thrombocytosis, thrombocytopenia, angioedema, leukocytoclastic vasculitis
Vision disorders: Narrow-angle glaucoma
Miscellaneous: CPK elevation, hyperuricemia, hyponatremia, weight loss
Warnings
Black box warnings
Agranulocytosis
- Available only through a restricted program called the Clozapine REMS
- Severe neutropenia, defined as an absolute neutrophil count (ANC) <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 for the general population and ≥1000/mm³ for patients with documented benign ethnic neutropenia
- Regularly monitor ANC during treatment
- Advise patients to immediately report symptoms consistent with severe neutropenia or infection (eg, fever, weakness, lethargy, sore throat)
Seizures
- Caution with history of seizure or other factors predisposing to seizure
- Risk is dose-related
Myocarditis and cardiomyopathy
- 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 rechallenge patients with history of clozapine-associated myocarditis or cardiomyopathy
Orthostatic hypotension, bradycardia, syncope
- Orthostatic hypotension, bradycardia, 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 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 (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature
Contraindications
Hypersensitivity (eg, photosensitivity, vasculitis, erythema multiforme, Stevens-Johnson syndrome)
Cautions
Only available through a restricted access program because of risk for neutropenia (ie, 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 <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 (eg, xerostomia, urinary retention, constipation)
Possible QT prolongation; use with caution in patients with history of long QT syndrome or other conditions that may increase risk (eg, hypokalemia, hypomagnesemia)
Possible increased serum levels and toxicity in patients with reduced activity of CYP isoenzymes 1A2, 2D6, or 3A4
Coadministration with other drugs that prolong QT interval or drugs that inhibit metabolism of clozapine (eg, 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
Pregnancy and lactation
Pregnancy category: B
Neonates exposed to antipsychotic drugs during 3rd trimester of pregnancy are at risk for EPS or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU support and prolonged hospitalization
Lactation: Drug enters breast milk; not recommended (American Academy of Pediatrics Committee states that this is "of concern")
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Clozaril, Fazaclo ODT (clozapine)
Mechanism of action
Demonstrates weak D2-receptor and D1-receptor blocking activity, but noradrenolytic, anticholinergic, antihistaminic, and arousal reaction inhibiting effects are significant; also possesses antiserotoninergic (5-HT1C, 5-HT2, 5-HT3) properties
Affinity for mesolimbic dopamine D4 receptor accounts for striking effects in control of behavioral and psychiatric symptoms with low incidence of EPS; histamine receptor blockade accounts for increased incidence of sleep disturbances
Absorption
Bioavailability: 50-60%
Onset: 15 min
Duration: 4-12 hr
Peak plasma time: 1.5-2.5 hr
Peak plasma concentration: 102-771 ng/mL
Distribution
Protein bound: 97%
Vd: 4.67 L/kg
Metabolism
Metabolized by hepatic P450 enzyme CYP1A2, N-demethylation, N-oxidation, 3'-carbon oxidation, epoxidation of chlorine-containing aromatic ring, substitution of chlorine by hydroxyl or thiomethyl groups, and sulfur oxidation; also CYP2D6 and CYP3A4
Metabolites: Norclozapine
Elimination
Half-life: 12 hr
Blood clearance: 250 mL/min
Total plasma clearance: 217 mL/min
Excretion: Urine (50%), feces (30%)
