Adult Dosing & Uses
Dosing Forms & Strengths
tablet
- 25mg
- 100mg
tablet, oral disintegrating (FazaClo ODT)
- 12.5mg
- 25mg
- 100mg
- 150mg
- 200mg
Recurrent Suicidal Behavior
12.5 mg PO qDay/BID; follow with daily dose increments of 25 to 50 mg/day, if well tolerated, to achieve target dose of 300 to 450 mg/day by end of 2 weeks; on occasions may be necessary to raise dose to 600-900 mg/day range obtain acceptable response
Monitor WBD and ANC
Treatment-Resistent Schizophrenia
12.5 mg PO qDay/BID; follow with daily dose increments of 25 to 50 mg/day, if well tolerated, to achieve target dose of 300 to 450 mg/day by end of 2 weeks; on occasions may be necessary to raise dose to 600-900 mg/day range obtain acceptable response
Monitor WBC and ANC
Geriatric Dosing
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)
Other Indications & Uses
Psychotic disorders
Pediatric Dosing & Uses
Not recommended
Drug Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
Frequency Not Defined
Common
- Hypotension, tachycardia
- Fever, sedation, seizures (high dose)
- Appetite incr, constipation, heartburn, nausea, polyphagia, sialorrhea, vomiting, weight gain
Less Common
- Syncope
- Extrapyramidal effects (tremor, restlessness, rigidity, akathesia)
- Dizziness, headache, insomnia, delerium, depression, fatigue, weakness, slurred speech, seizures (low dose)
- Hyperglycemia, potential for new-onset diabetes; monitor blood glucose in high-risk pts
- Leukopenia, neutropenia, thrombocytosis
- Shortness of breath, wheezing
- Polyuria, enuresis, impotence, dysmenorrhea
Rare
- Myocarditis
- Amnesia, hallucinations
- Parkinsonian syndrome, periodic cataplexy, neuroleptic malignant syndrome
- Anemia, leukocytosis, increased platelet count, agranulocytosis
- Change in libido
Postmarketing Reports
Obsessive compulsive symptoms
New onset diabetes mellitus
Pneumonia and lower respiratory tract infection which may be fatal
Cardiovascular System: atrial or ventricular tachycarida/fibrillation, periorbital edema, cardiac arrest, QT prolongation, and Torsades de Pointes
Contraindications & Cautions
Black Box Warnings
Agranulocytosis
- Because of significant risk, reserve for severely ill patients unresponsive to standard antipsychotics or to reduce risk of recurrent suicidal behavior
- Must have baseline WBC and ANC counts before initiating, regularly throughout therapy, and for at least 4 weeks after discontinuing
- Because of these requirements, only available only through special distribution system
Seizures
- Caution with history of, or other predisposing factors
- Greater likelihood with high doses
Myocarditis
- Associated with increased risk of fatal myocarditis, especially during (but not limited to) the 1st month of therapy
Other Cardiovascular & Respiratory Effects
- Orthostatic hypotension may occur; can be profound and accompanied by respiratory/cardiac arrest (associated with rapid dose escalation)
- Collapse, respiratory arrest, and cardiac arrest during initial treatment has occurred with patients being administered benzodiazepines or other psychotropic drugs
Increased Mortality in Elderly With Dementia-Related Psychosis
- Patients with dementia-related psychosis who are treated with antipsychotic drugs at increased risk of death as shown in short-term controlled trials; deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature
- Not approved for treatment of dementia-related psychosis
Contraindications
Hypersensitivity, concurrent use of myelosuppressive agents, narrow angle glaucoma, uncontrolled epilepsy, CNS depression (including coma), history of agranulocytosis or granulocytopenia, myeloproliferative disorders; WBC < 3500 cells/mm3 before or during therapy; phenylketonuria (aspartame contained in oral disintegrating tablet)
Cautions
Requires patient to be registered
Risk of agranulocytosis (drug is available only through distribution systems to ensure WBC and ANC monitoring)
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 ketoacidosis, hyperosmolar coma, or death; monitor blood glucose of high-risk patients
FDA Warning regarding off-label use for dementia in elderly
QT prolongation may occur; caution when prescribed in patients with history of long QT syndrome or other conditions that may increase risk (eg, hypokalemia, hypomagnesemia)
Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4; increased serum levels and toxicity may occur in patients with reduced activity of CYP 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 increased incidence of myocarditis that is particularly prevalent within first month of treatment; do not stop the medication abruptly; perform WBC testing every 2 wk for the duration of therapy
Pregnancy & Lactation
Pregnancy Category: B
Neonates exposed to antipsychotic drugs during the 3rd trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery
These complications vary in severity; in some cases, symptoms have been self-limited, while in other cases neonates have required intensive care unit support and prolonged hospitalization
Lactation: enters breast milk/not recommended (AAP Committee states "of concern")
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
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 antiserotonergic (5-HT1c, 5-HT2, 5-HT3) properties
Affinity for mesolimbic D4 dopamine receptor accounts for striking effects in control of behavioral and psychiatric symptoms with low incidence of extrapyramidal symptoms
Histamine receptor blockade accounts for increased incidence of sleep disturbances
Absorption
Bioavailability: 27-50%
Duration: 4-12 hr
Onset: 15 min
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
Hepatic P450 enzyme CYP1A2, N-demethylation, N-oxidation, 3'-carbon oxidation, epoxidation of the chlorine-containing aromatic ring, substitution of chlorine by hydroxyl or thiomethyl groups, & sulfur oxidation; also CYP2D6 and CYP3A4
Metabolites: norclozapine
Elimination
Half-Life: 12 hr
Clearance (total plasma): 217 mL/min
Clearance (blood): 250 mL/min
Excretion: Feces 30%; urine 50%
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