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CLOZAPINE
DIR Classification
Classification:Most-DIR concern
Severity Score:4
Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF
- WARNINGS AND PRECAUTIONS
- QT Interval Prolongation
- QT prolongation, Torsade de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing clozapine, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.
- Prior to initiating treatment with clozapine, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue clozapine if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue clozapine.
- Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of clozapine [see DRUG INTERACTIONS (7.1) and CLINICAL PHARMACOLOGY (12.3)].
- Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with clozapine.
- DRUG INTERACTIONS
- Drugs that Cause QT Interval Prolongation
- Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see WARNINGS AND PRECAUTIONS (5.10)].
- ADVERSE REACTIONS
- Postmarketing Experience
- Cardiovascular System
- Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction sometimes fatal, cardiac arrest, myocarditis sometimes fatal and periorbital edema.
- PATIENT COUNSELING INFORMATION
- QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take clozapine with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking clozapine before any new drug [see WARNINGS AND PRECAUTIONS (5.10), DRUG INTERACTIONS (7.1)].
Postmarketing Surveillance
Contingency Table:
Current Drug
Other Drugs
Rhabdomyolysis
220
42692
Other ADRs
58776
14058503
Odds Ratio = 1.233
Drug Property Information
ATC Code(s):
- N05AH02 - clozapine
- N05AH - "Diazepines, oxazepines and thiazepines"
- N05A - ANTIPSYCHOTICS
- N05 - PSYCHOLEPTICS
- N - NERVOUS SYSTEM
Active Ingredient:clozapine
Active Ingredient UNII:J60AR2IKIC
Drugbank ID:DB00363
PubChem Compound:2818
CAS Number:5786-21-0
Dosage Form(s):tablet
Route(s) Of Administrator:oral
Daily Dose:
- 300.0 mg/day N05AH02
Chemical Structure: 
SMILE Code:
CN1CCN(CC1)C2=C3C=CC=CC3=NC4=C(N2)C=C(C=C4)Cl
CN1CCN(CC1)C2=C3C=CC=CC3=NC4=C(N2)C=C(C=C4)Cl
Reference
COHORT STUDY:
N/AOTHER REFERENCE(S):
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