cloZAPine, Clozaril, FazaClo, Versacloz

 Indications

Schizophrenia unresponsive to or intolerant of standard

therapy with other antipsychotics (treatment refractory).

To reduce recurrent suicidal behavior in

schizophrenic patients.

Action

Binds to dopamine receptors in the CNS. Also has anticholinergic

and alpha-adrenergic blocking activity.

Produces fewer extrapyramidal reactions and less tardive

dyskinesia than standard antipsychotics but carries

high risk of hematologic abnormalities. Therapeutic

Effects: Diminished schizophrenic behavior. Diminished

suicidal behavior.

Pharmacokinetics

Absorption: Well absorbed after oral administration.

Distribution: Rapid and extensive distribution;

crosses blood-brain barrier and placenta.

Protein Binding: 95%.

Metabolism and Excretion: Mostly metabolized

on first pass through the liver (by CYP1A2, CYP2D6,

and CYP3A4 isoenzymes); (the CYP2D6 enzyme system

exhibits genetic polymorphism; 7% of population

may be poor metabolizers and may have significantlyq

clozapine concentrations and anqrisk of adverse effects).

Half-life: 8–12 hr.

TIME/ACTION PROFILE (antipsychotic effect)

ROUTE ONSET PEAK DURATION

PO unknown wk 4–12 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity; Bone marrow

depression; Severe CNS depression/coma; Uncontrolled

epilepsy; Clozapine-induced agranulocytosis or severe

granulocytopenia; Lactation: Discontinue drug or bottle-

feed.

Use Cautiously in: Long QT syndrome; Risk factors

for QT interval prolongation or ventricular arrhythmias

(i.e., recent myocardial infarction, heart failure, arrhythmias);

Concurrent use of CYP1A2, CYP2D6, or

CYP3A4 inhibitors or QT-interval prolonging drugs; Hypokalemia

or hypomagenesemia; Prostatic enlargement;

Angle-closure glaucoma; Malnourished or dehydrated

patients, patients with cardiovascular,

cerebrovascular, hepatic, or renal disease, or patients

on antihypertensives (use lower initial dose, titrate

more slowly); Risk factors for stroke (qrisk of stroke

in patients with dementia); Diabetes; Seizure disorder;

Patients at risk for falls; OB: Neonates atqrisk for extrapyramidal

symptoms and withdrawal after delivery

when exposed during the 3rd trimester; use only if benefit

outweighs risk to fetus; Pedi: Children 16 yr

(safety not established); Geri:qrisk of mortality in elderly

patients treated for dementia-related psychosis. 

Adverse Reactions/Side Effects

CNS: NEUROLEPTIC MALIGNANT SYNDROME, SEIZURES, dizziness,

sedation. EENT: visual disturbances. CV: CARDIAC

ARREST, DEEP VEIN THROMBOSIS, HF, MITRAL VALVE

INCOMPETENCE, MYOCARDITIS, TORSADE DE POINTES, VENTRICULAR

ARRHYTHMIAS, hypotension, tachycardia,

bradycardia, ECG changes, hypertension, syncope, QT

interval prolongation. GI: HEPATOTOXICITY, constipation,

abdominal discomfort, dry mouth,qsalivation,

nausea, vomiting, weight gain. GU: nocturnal enuresis.

Derm: rash, sweating. Endo: hyperglycemia, hyperlipidemia,

weight gain. Hemat: AGRANULOCYTOSIS, LEUKOPENIA.

Neuro: extrapyramidal reactions. Resp:

PULMONARY EMBOLISM. Misc: fever.

Interactions

Drug-Drug:qanticholinergic effects with other

agents having anticholinergic properties, including

antihistamines, quinidine, disopyramide, and

antidepressants. Concurrent use with strong CYP1A2

inhibitors, including fluvoxamine or ciprofloxacin

mayqlevels;pclozapine dose to 1⁄3 of the original dose

during concurrent use. Concurrent use with moderate

or weak CYP1A2 inhibitors, including oral contraceptives

or caffeine mayqlevels; considerpclozapine

dose. Concurrent use with CYP2D6 inhibitors or

CYP3A4 inhibitors, including cimetidine, escitalopram,

erythromycin, paroxetine, bupropion,

fluoxetine, quinidine, duloxetine, terbinafine, or

sertraline mayqlevels; considerpclozapine dose.

Concurrent use with CYP1A2 inducers or CYP3A4

inducers, including nicotine, carbamazepine, phenytoin,

or rifampin mayplevels; concurrent use with

strong CYP3A4 inducers not recommended.qCNS depression

with alcohol, antidepressants, antihistamines,

opioid analgesics, or sedative/hypnotics.

qhypotension with nitrates, acute ingestion of alcohol,

or antihypertensives.qrisk of bone marrow

suppression with antineoplastics or radiation therapy.

Use with lithiumqrisk of adverse CNS reactions,

including seizures.qrisk of QT interval prolongation

with other agents causing QT interval prolongation.

Drug-Natural Products: Caffeine-containing

herbs (cola nut, tea, coffee) mayqserum levels and

side effects. St. John’s wort maypblood levels and efficacy.

Route/Dosage

PO (Adults): 12.5 mg 1–2 times daily initially;qby

25–50 mg/day over a period of 2 wk up to target dose

of 300–450 mg/day. May then beqby up to 100 mg/

day once or twice weekly (not to exceed 900 mg/day).

Treatment should be continued for at least 2 yr in patients

with suicidal behavior.

Availability (generic available)

Tablets: 25 mg, 100 mg. Orally disintegrating tablets

(mint): 12.5 mg, 25 mg, 100 mg, 150 mg, 200

mg. Oral suspension : 50 mg/mL.