Clozaril

Clo·za·ril (klz-rl)

A trademark for the drug clozapine.

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clozapine

Clozaril, Denazapine (UK), Fazaclo ODT, Zaponex (UK)

Pharmacologic class: Dibenzodiazepine derivative

Therapeutic class: Antipsychotic agent

Pregnancy risk category B

FDA Boxed Warning

• Because of significant agranulocytosis risk, use only to treat severely ill patients with schizophrenia who don't respond to standard antipsychotic drugs, or to reduce risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who risk reexperiencing suicidal behavior. Obtain baseline white blood cell (WBC) and absolute neutrophil counts before therapy, regularly during therapy, and for at least 4 weeks afterward.
• Drug is associated with seizures; likelihood increases at higher doses. Use caution when giving to patients with history of seizures or other predisposing factors. Instruct patient not to engage in activities in which sudden loss of consciousness could cause serious risk to self or others.
• Drug may increase risk of fatal myocarditis, especially during first month of therapy. Discontinue promptly if myocarditis is suspected.
• Orthostatic hypotension with or without syncope may occur. Rarely, collapse is profound and accompanied by respiratory or cardiac arrest, or both. Orthostatic hypotension is more likely during initial titration when dosage is raised rapidly. In patients who've had even brief interval off drug (2 or more days since last dose), start with 12.5 mg once or twice daily.
• During initial therapy, collapse and respiratory and cardiac arrest may occur. Use caution when initiating therapy.
• Drug increased risk of death in elderly patients with dementia-related psychosis; most deaths have been cardiovascular or infectious. Drug isn't approved for dementia-related psychosis.

Action

Unclear. Thought to interfere with dopamine binding in limbic system of CNS, with high affinity for dopamine₄ receptors. May antagonize adrenergic, cholinergic, histaminergic, and serotonergic receptors.

Availability

Tablets: 25 mg, 100 mg

Tablets (orally disintegrating): 25 mg, 100 mg

⊘Indications and dosages

➣ Schizophrenia in patients unresponsive to other therapies

Adults: 12.5 mg P.O. daily or b.i.d.; increase daily in 25- to 50-mg increments, as tolerated, to target dosage of 300 to 450 mg/day by end of second week. Make subsequent dosage increases once or twice weekly in increments of 100 mg or less, to a maximum dosage of 900 mg/day P.O. in divided doses.

Dosage adjustment

• Renal impairment
• Elderly patients

Contraindications

• Hypersensitivity to drug
• Uncontrolled seizures
• Severe CNS depression or coma
• Concurrent use of drugs that cause agranulocytosis or bone marrow depression

Precautions

Use cautiously in:
• hypersensitivity to phenothiazines
• cardiac, hepatic, or renal impairment; CNS tumors; diabetes mellitus; history of seizures; prostatic hypertrophy; intestinal obstruction; paralytic ileus; angle-closure glaucoma
• elderly patients
• pregnant or breastfeeding patients
• children.

Administration

☞ Obtain WBC count before starting therapy. Don't give drug if WBC count is below 3,500/mm³.
• When discontinuing drug, taper dosage gradually over 1 to 2 weeks.
• Be aware that orally disintegrating tablets are meant to dissolve in mouth.

Route	Onset	Peak	Duration
P.O.	Unknown	2.5 hr	4-12 hr
P.O. (orally disint.)	Unknown	Unknown	Unknown

Adverse reactions

CNS: sedation, drowsiness, dizziness, vertigo, headache, tremor, insomnia, disturbed sleep, nightmares, agitation, lethargy, fatigue, weakness, confusion, anxiety, parkinsonism, slurred speech, depression, restlessness, extrapyramidal reactions, tardive dyskinesia, akathisia, syncope, neuroleptic malignant syndrome, autonomic disturbances, seizures

CV: hypotension, tachycardia, ECG changes, chest pain, myocarditis

EENT: blurred vision, dry eyes, nasal congestion, sinusitis

GI: nausea, vomiting, constipation, dyspepsia, salivation, dry mouth, anorexia

GU: urinary retention, urinary incontinence, urinary frequency and urgency, inhibited ejaculation

Musculoskeletal: muscle spasms, rigidity, back and muscle pain

Hematologic: agranulocytosis, leukopenia, hemolytic anemia, aplastic anemia, thrombocytopenia, neutropenia, eosinophilia

Respiratory: dyspnea, respiratory arrest

Skin: rash, sweating, Stevens-Johnson syndrome

Other: weight gain, fever

Interactions

Drug-drug. Anticholinergics, antihypertensives, digoxin, warfarin: increased effects of these drugs

Cimetidine, erythromycin: increased therapeutic and toxic effects of clozapine

Epinephrine: increased hypotension

Fluoxetine, fluvoxamine, paroxetine, sertraline: increased clozapine blood level

Phenytoin, rifampin: decreased clozapine blood level

Psychoactive drugs: additive psychoactive effect

Drug-diagnostic tests. Granulocytes, hematocrit, hemoglobin, platelets, white blood cells: decreased values

Liver function tests: abnormal values

Pregnancy test: false-positive result

Drug-food. Caffeine: increased clozapine blood level

Drug-herbs. Angel's trumpet, jimsonweed, scopolia: increased anticholinergic effects

Nutmeg: decreased clozapine efficacy

St. John's wort: decreased clozapine blood level

Drug-behaviors. Alcohol use: increased CNS depression

Smoking: decreased clozapine blood level

Patient monitoring

☞ Monitor WBC count weekly for first 6 months of therapy; if it's normal, WBC testing can be reduced to every other week. Notify prescriber immediately if WBC count decreases or agranulocytosis occurs.
• Monitor ECG and liver function test results.
• If drug must be withdrawn abruptly, monitor patient for psychosis and cholinergic rebound (headache, nausea, vomiting, diarrhea).
• Continue to monitor WBC count weekly for 4 weeks after therapy ends.

Patient teaching

• Tell patient to allow orally disintegrating tablet to dissolve in mouth.
• Teach patient about significant risk of agranulocytosis; tell him he'll need to undergo weekly blood testing to check for this blood disorder. Mention that clozapine tablets are available only through a special program that ensures required blood monitoring.
☞ Advise patient to immediately report new onset of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulcers, flulike symptoms, or other signs and symptoms of infection.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, herbs, and behaviors mentioned above.