Clozaril


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cloZAPine

(kloe-za-peen) ,

Clozaril

(trade name),

FazaClo

(trade name),

Versacloz

(trade name)

Classification

Therapeutic: antipsychotics
Pregnancy Category: B

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); genetic implication (the CYP2D6 enzyme system exhibits genetic polymorphism; ∼7% of population may be poor metabolizers and may have significantly ↑ clozapine concentrations and an ↑ risk of adverse effects).
Half-life: 8–12 hr.

Time/action profile (antipsychotic effect)

ROUTEONSETPEAKDURATION
POunknown wk4–12 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 (↑ risk of stroke in patients with dementia);Diabetes;Seizure disorder; Obstetric: Neonates at ↑ risk for extrapyramidal symptoms and withdrawal after delivery when exposed during the 3rd trimester; use only if benefit outweighs risk to fetus; Pediatric: Children <16 yr (safety not established); Geriatric: ↑ risk of mortality in elderly patients treated for dementia-related psychosis.

Adverse Reactions/Side Effects

Central nervous system

  • neuroleptic malignant syndrome (life-threatening)
  • seizures (life-threatening)
  • dizziness (most frequent)
  • sedation (most frequent)

Ear, Eye, Nose, Throat

  • visual disturbances

Cardiovascular

  • cardiac arrest (life-threatening)
  • deep vein thrombosis (life-threatening)
  • myocarditis (life-threatening)
  • torsade de pointes (life-threatening)
  • ventricular arrhythmias (life-threatening)
  • hypotension (most frequent)
  • tachycardia (most frequent)
  • bradycardia
  • ECG changes
  • hypertension
  • syncope
  • QT interval prolongation

Gastrointestinal

  • constipation (most frequent)
  • abdominal discomfort
  • dry mouth
  • ↑ salivation
  • nausea
  • vomiting
  • weight gain

Genitourinary

  • nocturnal enuresis

Dermatologic

  • rash
  • sweating

Endocrinologic

  • hyperglycemia
  • hyperlipidemia
  • weight gain

Hematologic

  • agranulocytosis (life-threatening)
  • leukopenia (life-threatening)

Neurologic

  • extrapyramidal reactions

Respiratory

  • pulmonary embolism (life-threatening)

Miscellaneous

  • fever

Interactions

Drug-Drug interaction

↑ anticholinergic effects with other agents having anticholinergic properties, including antihistamines, quinidine, disopyramide, and antidepressants.Concurrent use with strong CYP1A2 inhibitors, including fluvoxamine or ciprofloxacin may ↑ levels; ↓ clozapine dose to 1/3 of the original dose during concurrent use.Concurrent use with moderate or weak CYP1A2 inhibitors, including oral contraceptives or caffeine may ↑ levels; consider ↓ clozapine doseConcurrent use with CYP2D6 inhibitors or CYP3A4 inhibitors, including cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline may ↑ levels; consider ↓ clozapine doseConcurrent use with CYP1A2 inducers or CYP3A4 inducers, including nicotine, carbamazepine, phenytoin, or rifampin may ↓ levels; concurrent use with strong CYP3A4 inducers not recommended↑ CNS depression with alcohol, antidepressants, antihistamines, opioid analgesics, or sedative/hypnotics.↑ hypotension with nitrates, acute ingestion of alcohol, or antihypertensives.↑ risk of bone marrow suppression with antineoplastics or radiation therapy.Use with lithium ↑ risk of adverse CNS reactions, including seizures.↑ risk of QT interval prolongation with other agents causing QT interval prolongation.Caffeine-containing herbs (cola nut, tea, coffee) may ↑ serum levels and side effects.St. John’s wort may ↓ blood levels and efficacy.

Route/Dosage

Oral (Adults) 12.5 mg 1–2 times daily initially; ↑ by 25–50 mg/day over a period of 2 wk up to target dose of 300–450 mg/day. May then be ↑ by 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 tabletsmint: 12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg
Oral suspension : 50 mg/mL

Nursing implications

Nursing assessment

  • Monitor patient’s mental status (orientation, mood, behavior) before and periodically during therapy. Titrate slowly and monitor closely; may cause orthostatic hypotension, bradycardia, syncope, and cardiac arrest.
  • Monitor BP (sitting, standing, lying) and pulse rate before and frequently during initial dose titration.
  • Assess weight and BMI initially and throughout therapy. Refer as appropriate for nutritional/weight management and medical management.
  • Observe patient carefully when administering medication to ensure that medication is actually taken and not hoarded or cheeked.
  • Monitor for signs of myocarditis (unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs and symptoms of heart failure, ECG changes, such as ST-T wave abnormalities, arrhythmias, or tachycardia during first month of therapy). If these occur, clozapine should be discontinued and not restarted.
  • Monitor patient for onset of akathisia (restlessness or desire to keep moving) and extrapyramidal side effects ( parkinsonian—difficulty speaking or swallowing, loss of balance control, pill-rolling motion of hands, mask-like face, shuffling gait, rigidity, tremors and dystonic muscle spasms, twisting motions, twitching, inability to move eyes, weakness of arms or legs) every 2 mo during therapy and 8–12 wk after therapy has been discontinued. Notify health care professional if these symptoms occur; reduction in dose or discontinuation of medication may be necessary. Trihexyphenidyl or benzotropine may be used to control these symptoms.
  • Monitor for possible tardive dyskinesia (uncontrolled rhythmic movement of mouth, face, and extremities; lip smacking or puckering; puffing of cheeks; uncontrolled chewing; rapid or worm-like movements of tongue). Report these symptoms immediately; may be irreversible.
  • Monitor frequency and consistency of bowel movements. Increasing bulk and fluids in the diet may help to minimize constipation.
  • Clozapine lowers the seizure threshold. Institute seizure precautions for patients with history of seizure disorder.
  • Transient fevers may occur, especially during first 3 wk of therapy. Fever is usually self-limiting but may require discontinuation of medication. Also, monitor for development of neuroleptic malignant syndrome (fever, respiratory distress, tachycardia, seizures, diaphoresis, hypertension or hypotension, pallor, tiredness). Notify health care professional immediately if these symptoms occur.
  • Assess respiratory status during therapy. If deep-vein thrombosis, acute dyspnea, chest pain, or other respiratory signs and symptoms occur, consider pulmonary embolism.
  • Lab Test Considerations: Monitor WBC, absolute neutrophil count (ANC), and differential count before initiation of therapy. ANC must be ≥2000/mm3 and WBC must be ≥3500/mm3 for patient to begin therapy. If ANC <1000/mm3 or WBC <2000/mm3, discontinue and do not rechallange. WBC and ANC must be monitored weekly for the first 6 mo, then biweekly for the second 6 mo, then, if maintained within acceptable parameters, every 4 wk during therapy and weekly for 4 wk after discontinuation of clozapine or until WBC ≥3500/mm3 and ANC ≥2000/mm3. If a substantial drop in ANC or WBC, single drop or cumulative drop within 3 wk of WBC ≤3,000/mm3 or ANC ≤1500/mm3, repeat WBC and ANC. If repeat values are: WBC 3000/mm3 to 3500/mm3 and/or ANC > 2000/mm3, then monitor twice weekly. If mild leukopenia or granulocytopenia occurs (WBC 3000/mm3 to 3500/mm3 and/or ANC 1500/mm3 to 2000/mm3), monitor twice weekly until WBC >3500/mm3 and ANC >2000/mm3, then return to previous monitoring frequency. If moderate leukopenia or granulocytopenia (WBC 2000/mm3 to 3000/mm3 and/or ANC 1000/mm3 to 1500/mm3), interrupt therapy. Monitor daily until WBC >3000/mm3 and ANC >1500/mm3, then twice weekly until WBC >3500/mm3 and ANC >2000/mm3, may rechallenge at this level. If rechallenged, monitor weekly for 1 yr before returning to usual monitoring schedule of every 2 wk for 6 mo and then every 4 weeks. Because of the risk of agranulocytosis, clozapine is available only through theClozaril National Registry, Fazaclo Patient Registry, or Versacloz Patient Registry,which combines WBC testing, patient monitoring, and controlled distribution through participating pharmacies.
    • Assess fasting blood glucose and cholesterol levels initially and throughout therapy.
  • Overdose is treated with activated charcoal and supportive therapy. Monitor patient for several days because of risk of delayed effects.
    • Avoid use of epinephrine and its derivatives when treating hypotension, and avoid quinidine and procainamide when treating arrhythmias.

Potential Nursing Diagnoses

Risk for other-directed violence (Indications)
Disturbed thought process (Indications)
Risk for injury (Side Effects)

Implementation

  • Do not confuse clozapine with clonazepam or clonidine. Do not confuse Clozaril with Colazal.
  • Oral: Administer capsules with food or milk to decrease gastric irritation.
    • Leave oral disintegrating tablet in blister until time of use. Do not push tablet through foil. Just before use, peel foil and gently remove disintegrating tablet. Immediately place tablet in mouth and allow to disintegrate and swallow with saliva. If 1/2 tablet dose used, destroy other half of tablet.
    • Oral solution may be taken without regard to food. Shake bottle for suspension for 10 sec prior to withdrawing. Use oral syringes and oral adaptor provided for accurate dosing. Do not store dose in syringe; wash between doses.

Patient/Family Teaching

  • Instruct patient to take medication as directed. Patients on long-term therapy may need to discontinue gradually over 1–2 wk.
  • Explain purpose and procedures for Clozaril National Registry, Fazaclo Patient Registrry, Versacloz Patient Registry to patient.
  • Inform patient of possibility of extrapyramidal symptoms. Instruct patient to report these symptoms immediately.
  • Inform patient that cigarette smoking can decrease clozapine levels. Risk for relapse increases if patient begins or increases smoking.
  • Advise patient to change positions slowly to minimize orthostatic hypotension.
  • May cause seizures and drowsiness. Caution patient to avoid driving or other activities requiring alertness while taking clozapine.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any other Rx, OTC, or herbal products. Caution patient to avoid concurrent use of alcohol and other CNS depressants.
  • Instruct patient to use frequent mouth rinses, good oral hygiene, and sugarless gum or candy to minimize dry mouth.
  • Advise patient to notify health care professional of medication regimen before treatment or surgery.
  • Instruct patient to notify health care professional promptly if unexplained fatigue, dyspnea, tachypnea, chest pain, palpitations, sore throat, fever, lethargy, weakness, malaise, or flu-like symptoms occur.
  • Advise female patients to notify health care professional if pregnancy is planned or suspected, or if breast feeding or planning to breast feed.
  • Advise patient of need for continued medical follow-up for psychotherapy, eye exams, and laboratory tests.

Evaluation/Desired Outcomes

  • Decreased positive symptoms (delusions, hallucinations) of schizophrenia.
  • Decrease in negative symptoms (social withdrawal, flat, blunt affect) of schizophrenia.

Clozaril

(klō′zə-rĭl′)
A trademark for the drug clozapine.
References in periodicals archive ?
Lead investigator Professor Robert Kerwin said that wider use of Clozaril could save between 50 and 100 lives a year in the UK.
We already knew that Clozaril could help people with schizophrenia,'' said Prof Kerwin, who is professor of clinical neuropharmacology at the Institute of Psychiatry, King's College, London.
said in an interview that the reduction in the frequency of monitoring after 1 year was based on considerations of data from the Clozaril National Registry and experience in the United Kingdom and Australia.
Novartis, which manufactures Clozaril, the trade formulation, is planning to send out a "Dear Health Care Provider" letter explaining the changes in the monitoring schedule as well as several other unrelated changes on the label.
Postmarketing data suggest that Clozaril is "associated with an increased risk of fatal myocarditis," especially during the first month of therapy.
Data from clozapine treatment registries in the United Kingdom and Texas also showed a reduced suicide rate associated with Clozaril.
This suggests that Clozaril is a very effective medication for controlling aggression and the symptoms of psychosis," Dr.
In this study, FazaClo was administered without any liquids and Clozaril was administered with liquids.
drug levels in the blood of patients are equal) between Clozaril and Clozapine," stated Sanford Bolton, Ph.
They knew they were being switched off - and back onto - their long standing medication, Clozaril.
Weekly white blood cell counts and weekly drug dispensing mandatory because of the risk of agranulocytosis, which can be reversed if detected early Postmarkering data suggest that Clozaril is "associated with an increased risk of fatal myocarditis," especially during the first month.