Clozapine

What is Clozapine?

• Clozapine (Clozaril; FazaClo ODT; Versacloz) is an atypical antipsychotic used to treat the symptoms of schizophrenia and in people who have not been helped by other medications or who have tried to kill themselves and are likely to try to kill or harm themselves again.

Clozapine

Clozapine 3D ball

Clozapine 3D spacefill

What are the uses of this medicine?

Clozapine (Clozaril; FazaClo ODT; Versacloz) is used for:

• Treatment-resistant schizophrenia.
• Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder.

How does this medicine work?

• The mechanism of action of clozapine is unknown.
• However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2) and the serotonin type 2A (5-HT 2A) receptors.
• Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

Who Should Not Use this medicine ?

This medicine cannot be used in patients with:

• a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of clozapine tablets.

What drug interactions can this medicine cause?

• Tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.

Be sure to mention any of the following:

• antihistamines such as diphenhydramine (Benadryl)
• antibiotics such as ciprofloxacin (Cipro) and erythromycin (E.E.S., E-Mycin, others)
• benztropine (Cogentin)
• cimetidine (Tagamet)
• bupropion (Aplenzin, Wellbutrin, Zyban, in Contrave)
• cyclobenzaprine (Amrix)
• escitalopram (Lexapro)
• medications for anxiety, high blood pressure, mental illness, motion sickness, or nausea; medications for irregular heartbeat such as encainide, flecainide, propafenone (Rythmol), and quinidine (in Nuedexta)
• oral contraceptives
• medications for seizures such as carbamazepine (Equetro, Tegretol, Teril, others) or phenytoin (Dilantin, Phenytek)
• rifampin (Rifadin, Rimactane, in Rifamate, in Rifater)
• sedatives
• selective serotonin reuptake inhibitors (SSRIs) such as duloxetine (Cymbalta), fluoxetine (Prozac, Sarafem, Selfemra, others), fluvoxamine (Luvox), paroxetine (Brisdelle, Paxil, Pexeva), and sertraline (Zoloft)
• sleeping pills
• terbinafine (Lamisil)
• tranquilizers

Is this medicine FDA approved?

• Clozapine was introduced into clinical practice in 1971, but subsequently withdrawn in 1975 after reports of fatal agranulocytosis with its use.
• Nevertheless, because of its potent activity, clozapine was approved for restricted use in refractory schizophrenia in the United States in 1989 and only with surveillance using close monitoring of complete blood counts.
• As a result, use of clozapine has been limited.

How should this medicine be used?

• Prior to initiating treatment with clozapine tablets, a baseline ANC must be obtained.

Recommended dosage:

• Starting Dose: 12.5 mg once daily or twice daily.
• Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated.
• Target Dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks.
• Subsequent Increases: increase in increments of 100 mg or less, once or twice weekly.
• Maximum Daily Dose: 900 mg

Administration:

• Clozapine comes as a tablet, an orally disintegrating tablet, and an oral suspension to take by mouth.
• It is usually taken once or twice daily.
• Take clozapine at around the same time every day.
• Do not try to push the orally disintegrating tablet through the foil packaging.
• Instead, use dry hands to peel back the foil.
• Immediately take out the tablet and place it on your tongue.
• The tablet will quickly dissolve and can be swallowed with saliva.
• No water is needed to swallow disintegrating tablets.
• Clozapine controls schizophrenia but does not cure it.
• It may take several weeks or longer before you feel the full benefit of clozapine.
• Continue to take clozapine even if you feel well.
• Do not stop taking clozapine without talking to your doctor.
• Your doctor will probably want to decrease your dose gradually.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As a tablet, an orally disintegrating tablet (tablet that dissolves quickly in the mouth), and an oral suspension (liquid)

This medicine is available in fallowing brand namesː

• Clozaril; FazaClo ODT; Versacloz

What side effects can this medication cause?

The most common side effects of this medicine include:

• CNS reactions (sedation, dizziness/vertigo, headache, and tremor)
• cardiovascular reactions (tachycardia, hypotension, and syncope)
• autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances)
• gastrointestinal reactions (constipation and nausea)
• fever

Less common, but serious side effects may include:

• Severe Neutropenia
• Orthostatic Hypotension, Bradycardia, and Syncope
• Falls
• Seizures
• Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Gastrointestinal Hypomotility with Severe Complications
• Eosinophilia
• QT Interval Prolongation
• Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
• Neuroleptic Malignant Syndrome
• Hepatotoxicity
• Fever
• Pulmonary Embolism
• Anticholinergic Toxicity
• Interference with Cognitive and Motor Performance
• Tardive Dyskinesia
• Cerebrovascular Adverse Reactions
• Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation

What special precautions should I follow?

• Clozapine tablets can cause neutropenia, defined as a reduction below pre-treatment normal levels of blood neutrophils.
• Clozapine tablets are only available through a restricted program under a REMS called the Clozapine REMS Program because of the risk of severe neutropenia.
• Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. Use clozapine tablets cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension.
• Clozapine tablets may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. Complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
• Seizure has been estimated to occur in association with clozapine. Use caution when administering clozapine tablets to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse).
• Myocarditis and cardiomyopathy have occurred with the use of clozapine tablets.
• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine tablets are not approved for the treatment of patients with dementia-related psychosis.
• Severe gastrointestinal adverse reactions have occurred with the use of clozapine tablets, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. The risk of severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible.
• If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients.
• Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred with clozapine tablets treatment. Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur.
• QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine tablets treatment. Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs).
• Atypical antipsychotic drugs, including clozapine tablets, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk.

• These metabolic changes include:
• Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes.
• Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics.
• Weight Gain: Significant weight gain has occurred. Monitor weight gain.

• Antipsychotic drugs including clozapine tablets can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Immediately discontinue and monitor closely. Assess for co-morbid conditions.
• Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur.
• During clozapine therapy, patients have experienced transient, clozapine-related fever. Evaluate for infection and for neutropenia, NMS.
• Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with clozapine tablets. Consider PE if respiratory distress, chest pain, or deep-vein thrombosis occur.
• Clozapine tablets have potent anticholinergic effects. When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.
• Clozapine tablets can cause sedation and impairment of cognitive and motor performance. Advise caution when operating machinery, including automobiles.
• Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine tablets. There is no known treatment for TD. However, the syndrome may remit partially or completely if treatment is discontinued.
• Clozapine tablets should be used with caution in patients with risk factors for cerebrovascular adverse reactions.
• If abrupt discontinuation of clozapine tablets is necessary, monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.
• Clozapine is present in human milk. Because of the potential for serious adverse reactions in nursing infants from clozapine tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
• Because it is associated with severe and potentially fatal side effects (agranulocytosis), its use is restricted to refractory schizophrenia, and monitoring during therapy is required. Clozapine therapy is associated with serum aminotransferase elevations and in rare instances has been linked to clinically apparent acute liver injury.

What to do in case of emergency/overdose?

Symptoms of overdosage may include:

• sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation.
• There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure.
• Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg.

Management of overdosage:

• In case of overdose, call the poison control helpline of your country. In the United States, call 1-800-222-1222.

• Overdose related information is also available online at poisonhelp.org/help.
• In the event that the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services. In the United States, call 911.
• There is no available specific antidote to an overdose of clozapine tablets.
• Establish and maintain an airway; ensure adequate oxygenation and ventilation.
• Monitor cardiac status and vital signs. Use general symptomatic and supportive measures.
• Consider the possibility of multiple-drug involvement.

Can this medicine be used in pregnancy?

• Pregnancy Category B.
• There are no adequate or well-controlled studies of clozapine in pregnant women.
• Because animal reproduction studies are not always predictive of human response, clozapine tablets should be used during pregnancy only if clearly needed.

Can this medicine be used in children?

• Safety and effectiveness in pediatric patients have not been established.

What are the active and inactive ingredients in this medicine?

Active ingredient:

• clozapine

Inactive ingredients:

• colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate.
• In addition, the 25 mg tablets contain FD&C Red No. 40 Aluminum Lake and the 50 mg, 100 mg and 200 mg tablets contain FD&C Blue No. 2 Aluminum Lake.

Who manufactures and distributes this medicine?

Manufactured for:

• Mylan Pharmaceuticals Inc.
• Morgantown, WV U.S.A.

Manufactured by:

• Mylan Laboratories Limited
• Hyderabad, India

Distributed by:

• Mylan Institutional Inc.
• Rockford, IL U.S.A.

What should I know about storage and disposal of this medication?

• Store at 20° to 25°C (68° to 77°F).
• Keep out of reach of children.

Antipsychotic agents

First Generation

• Phenothiazines
  • Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, Thioridazine, Trifluoperazine

• Other
  • Haloperidol, Lithium, Loxapine, Molindone, Pimozide

Second Generation (Atypicals)

• Aripiprazole, Asenapine, Brexpiprazole, Cariprazine, Clozapine, Iloperidone, Lurasidone, Olanzapine, Paliperidone, Pimavanserin, Quetiapine, Risperidone, Ziprasidone

• Dailymed label info on Clozapine
• FDA Clozapine

Clozapine Resources
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