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Clozapine

Brands and Forms

  • Clozaril
    • tablet: 12.5mg, 25mg scored, 50mg, 100mg scored, 200m
  • FazaClo
    • orally disintegrating tablet: 12.5mg, 25mg, 100m

Uses of Clozapine

Clozapine is used for treatment-resistent cases of Schizophrenia, Bipolar Disorder and Schizoaffective Disorder. It is one of the most effective medications for those conditions. It can also help to reduce suicidal thoughts and behaviors. However, the risk of agranulocytosis and the need for close medical monitoring limits its clinical use.

How Clozapine Works

Clozapine is usually classified as an Atypical Antipsychotic. It interferes with dopamine binding at D1, D2, D3, and D5 receptors in the central nervous system, and antagonizes adrenergic, cholinergic, histaminergic, and serotonergic neurotransmission.

Cautions when Using Clozapine

Agranulocytosis, the drop in white blood cell concentrations to dangerously low levels, which would prevent the body from effectively fighting infections, is a significant risk with Clozapine that requires careful medical monitoring.

In elderly individuals with Dementia, use of Antipsychotics has been associated with increased rates of sudden death. It is unclear whether the antipsychotic use is a cause, or simply a marker, of deteriorating health in these individuals.

In people with a known seizure disorder, glaucoma, or prostate enlargement, consider obtaining the advice of the appropriate medical specialist before using Clozapine.

Weight gain and metabolic side-effects (elevated glucose, lipids and cholesterol) can be very pronounced side-effects of Clozapine.

Dosing of Clozapine

The usual therapeutic range of Clozapine is 300-600mg/day, though doses of up to 900mg/day. At doses below 300mg/day it can be given once daily, preferably at night due to the sedation it causes, though twice daily dosing is also common. Still, a larger dose is usually given at bedtime.

The initial dose is 12.5-25mg/day, and then increased every day by 25-50mg (or more slowly depending on how the individual tolerates the medication) until desired dose is reached, which is usually 300mg/day. At this point, waiting several weeks is recommended to give a chance for therapeutic effects to appear. Above 450mg/day, dose can be increased by 100mg every week.

When wanting to stop Clozapine, the dose should be reduced gradually over a period of 6-8 weeks. Stopping the medication suddenly can lead to a dramatic and rapid rebound in psychotic symptoms and mental disorganization.

Onset of action

Therapeutic effects can sometimes be seen within the first week of use. However, full effects may require several months at a therapeutic dose to appear. If there are no significant effects after 6 months at a dose in the usual therapeutic range, then the medication may not work at all.

Kidney impairment

Use with caution.

Liver impairment

Use with caution.

Side-effects of Clozapine

Below is a list of most of the reported side-effects of Clozapine. Most of these side-effects occur in only a minority of individuals, and many also resolve with time while the medication is continued.

Cardiovascular: rapid heart rate; elevated or decreased blood pressure; chest pain/angina; cardiac arrhythmias; cardiomyopathy (rare); deep vein thrombosis (rare); myocarditis (rare).

Central Nervous System: somnolence/drowsiness; dizziness; insomnia; vertigo; headache; fainting; tremor; disturbed sleep/nightmares; hypokinesia/akinesia; confusion; rigidity; unsteadiness; epileptiform movements/myoclonic jerks; lethargy; slurred speech; weakness; abnormal EEG; delirium; mild cataplexy; myoclonus; paresthesia; seizures.

Dermatologic: rash; excessive sweating.

Endocrine/Metabolic: weight gain; metabolic syndrome (insulin resistence, elevated glucose, lipids and cholesterol); hyponatremia.

Eyes, Ears, Nose and Throat: visual disturbances; nasal congestion; throat discomfort; narrow-angle glaucoma (rare).

Gastrointestinal: excessive salivation; constipation; nausea; vomiting; dyspepsia; dry mouth; abdominal discomfort/heartburn; diarrhea; appetite loss; acute pancreatitis (rare); dysphagia; fecal impaction; intestinal obstruction/paralytic ileus (rare); salivary gland swelling; elevated liver enzymes; hepatitis (rare).

Genitourinary: urinary abnormalities; abnormal ejaculation; incontinence; urinary retention; urinary urgency/frequency; acute interstitial nephritis (rare); priapism.

Hematologic: leukopenia/decreased WBC/neutropenia; agranulocytosis; eosinophilia; elevated hemoglobin/hematocrit; erythrocyte sedimentation rate increase; sepsis; thrombocytopenia; thrombocytosis.

Muskuloskeletal: muscle aches and pains; muscle weakness; myasthenic syndrome; rhabdomyolysis (rare).

Psychiatric: anxiety; agitation; restlessness; depressed mood; worsening psychosis; obsessive-compulsive symptoms.

Respiratory: shortness of breath; aspiration; pleural effusion; pulmonary embolism (rare).

Common side-effects of Clozapine

Sedation/drowsiness/fatigue, excessive salivation (may need to keep a towel over one's pillow at night), weight gain, dizziness, constipation, insomnia, vertigo, nausea, dyspepsia.

Rare but serious side-effects of note of Clozapine

  • Agranulocytosis (a drop in white blood cell concentrations to dangerously low levels, which would prevent the body from effectively fighting infections)
  • Cardiomyopathy (deteriorating functioning of the heart muscle)
  • Cardiac arrhythmias
  • Pulmonary embolism
  • Severe hyperglycemia (elevated blood sugar)
  • Seizures (risk is higher at doses above 550mg/day, and an anticonvulsant may be required)
  • Sudden death in elderly individuals with dementia.

Clozapine overdose

Aspiration pneumonia, cardiac arrhythmias, delirium, drowsiness, excessive salivation, hypotension, respiratory depression or failure, seizures, tachycardia, coma. Can be lethal.

Clozapine and pregnancy

Category B: animal studies do not show adverse effects, but no controlled human studies have been done; should only be used in pregnancy if clearly needed and if benefits outweigh potential risks.

Clozapine, weight gain and metabolic syndrome

Up to 50% of people taking Olanzapine will gain about 7% of their total body weight within 8 weeks of starting the medication [ref, ref]. Metabolic side-effects, including elevated glucose and lipids can also occur, which in the long-term increase the risk for heart disease and vascular problem.

See here for further information on these side-effects, and how they can be managed.

Medical Monitoring for Clozapine

To monitor for signs of agranulocytosis, a complete blood count (CBC) must be measured prior to starting the medication and then every week for the first 6 months of treatment, and then every 2 weeks thereafter.

  • White blood cells (WBC) above 3.5x10⁹/L and Neutrophils above 2.0x10⁹/L is acceptable
  • If WBC is between 2.0-3.5x10⁹/L, or Neutrophils are between 1.5-2.0x10⁹/L, measure CBC every two days until blood levels normalize, and then measure CBC weekly for 1 year.
  • If WBC falls below 2.0x10⁹/L or Neutrophils fall below 1.5x10⁹/L, discontinue Clozapine.

Monitoring for weight gain and a metabolic syndrome requires the following measures to be taken prior to starting the medication, then monthly for the first 3 months of use, and then every 3 months:

  • Body Mass Index (BMI)
  • waistline circumference at umbilicus
  • blood pressure
  • fasting blood glucose
  • fasting blood lipids and cholesterol

Due to the risk of cardiac arrhythmias and cardiomyopathy, an electrocardiogram should be measured prior to starting the medication, then one month after starting, one month after every dose increase.

Symptoms of shortness of breath or chest pain should be investigated for possible cardiac arrhythmias, cardiomyopathy, or pulmonary embolism.

Drug Interactions with Clozapine

  • Use extreme caution if combining Clozapine with Carbamazepine, which can also cause agranulocytosis.
  • Use caution if combining with other CNS depressant medications.
  • Use caution if combining with antihypertensives.
  • Clozapine blood levels can be increased by drugs that inhibit CYP-450 (eg, caffeine, Cimetidine, Ciprofloxacin, Erythromycin, Fluoxetine, Fluvoxamine, Modafinil, Nefazodone, Risperidone, Ritonavir).