Clozapine

Class

Second Generation Antipsychotic

Neuroscience-based Nomenclature (NbN)

Pharmacological Target

Dopamine, serotonin, norepinephrine

Mode of Action

Receptor Antagonist (D2, 5-HT2, NE alpha-2)

Brand Name

Clozaril, Fazaclo, Leponex

Monograph

Monograph Link

Adverse Reactions

  Sedation
  Dizziness
  Weight gain
  EPS (low)
  Galactorrhea (low)
  Risk of tardive dyskinesia (low)
  NMS
  Risk of agranulocytosis (monitoring required)

Warnings

  Class Warning: Increased Mortality in Elderly Patients with Dementia Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
  Class Warning: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Smoking

Bioavailability

50 – 60% (not affected by food)

Volume of distribution (Vd)

4.65 L/Kg

Protein binding

97%

Elimination half-life

Steady state: 12 hours (range: 6-30 hours)

Time to peak (Tmax)

2.5 hours (range 1-6 hours)

Metabolism

Extensive hepatic metabolism (CYP1A2, CYP2D6, CYP3A4); forms metabolites with limited or no activity

Excretion

  Urine: approximately 50% (trace amounts)
  Feces: 30% (trace amounts)

Special populations

  Renal impairment: in mild to moderate renal impairment the initial dose should be 12.5 mg given once on the first day, and dosage increase should be slow and in small increments.
  Hepatic impairment: use with caution along with regular monitoring of liver function tests

Hepatic impairment#

Patients with stable pre-existing liver disorders may receive clozapine, but need regular liver function tests. In patients in whom, during clozapine treatment, symptoms of possible liver dysfunction such as nausea, vomiting and/or anorexia develop, liver function tests should be performed immediately. If the elevation of these values is clinically relevant or if symptoms of jaundice occur, treatment with Clozapien must be discontinued. It may be resumed only when the liver function tests have returned to normal values. In such cases, liver function should be closely monitored after the re-introduction of the drug.

Renal impairment

In patients suffering from mild to moderate renal impairment, an initial dose of 12.5 mg/day (half a 25 mg tablet) is recommended.

Overview

  Clozapine may enhance the central effects of alcohol, MAO inhibitors, CNS depressants including narcotics, antihistamines, and benzodiazepines, as well as the effects of anticholinergic and antihypertensive agents.
  Caution is advised with patients who are receiving (or have recently received) benzodiazepines or other psychotropic drugs, as these patients may have an increased risk of circulatory collapse accompanied by respiratory and/or cardiac arrest.
  Owing to its anti-alpha-adrenergic properties, clozapine may reduce the blood pressure increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the pressor effect of epinephrine.
   Clozapine should not be used with other agents, such as carbamazepine, having a known potential to suppress bone marrow function. In particular, the concomitant use of long-acting depot antipsychotic drugs should be avoided because these medications, which may have the potential to be myelosuppressive, cannot be rapidly removed from the body.
  Concomitant use of valproic acid with clozapine may alter the plasma levels of clozapine. Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where clozapine was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
  As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QTc interval, or causing electrolyte imbalance.
  Clozapine is a substrate for many CYP 450 isoenzymes, in particular 1A2 and 3A4. Caution is called for in patients receiving concomitant treatment with other drugs which are either inhibitors or inducers of these enzymes.

Drugs That Inhibit CYP Isozymes

  Drugs known to inhibit the activity of the major isozymes involved in the metabolism of clozapine and with reported interactions include, cimetidine (2D6, 3A4), and erythromycin (3A4). Other potent inhibitors of CYP3A, such as azole antimycotics and protease inhibitors, could potentially also increase clozapine plasma concentrations; however, no interactions have been reported to date.
  Substantial elevation of the plasma concentration of clozapine has been reported in patients receiving the drug in combination with fluvoxamine (1A2), ciprofloxacin (1A2) and oral contraceptives (1A2, 3A4, 2C19). Smaller elevations in clozapine plasma concentrations have also been reported in patients receiving the drug in combination with other selective serotonin re-uptake inhibitors (SSRIs) such as paroxetine, sertraline, fluoxetine and citalopram (possibly a weak inhibitor of CYP1A2 and possibly the least likely among SSRIs to cause a clinically significant interaction with clozapine).
  The plasma concentration of clozapine is increased by caffeine (1A2) intake and decreased by nearly 50% following a 5-day caffeine-free period.

Drugs That Induce CYP Isozymes

  Drugs known to induce the activity of 3A4 and with reported interactions with clozapine include, for instance, carbamazepine, phenytoin and rifampicin.
  Known inducers of 1A2 include, for instance, omeprazole and tobacco smoking. In cases of sudden smoking cessation, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.