DESCRIPTION / DEFINITIONS: Clozaril® (clozapine) is a atypical antipsychotic. It is a drug prescribed for the acute and maintenance treatment of Schizophrenia in adults and in adolescents 13 to 17 years of age and for acute and maintenance treatment of manic and mixed episodes associated with Bipolar I Disorder with or without psychotic features in adults and in pediatric patients 10 to 17 years of age.
ADDICTION / DEPENDENCE: Half life and metabolism, Black Box Warning.
SIDE EFFECTS: Seizures, myocarditis, respiratory arrest, cardiac arrest (see list below).
WITHDRAWAL SYMPTOMS: Drowsiness, sedation, seizures, dizziness (see list below).
TREATMENT: Medical detoxification.
Clozaril® (clozapine) is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, Clozaril should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. According to its label, “The mechanism of Clozaril-induced agranulocytosis is unknown; nonetheless, the possibility that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression warrants consideration.”
HALF LIFE AND METABOLISM
The biological half life of a substance is the time it takes for a drug to lose half of its pharmacologic activity. This is significant because it affects how soon withdrawal symptoms may appear.
The half life of Clozaril is between 8 and 12 hours.
Clozaril is mainly metabolized through the P450 pathway in the liver and the enzymes primarily handling the metabolism are CYP3A4, CYP1A2 and CYP2D6.
The CYP enzymes are the major enzymes involved in drug metabolism, and since many drugs may increase or decrease the activity of various CYP isozymes, this is a major source of adverse drug interactions, since changes in CYP enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels, possibly causing an overdose.
BLACK BOX WARNING
The Food and Drug Administration (FDA) has decided that some drugs pose very serious risks and have required these drugs have what is called a black box warning. Clozaril has a black box warning. Here is the warning.
BOXED WARNING1. Agranulocytosis
Because of a significant risk of agranulocytosis, a potentially life-threatening adverse event, Clozaril® (clozapine) should be reserved for use in (1) the treatment of severely ill patients with schizophrenia who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment, or (2) for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of reexperiencing suicidal behavior.
Patients being treated with clozapine must have a baseline white blood cell (wbc) count and absolute neutrophil count (anc) before initiation of treatment as well as regular wbc counts and ancs during treatment and for at least 4 weeks after discontinuation of treatment (see warnings).
Clozapine is available only through a distribution system that ensures monitoring of wbc count and anc according to the schedule described below prior to delivery of the next supply of medication (see warnings).
Seizures have been associated with the use of clozapine. Dose appears to be an important predictor of seizure, with a greater likelihood at higher clozapine doses. Caution should be used when administering clozapine to patients having a history of seizures or other predisposing factors. Patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others. (see warnings.)
Analyses of postmarketing safety databases suggest that clozapine is associated with an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. In patients in whom myocarditis is suspected, clozapine treatment should be promptly discontinued. (see warnings.)
4. Other adverse cardiovascular and respiratory effects
Orthostatic hypotension, with or without syncope, can occur with clozapine treatment. Rarely, collapse can be profound and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation. In patients who have had even a brief interval off clozapine, i.e., 2 or more days since the last dose, treatment should be started with 12.5mg once or twice daily. (see warnings and dosage and administration.)
Since collapse, respiratory arrest and cardiac arrest during initial treatment has occurred in patients who were being administered benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug. (see warnings.)
5. Increased mortality in elderly patients with dementia-related psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. 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. Clozaril® (clozapine) is not approved for the treatment of patients with dementia-related psychosis.
The following information is taken from the Clozaril label:
Clozaril can be a very difficult drug to stop taking:
Withdrawal from Clozaril should only be done under the care of a health practitioner. The safest way is to withdraw at an inpatient medical detox facility with a protocol that includes hydration, vitamins and supplements for biological balancing. Call us to talk to a Detox Advisor.