Clozapine

ADMINISTRATION ROUTES:

PO

ALTERNATIVE NAMES:

Clopine, Clozaril

ICU INDICATIONS:

1. Treatment of schizophrenia in patients intolerant or unresponsive to at least two classic antipsychotics

Note: Clozapine should rarely, if ever, be commenced in patients in ICU. Any patient who is taking clozapine who is admitted to the ICU for any reason should be discussed with a Psychiatrist. Clozapine can only be prescribed by a Psychiatrist or a Psychiatry registrar in New Zealand (this is a Legal Requirement)

PRESENTATION AND ADMINISTRATION:

PO:

Clopine 25mg, 50 mg, 100 mg and 200 mg tablets (yellow) Clozaril 25mg and 100 mg tablets (lightish yellow) Clopine oral suspension 50 mg/mL (yellow)

DOSAGE:

PO:

Starting dose usually 12.5 mg once daily. Subsequent dose range 25-300 mg once daily

Seek advice of a Psychiatrist (see ICU INDICATIONS)

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Seek the advice of a Psychiatrist

DOSAGE IN PAEDIATRICS:

PO:

Seek the advice of a Psychiatrist

CLINICAL PHARMACOLOGY:

Clozapine is an 'atypical' antipsychotic drug

CONTRAINDICATIONS:

1. Previous hypersensitivity to clozapine
2. Myeloproliferative disorders
3. Uncontrolled epilepsy
4. History of clozapine induced agranulocytosis or severe granulocytopaenia
5. Clozapine should not be used simultaneously with other agents with potential to cause agranulocytosis or otherwise suppress bone marrow function

WARNINGS:

Agranulocytosis:

Clozapine can cause life threatening agranulocytosis

Eosinophilia:

In clinical trials, 1% of patients developed eosinophilia, which, in rare cases, can be substantial

Seizures:

Seizure has been estimated to occur in association with clozapine use at a cumulative incidence of approximately 5% after 1 year. Caution should be used in administering clozapine to patients having a history of seizures or other predisposing factors

Myocarditis

Clozapine may cause myocarditis which can be fatal. Prompt discontinuation of clozapine treatment is warranted upon suspicion of myocarditis

Other Adverse Cardiovascular and Respiratory Effects:

Orthostatic hypotension with or without syncope can occur with clozapine treatment and may represent a continuing risk in some patients. Rarely (approximately 1 case per 3000 patients), collapse can be profound and be accompanied by respiratory and/or cardiac arrest

Hyperglycaemia and Diabetes Mellitus:

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine

Neuroleptic Malignant Syndrome (NMS):

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs including clozapine

PRECAUTIONS:

General:

Fever

During clozapine therapy, patients may experience transient temperature elevations above 38°C, with the peak incidence within the first 3 weeks of treatment. While this fever is generally benign and self limiting, it may necessitate discontinuing patients from treatment

Pulmonary Embolism and Deep Vein Thrombosis

The possibility of pulmonary embolism should be considered in patients receiving clozapine who present with deep vein thrombosis, acute dyspnoea, chest pain or with other respiratory signs and symptoms. As of December 31, 1993, there were 18 cases of fatal pulmonary embolism in association with clozapine therapy in users 10-54 years of age. Based upon the extent of use observed in the Clozaril National Registry, the mortality rate associated with pulmonary embolus was 1 death per 3450 person-years of use. This rate was about 27.5 times higher than that in the general population of a similar age and gender (95% Confidence Interval; 17.1, 42.2). Deep vein thrombosis has also been observed in association with clozapine therapy

Hepatitis

Caution is advised in patients using clozapine who have concurrent hepatic disease. Hepatitis has been reported in both patients with normal and pre-existing liver function abnormalities. In patients who develop nausea, vomiting, and/or anorexia during clozapine treatment, liver function tests should be performed immediately. If the elevation of these values is clinically relevant or if symptoms of jaundice occur, treatment with clozapine should be discontinued

Anticholinergic Toxicity

Clozapine has potent anticholinergic effects and care should be exercised in using this drug in the presence of narrow angle glaucoma. Clozapine use has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, faecal impaction and paralytic ileus

Laboratory Tests:

No tests in addition to routine ICU tests are indicated

Drug/Laboratory Test Interactions:

None noted

IMPORTANT DRUG INTERACTIONS IN ICU:

The risks of using clozapine in combination with other drugs have not been systematically evaluated.

The mechanism of clozapine 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. Therefore, clozapine should not be used with other agents having a well-known potential to suppress bone marrow function.

Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately 1 case per 3000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest. Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even clozapine by itself. Although it has not been established that there is an interaction between clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug. Clozapine may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-type drugs.

Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, nicotine, and rifampin may decrease clozapine plasma levels, resulting in a decrease in effectiveness of a previously effective clozapine dose.

Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, and erythromycin may increase plasma levels of clozapine, potentially resulting in adverse effects.

ADVERSE REACTIONS:

Central Nervous System:

Drowsiness/sedation, dizziness/vertigo, headache, tremor, syncope, disturbed sleep/nightmares, restlessness, hypokinesia/akinesia, agitation, seizures, rigidity, akathisia

Cardiovascular System:

Tachycardia, hypotension, hypertension, chest pain/angina, ECG changes, myocarditis

Gastrointestinal System:

Salivation, constipation, nausea, abdominal discomfort/heartburn, nausea/vomiting

Skin:

Rash

Haematological System:

Leukopaenia, neutropaenia, agranulocytosis, eosinophilia