Clozapine

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish): Clozapina; Clozapinum; HF-1854; Klotsapiini; Klozapin; Klozapina; Klozapinas.

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed. (Clozapine). A yellow crystalline powder. Practically insoluble in water soluble in alcohol freely soluble in dichloromethane. It dissolves in dilute acetic acid.

The United States Pharmacopeia 31, 2008 (Clozapine). A yellow crystalline powder. Insoluble in water soluble in alcohol, in acetone, and in chloroform sparingly soluble in acetonitrile.

Stability. A suspension of clozapine 100 mg in 5 mL, made by crushing clozapine tablets and suspending the powder in a syrup-based mixture containing carboxymethylcellulose preserved with methyl hydroxybenzoate and propyl hydroxybenzoate (Guy’s Hospital paediatric base formula), was considered to be stable for at least 18 days after preparation.

Adverse Effects and Treatment

Although clozapine may share some of the adverse effects seen with the classical antipsychotics (see Chlorpromazine), the incidence and severity of such effects may vary antimuscarinic effects with clozapine may be more pronounced. Sedation and weight gain may also be more prominent. Clozapine can cause reversible neutropenia which may progress to a potentially fatal agranulocytosis strict monitoring of white blood cell counts is essential (see Precautions, below). Eosinophilia may also occur. Anaemia, thrombocytopenia, and thrombocythaemia have been reported rarely.

Extrapyramidal disorders, including tardive dyski-nesia, appear to be rare with clozapine. Clozapine has little effect on prolactin secretion. Clozapine appears to have a greater epileptic potential than chlorpromazine but a comparable risk of cardiovascular effects such as tachycardia and orthostatic hypotension. In rare cases, circulatory collapse with cardiac and respiratory arrest has occurred, and hypertension has also been reported. Clozapine is also associated with an increased risk of developing myocarditis that may, in rare cases, be fatal cardiomyopathy and pericarditis have also been reported.

Additional adverse effects of clozapine include dizziness, hypersalivation (particularly at night), headache, nausea, vomiting, constipation (which, in a few cases, has led to gastrointestinal obstruction, faecal impac-tion, and paralytic ileus), urinary incontinence and retention, fatigue, and transient fever which must be distinguished from the signs of impending agranulocytosis. There have also been rare reports of dysphagia, parotid gland enlargement, confusion, delirium, thromboembolism, acute pancreatitis, hepatitis and cholestatic jaundice, and very rarely fulminant hepatic necrosis. Isolated cases of acute interstitial nephritis have been reported.

Abnormalities of glucose homoeostasis and the onset of diabetes mellitus occur uncommonly severe hyperglycaemia, sometimes leading to ketoacidosis or hyperosmolar coma, has been reported very rarely. There have also been rare reports of hyper-cholesterolaemia and hypertriglyceridaemia. Many of the adverse effects of clozapine are most common at the start of therapy and may be minimised by gradual increase in dosage.

Effects on the blood.

Clozapine can cause reversible neutropenia which, if the drug is not withdrawn immediately, may progress to a potentially fatal agranulocytosis. Particular concern over this adverse effect dates from 1975 when 17 cases of neutropenia or agranulocytosis, 8 of them fatal, were reported in Finland the calculated incidence of agranulocytosis or severe granulocytopenia during this Finnish epidemic was 7.1 per 1000. These reports led to the withdrawal of clozapine in some countries or to restrictions in its use and intense haematological monitoring in others. After studies showing the efficacy of clozapine in severely ill schizophrenic patients unresponsive to adequate therapy with classical antipsychotics, the drug became available in the UK and USA in 1990 with strict procedures for monitoring of white blood cell counts.

The UK CSM provided data on the reports it had received between July 1963 and January 1993 on agranulocytosis and neutropenia. Clozapine was one of the individual drugs most frequently implicated, with 14 reports of agranulocytosis (1 fatal) and 119 of neutropenia (none fatal). Various estimates of the incidence of clozapine-associated agranulocytosis have been made analysis of data from 11 555 patients given clozapine in the USA showed a cumulative incidence of agranulocytosis of 8.0 per 1000 at 1 year and 9.1 per 1000 at 1 / years with the risk being increased in elderly patients. The majority of cases of agranulocytosis occurred within 3 months of the start of treatment with the risk peaking in the third month.

The manufacturers report a lower incidence of agranulocytosis of 4.8 per 1000 patients for the first 6 months and an annual rate of 0.8 per 1000 patients during the next 2/ years. These figures were based on data on 56 000 patients in the USA given clozapine up to the end of March 1993. Analysis of data on 6316 patients registered in the UK and Ireland between January 1990 and July 1994 to receive (although not necessarily given) clozapine produced a cumulative incidence of agranulocytosis of 0.7% during the first year and 0.8% over the whole study period. Most cases of agranulocytosis and neutropenia occurred during the first 6 to 18 weeks of treatment. The incidence of agranulocytosis (0.07%) and neutropenia (0.7%) seen during the second year of therapy was of the same order of magnitude noted for some phenothiazine antipsychotics.

These data and comparable data from the USA were considered to indicate that mandatory haematological monitoring (see Precautions, below) helped to reduce the risks of clozapine-in-duced neutropenia and agranulocytosis and associated deaths.

The mechanism for clozapine-induced agranulocytosis is unclear and may be the result of direct toxicity or an immune response.

Predisposing factors for development of agranulocytosis have not been identified, apart from a possible excess of cases in female patients and an increased risk with increasing age. Furthermore, both agranulocytosis and neutropenia do not appear to be dose-related effects with clozapine. A postulated higher incidence of agranulocytosis in patients of Jewish background may be related to genetic factors. Africans and Afro-Caribbeans appear to be at increased risk of developing neutropenia and it has been noted that many patients from these ethnic groups are currently already excluded from treatment with clozapine because their normal white blood cell and neutrophil counts are below the recommended range for treatment (see Precautions, below).

However, UK licensed product information recommends that patients who have low white blood cell counts due to benign ethnic neutropenia may begin clozapine treatment with the agreement of a haematologist. Evidence would suggest that development of clozapine-induced leucopenia or granulocytopenia precludes retreatment with clozapine at any future date in a series of 9 re-treated patients, all developed leucopenia or agranulocytosis again. In the USA, patients who have had clozapine withdrawn because of moderate leucopenia (judged to be when counts fall to 2000 to 3000 cells/mm) are considered eligible for a return to clozapine treatment when this count returns to normal such patients are considered to have a five- or sixfold greater risk of agranulocytosis.

Effects on body-weight.

Most antipsychotic drugs are associated with weight gain. A meta-analysis found evidence of weight gain in patients receiving both classical (chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, thioridazine, tiotixene, or trifluoperazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone) antipsychotics. Two drugs, molindone and pimozide, appeared in contrast to be associated with weight loss, although in the case of pimozide this could not be confirmed statistically. Placebo treatment was also associated with weight loss. However, a later review considered that there was overwhelming evidence that atypical antipsychotics induced more weight gain than classical antipsychotics. A separate review calculated the average monthly weight gain associated with atypical antipsychotics to be:

• olanzapine (2.28 kg)
• zotepine (2.28 kg)
• quetiapine (1.76 kg)
• clozapine (1.72 kg)
• risperidone (0.96 kg)
• ziprasidone (0.80 kg)

Weight gain occurred most frequently during the first 6 to 12 months of treatment. It was recommended that if weight gain was more than 2 kg during the first 2 weeks, a strict dietary regimen should be started immediately. However, more recent opinion is that a change of antipsychotic may be necessary. Anti-obesity drugs have been tried although their routine use is not generally recommended.

Effects on carbohydrate metabolism.

Treatment with clozapine may be associated with an increased risk of glucose intolerance and diabetes mellitus a similar association has also been noted for some other atypical antipsychotics. Data received by WHO indicated that up to December 2000, there had been 480 reports of glucose intolerance with clozapine, 253 with olanzapine, and 138 with risperidone. In some cases weight gain was also reported, which may predispose to development of glucose intolerance. Other risk factors identified included an underlying diabetic condition, male gender, and use with some other medications including valproate, SSRIs, and buspirone. Regular monitoring of weight, blood glucose, and blood lipids was recommended in patients receiving clozapine, olanzapine, andrisperidone.

Glucose intolerance has also been reported for the atypical anti-psychotic quetiapine.

Other reviewers have also found similar evidence of an increased risk of diabetes with atypical antipsychotics. In September 2003 the FDA therefore requested labelling changes for all atypical antipsychotics to include the following recommendations and warnings:

• patients with diabetes mellitus receiving atypical antipsychotics should be monitored regularly for worsening glucose control
• patients with risk factors for diabetes mellitus should undergo fasting blood glucose testing at the start of, and during, treatment with atypical antipsychotics
• all patients given atypical antipsychotics should be monitored during treatment and those who develop hyperglycaemia should undergo fasting blood glucose testing
• in some cases hyperglycaemia resolved on withdrawal but some patients needed to continue antidiabetic therapy despite withdrawal

However, the American Diabetes Association and several other American medical associations consider that the risks vary between atypical antipsychotics and have recommended that this should be taken into account when prescribing. The risk of weight gain, diabetes, and dyslipidaemia was considered to be greatest for clozapine and olanzapine, with risperidone and quetiapine having intermediate effects, and aripiprazole and ziprasidone having little effect (see also Effects on Body-Weight, above). They recommended that baseline monitoring should include:

• personal and family history of obesity, diabetes, dyslipidaemia, hypertension, or cardiovascular disease
• weight, height, and waist circumference
• blood pressure
• fasting blood glucose
• fasting lipid profile

Patients at risk for diabetes should receive an atypical drug with a lower propensity for weight gain and glucose intolerance. Follow-up monitoring should consist of reassessment of weight at 4, 8, and 12 weeks, and it was recommended that a change of anti-psychotic should be considered for any patient who gained more than 5% of their original weight during treatment. Fasting plasma glucose and blood pressure should be assessed at 3 months and annually or more frequently thereafter according to risk. Lipid levels should also be assessed after 3 months and, if normal, at 5-year intervals thereafter. Any patient with worsening glycae-mia or dyslipidaemia should be changed to an antipsychotic that has not been associated with significant weight gain or diabetes.

Effects on the cardiovascular system.

The UK CSM issued a warning in November 1993 of the risk of myocarditis with clozapine. Three patients who died while taking clozapine had evidence of myocarditis. The CSM had also received one other report of myocarditis and one of cardiomyopathy associated with clozapine. The Australian Adverse Drug Reactions Advisory Committee (ADRAC) subsequently reported another 5 cases of clozapine-associated myocarditis in November 1994. A later report from Australia identified 15 cases of myocarditis, including 5 fatalities, between January 1993 and March 1999 (these figures were established using both data from ADRAC and the Australian manufacturers).

Between September 1989 and December 1999 the FDA had received reports of 28 cases of myocarditis (18 fatal) and 41 of cardiomyopathy (10 fatal) temporally associated with clozapine use. A review by the pharma-covigilance authorities in New Zealand stated that by November 1999 the manufacturers (Novartis) had analysed 125 reports of myocarditis received worldwide including 35 fatalities 53% had occurred during the first month of treatment but about 5% occurred more than 2 years after starting treatment. A more recent review of reports submitted to ADRAC between 1993 and 2003 identified 116 cases of myocarditis of these, 60 patients were known to have recovered and 12 died. Myocarditis developed within a median of 17 days of starting clozapine therapy.

In a reminder article, the CSM has also commented that myocarditis occurs most commonly in the first 2 months whereas cardiomyopathy generally develops later in therapy. Pericarditis and peri-cardial effusions have also been reported. As myocarditis can be difficult to diagnose and confirmation is not always possible, the CSM recommended that if there was a high clinical suspicion of myocarditis, antipsychotic medication should be stopped. Presenting features might include persistent tachycardia at rest, heart failure, arrhythmia, or symptoms mimicking myocardial infarction or pericarditis. Patients who have developed clozapine-in-duced myocarditis or cardiomyopathy should not be re-exposed to clozapine.

There is also evidence that clozapine may be associated with fatal thromboemholism. Between February 1990 and December 1999, the FDA had received 99 reports of venous thromboem-bolism associated with clozapine treatment. Of these reports, 83 mentioned pulmonary embolism with or without deep-vein thrombosis and 16 mentioned deep-vein thrombosis alone 63 deaths were due to pulmonary embolism. The Swedish Adverse Reactions Advisory Committee had received reports on 6 cases (5 fatal) of pulmonary embolism and 6 of venous thrombosis associated with clozapine treatment as of March 2000. The effect seemed to occur mainly in the first 3 months of treatment, and the majority of the cases involved men. However, analysis of data from Germany and Switzerland suggests that the incidence of clozapine-associated thromboembolism is no different from that in psychiatric patients treated with classical antipsychotics or no antipsychotics at all.

There have been isolated reports of paradoxical hypertension in patients receiving clozapine. Use with atenolol has controlled the hypertension and allowed clozapine therapy to be continued.

Some studies have suggested that serious cardiovascular effects might occur more frequently and might be more severe in healthy subjects given clozapine than in patients with schizophrenia. The manufacturers had therefore requested that pharma-cokinetic studies of clozapine should be performed in patients with treatment-resistant schizophrenia rather than in healthy sub-jects.

For further details of effects of clozapine on the cardiovascular system, see Benzodiazepines under Interactions.

Effects on fluid and electrolyte homoeostasis.

Hyponat-raemia has been reported to be associated with clozapine, as with other antipsychotics. It was emphasised that hy-ponatraemia should be excluded as a possible trigger when considering the epileptogenic potential of clozapine.

Effects on the gastrointestinal tract.

The UK CSM had received 20 reports of serious gastrointestinal reactions resembling obstruction associated with clozapine treatment as of March 1999, of which 3 were fatal. These reactions were thought to be due to the antimuscarinic actions of clozapine and, therefore, more likely to occur when clozapine was taken with other drugs with antimuscarinic actions such as tricyclic antidepressants, some antiparkinsonian drugs, and other antipsychotics care was also warranted in those patients with a history of colonic disease or previous bowel surgery. It was also important to recognise and treat constipation in patients receiving clozapine to prevent the development of more serious complications such as obstruction and paralytic ileus.

Effects on the kidneys.

There have been reports” of acute interstitial nephritis associated with clozapine treatment. All 3 patients had acute renal failure which resolved when the drug was stopped. The authors of 1 report noted that the UK CSM had received 7 reports of acute renal failure associated with clozapine treatment, including 1 death, between December 1989 and February 1999.

Effects on lipid metabolism.

The increased risk of hyperlip-idaemia with some atypical antipsychotics is discussed under Adverse Effects of Chlorpromazine. See also Effects on Carbohydrate Metabolism.

Effects on the nervous system.

As with other antipsychotics (see Convulsions), clozapine can lower the seizure threshold and cause EEG abnormalities, although treatment with clozapine appears to be associated with a higher frequency of seizures. A review of 1418 patients treated with clozapine in the USA between 1972 and 1988 found that 41 had experienced generalised tonic-clonic seizures. It was considered that the risk of clozapine-induced seizures was dose-related. The seizure frequency was calculated to be:

• 1 % at a dosage less than 300 mg daily
• 2.7% at 300 to 599 mg daily
• 4.4% with a dosage of 600 mg or more daily

Six of the patients had been taking other drugs reported to lower the seizure threshold. Therapy with clozapine was continued in 31 of the 41 patients by reducing the total daily dose of clozapine antiepileptic drug therapy was begun in about half of the patients.

The UK CSM considered that, although the epileptogenic effect of clozapine was claimed to be dose-related, the metabolism and plasma concentrations of clozapine were highly variable, and data from 8 cases reported to the CSM suggested that convulsions might possibly be related to high plasma concentrations in susceptible individuals. A low initial dosage followed by careful increases according to response and downward titration thereafter to a maintenance dose was recommended to avoid convulsions in susceptible individuals.

Effects on the pancreas.

There have been isolated reports of pancreatitis associated with clozapine therapy” and overdos-age. A systematic review of the FDA’s surveillance database and published case reports up to February 2002 found 192 patients who had pancreatitis (22 fatalities) after treatment with one or more antipsychotics. This included monotherapy with clozapine (72 patients), olanzapine (62), risperidone (31), and haloperi-dol (12). Most cases occurred within 6 months of starting therapy.

Extrapyramidal disorders.

Clozapine retains a place in therapy, despite its propensity to cause agranulocytosis, because, in part, of its reduced rate of extrapyramidal effects. Other drugs in the class have since been developed. However, although atypical antipsychotics carry a lower risk of causing extrapyramidal disorders, the risk is not zero acute effects and tar-dive syndromes have been reported with these drugs, and the developing tendency to use them for high-dose therapy may perhaps narrow the margin of advantage.

Hypersalivation.

Hypersalivation has been reported to occur in up to 54% of patients receiving clozapine. The pathophysiol-ogy for this effect is unclear, but proposed mechanisms include action at muscarinic (M₃ and M₄) receptors, blockade of α₂-adrenoceptors, or distortion of the swallowing reflex. Management strategies have included chewing gum to increase frequency of swallowing or reduction of clozapine dosage in stabilised patients antimuscarinics or α₂-agonists have been tried when other methods have failed. However, antimuscarinics could potentially exacerbate the antimuscarinic adverse effects of clozapine, and intranasal ipratropium bromide has been tried as an alternative with beneficial results in one small uncontrolled study.

Neuroleptic malignant syndrome.

A review of the literature suggested that clozapine may produce fewer extrapy-ramidal effects and a lower rise in creatine kinase concentrations than classical antipsychotics. The incidence of neuroleptic malignant syndrome (NMS) with clozapine appeared to be similar to that with classical antipsychotics however, its presentation may differ, with fever and rigidity less frequent, and possibly less severe, but diaphoresis more common. Nevertheless, a later review concluded that manifestations of NMS associated with the atypical antipsychotics clozapine, olanzapine, quetiap-ine, and risperidone were of similar nature and severity to those associated with classical antipsychotics. NMS has also been reported with the use of amisulpride and aripiprazole.

Withdrawal.

Abrupt withdrawal of clozapine may be associated with symptoms that have been described as ‘cholinergic rebound’ although the manifestations, which may include headache, profuse sweating, hypersalivation, bronchoconstriction, agitation, enuresis, and diarrhoea also have some common features with the serotonin syndrome motor disorders and exacerbation of extrapyramidal disorders have also occurred. In addition, as with other antipsychotics, abrupt withdrawal of clozapine may be associated with rapid relapse of the original psychosis.

In a retrospective case-note study of 29 schizophrenic patients whose clozapine treatment was withdrawn, abrupt withdrawal in 20 resulted in a marked, immediate deterioration in their mental state. Of 3 further patients who experienced delirium with psychotic symptoms shortly after stopping clozapine, symptoms developed in 1 within 24 hours despite gradual withdrawal of clozapine over a 2-week period. All the patients responded rapidly to resumption of low doses of clozapine.