Abstract
In this journal Les R.H. Drew recently wrote that an urgent review was needed of the strict controls on clozapine, which are mainly directed at preventing agranulocytosis. He also referred to the extensive international literature on monitoring systems for clozapine treatment and suggested that new requirements might be appropriate with respect to other disabling and potentially fatal complications associated with clozapine [1]. It may be of interest to readers of this journal that in the European Union the use of clozapine is not restricted to hospitals. White blood cell counts (WBC) are mandatory weekly during the first 18 weeks and every four weeks thereafter. The results have to be reviewed by the prescribing doctor, but the patient does not have to see the doctor every time.
The recently published update of the Netherlands Clozapine Collaboration Group's guideline for the use of clozapine takes a more flexible stand regarding continued mandatory WBC [2]. The risk of death due to agranulocytosis if the four-weekly WBC is discontinued after the first year of clozapine treatment is estimated to be 0.01 to 0.38/1000 patient years [3]. In the second six months of clozapine treatment these risks are approximately twice as high. In comparison, in 2003 inhabitants of the Netherlands had a risk of death due to a private accident, a traffic accident or an accident at work of 0.15, 0.06 and 0.07/1000 respectively. Therefore in the opinion of the Netherlands Clozapine Collaboration Group if a mentally competent and adequately informed patient explicitly wants to stop having routine blood tests, this is permissible after the first six months of clozapine treatment. However, WBC must be monitored immediately if there is any clinical suspicion of agranulocytosis. Even if the routine blood tests are stopped, low frequency tests, for example four times a year, are still advisable, because they may trace slow progressive drops in WBC.
The Dutch guideline introduces risk management with regard to other potentially fatal complications. Constipation is a frequent side effect of clozapine treatment and may lead to gastro-intestinal hypomotility with 4 fatalities/1000 users of clozapine [4]. The guideline therefore recommends preventive prescription of a laxative (macrogol-electrolytes) and regular (weekly) inquiry about any constipation during titration. The incidence of diabetic ketoacidosis (DKA) varies between 1.6 and 3.1/1000 patient years [5,6]. The mortality of incident cases is 20% to 30% [5,7]. Mandatory measurement of fasting plasma glucose at baseline, monthly during the first three months of treatment and then annually, may help detect early deterioration of glucose metabolism. If there are practical problems with the fasting glucose test it can be replaced by HbA1c in combination with the non-fasting glucose level.
The situation regarding myocarditis is complicated by the huge regional differences in incidence of this side effect. An incidence as high as 1.3% to 3.4% has been reported for Australia [8]. In Europe the risk seems to be lower [9]. The Dutch guideline advocates a stepped risk management approach with special attention during the first two months to flu-like symptoms (unexplained fever, fatigue, lethargy), hypotension or tachycardia. Should any of these symptoms occur, as a second step laboratory tests (hypereosinophilia, C-reactive protein (CRP), creatine kinase-MB (CK-MB), troponin) may help to differentiate myocarditis from benign side effects which commonly occur during clozapine initiation. If dyspnoea, orthopnoea, increased central venous pressure, third or fourth sound, pericardial friction rub, souffle consistent with mitral or tricuspid insufficiency, peripheral oedema and/or crepitations over the lungs are observed, the patient must be referred to a cardiologist urgently (third step).
In addition to these and other risk management procedures, the Dutch guideline describes possible indications for clozapine in schizophrenia spectrum and other disorders and management of common side effects. An English version of the guideline for the use of clozapine is available on the website of the Netherlands Clozapine Collaboration Group.