Clozapine was synthesized in 1958. In 1972, it was first introduced in Switzerland, Austria, and Germany, and within the following years in 30 other countries. In September 1975 Idänpään-Heikkilä et al.1 published a letter to The Lancet editor, describing a series of cases of Finnish patients suffering from serious blood dyscrasias, such as agranulocytosis, associated with the use of clozapine in mono or polytherapy. Due to this fact, Spain, as many other countries, withdrew clozapine from the market.
Nevertheless, given its efficacy in treatment-resistant schizophrenia, Spain reauthorised its prescription and dispensation in 1993, subject to precautionary measures. In order to prevent blood disorders, a haematological control protocol was established that ensured early detection of changes in the white blood cells count, allowing an immediate withdrawal before agranulocytosis. This protocol involved filling monitoring sheets that had to be sent regularly to the National Pharmacovigilance Service of the regulatory Spanish Medicines Agency (AEMPS). In addition, the doctor who prescribed the drug for the first time had to provide the patient with a booklet that had to be updated periodically, stating the frequency of haematological controls, dose to be administered and leukocyte counts. The booklet was signed by the prescriber. This national follow-up procedure also helped acquire a better understanding of other drug characteristics, such as therapeutic response, relapse prediction or other side effects.2
On October 4, 2017, the AEMPS published an informative note cancelling the obligation to submit the haematological results for patients undergoing treatment with drugs containing clozapine.3 The AEMPS delegated full responsibility on following the requirements established in the prescribing information sheet to the treating physicians. Although this note acknowledged that regular haematological controls had been effective in preventing agranulocytosis, it released physicians from notifying results to the AEMPS, which aimed to erase the bureaucratic burden that it entailed. However, it emphasised that clozapine still had to be considered a “special medical control” drug, with restrictions on its prescription, use and pharmaceutical dispensation. In 2011, Pons et al.4 had already considered the need to review this monitoring protocol due to the high cost for patients and health services, noting the increased risk of agranulocytosis the first six months from the start of treatment, but pointing out a significant risk reduction after the first year.
On December 5, 2019, a new Spanish Royal Decree repealed the identification of certain drugs, including clozapine, with the “special medical control” label. This decision was based on the understanding that this drug classification had been superseded by Pharmacovigilance legislation.5 Three months later, the Spanish Government declares a national state of alarm to face the unprecedented health crisis caused by SARS-CoV-2.
This sequence of official repeals related to historical procedures on the follow-up of patients on clozapine in Spain, added to the urgent reorganisation of health services to cope with the outbreak of SARS-CoV-2, could affect patient access to mandatory haematological controls. In fact, possible changes in haematological monitoring during the beginning of the COVID-19 pandemic could have been extended or even perpetuated in some regions.
Bearing all this in mind and the fact that almost five years have passed since the end of mandatory leukocyte count notifications to the AEMPS, it seems appropriate to evaluate the current situation of these patients in Spain. For instance, it would be advisable to know the number of adverse reactions, hospital admissions and deaths related to haematological alterations during the last five years, as well as the different protocols developed locally and/or regionally for the haematological control of these patients. This would yield relevant information to determine if the current monitoring systems offer the same level of safety as the national procedure established before the AEMPS informative note in 2017, and if health services across the country have shown enough resilience to maintain haematological monitoring, according to the prescribing information sheet, during a health crisis such as the COVID-19 pandemic.
Conflicts of interestNone.