Clozapine × Metamizole sodium

Both clozapine and metamizole cause agranulocytosis, a sharp fall in neutrophils that can lead to severe and fatal infection (both labels). With metamizole, the reaction does not depend on the dose, can start at any time during treatment or shortly after stopping, and can occur in people who took it before without problems (metamizole label). Metamizole is a pyrazolone analgesic. Pyrazolone analgesics are on the clozapine label's list of bone marrow suppressants, which increase the risk and severity of bone marrow suppression when combined with clozapine. Metamizole also lowers fever, and fever is exactly the sign that calls for an urgent blood count in a patient taking clozapine. Metamizole induces the enzyme CYP3A4 (metamizole label), and cytochrome P450 inducers can lower clozapine levels (clozapine label), but neither label addresses this pair directly.

Agranulocytosis starts with fever, chills, sore throat and painful sores on the lining of the mouth, nose, throat, genital or anal area (metamizole label). In a patient taking clozapine, any sign of infection or a flu-like illness is a warning sign (clozapine label). Metamizole lowers fever, so some early signs may go unnoticed (metamizole label). The full blood count shows a fall in the absolute neutrophil count.

The combination is contraindicated (Spanish clozapine label, sections 4.3 and 4.5). This label rules out starting clozapine together with substances known to have a substantial potential to cause agranulocytosis. It also rules out using clozapine with bone marrow suppressants, a list that includes pyrazolone analgesics. The Spanish medicines agency (AEMPS) advises taking a careful history before prescribing metamizole and not giving it to patients who take medicines that can cause agranulocytosis (AEMPS safety note 15/2018). Metamizole is therefore not an option for pain or fever in a patient taking clozapine. If the patient is already taking both, consider checking the absolute neutrophil count (ANC) more often than the standard schedule (US clozapine label, FDA). If fever, chills, sore throat or mouth ulcers appear, order a full blood count with differential and stop metamizole at once, without waiting for the result (metamizole label). At a temperature of 38.5 °C or higher, interrupt clozapine and obtain an ANC (US clozapine label, FDA). If the ANC falls below 1000/mm³, stop clozapine immediately, repeat the count daily and do not re-expose the patient to clozapine (Spanish clozapine label).