Metamizole sodium

Mechanism

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.

Symptoms

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.

Management

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).

Mechanism

The metamizole label states it literally: it can reduce the antiplatelet effect of acetylsalicylic acid when given concomitantly, so caution is needed in patients on low-dose aspirin for cardioprotection. The mechanism mirrors the one described for ibuprofen, competition for access to platelet cyclooxygenase, and it hits the very indication that tolerates no loss of efficacy.

Symptoms

Loss of antiplatelet effect gives no warning symptom. What shows up is the event the aspirin was meant to prevent, and only in patients with coronary disease or previous stroke. Metamizole keeps its own haematological warning signs.

Management

For a patient on 100 mg aspirin for cardioprotection, paracetamol is the analgesic of choice, as it does not compete for platelet cyclooxygenase. If metamizole is necessary, use short courses and avoid giving it right before the aspirin dose.

Mechanism

Metamizole is a pyrazolone with central analgesic and spasmolytic action, not a classic NSAID, so the ban on stacking NSAIDs does not apply and direct gastric damage is lower. What it does bring is a risk of its own: the European review summarised by AEMPS confirmed agranulocytosis as a rare, unpredictable reaction and recommended short courses at the lowest dose. The pair is not metabolically neutral either, since metamizole induces CYP2B6 and CYP3A4.

Symptoms

The signal not to miss belongs to metamizole: returning fever, sore throat, mouth ulcers, an infection that will not clear. Any of these during treatment means stopping it and checking a full blood count. From ibuprofen, the digestive and renal risks continue unchanged by the pairing.

Management

They can be alternated in severe acute pain when one alone is not enough, over a few days. Metamizole is not continued unmonitored and is stopped at any new fever or infection. In patients on bupropion, methadone, valproate, ciclosporin, tacrolimus or sertraline, metamizole lowers their levels and another analgesic is the better choice.

Mechanism

Ketorolac carries the highest digestive risk of the group and its label contraindicates it in patients on aspirin or other NSAIDs. Metamizole does not fall into that category, so the pair is not contraindicated, yet it stacks two different risks on the same patient: gastrointestinal bleeding from ketorolac and agranulocytosis from metamizole. The added analgesia is modest against that weight.

Symptoms

From ketorolac: black stools, coffee-ground vomit, epigastric pain, reduced urine output. From metamizole: returning fever, sore throat, mouth ulcers. The combination over 65 or with a prior ulcer concentrates both scenarios.

Management

The ketorolac course is short by label and admits no other NSAID alongside; metamizole may accompany it in severe acute pain, but it is worth checking whether paracetamol fills the gap first. Keep gastric protection while ketorolac lasts and watch the blood count if metamizole continues.

Mechanism

No label names this pair. The risks come from the properties of each drug. Metamizole can cause agranulocytosis, and this reaction does not depend on the dose (metamizole label). The venlafaxine label also lists agranulocytosis, neutropenia and aplastic anaemia among rare adverse reactions, and thrombocytopenia among very rare ones. Venlafaxine may reduce platelet function and raises the risk of bleeding, including gastrointestinal bleeding (venlafaxine label). Gastrointestinal bleeding has also occurred with metamizole. Many of those patients were taking other drugs linked to such bleeding, such as nonsteroidal anti-inflammatory drugs (metamizole label). Metamizole may act partly through the central nervous system (metamizole label), and the venlafaxine labels ask for caution with other drugs active in the central nervous system. Metamizole induces the enzymes CYP2B6 and CYP3A4 and may lower the levels of the drugs its label names, but venlafaxine is not on that list. The enzyme CYP2D6 mainly converts venlafaxine to its active metabolite (both labels).

Symptoms

Bleeding with venlafaxine ranges from bruises, haematomas, nosebleeds and petechiae to life-threatening gastrointestinal bleeding (venlafaxine label). Gastrointestinal bleeding shows as black stools, vomiting blood or coffee-ground material, and weakness. Agranulocytosis starts with fever, chills, sore throat and painful changes in the lining of the mouth, nose, throat, genital or anal area. Metamizole lowers fever, so some of these signs may go unnoticed (metamizole label). Other signs of a blood disorder are bruising, bleeding, pallor, persistent fever and general malaise (metamizole label).

Management

The combination is acceptable under supervision. No label forbids it or names the pair. The venlafaxine labels advise caution when it is taken with other substances active in the central nervous system (Spanish Agency of Medicines and Medical Devices, AEMPS, section 4.5; US Food and Drug Administration, FDA, section 7.2). Use venlafaxine with caution in patients predisposed to bleeding (AEMPS, 4.4). Tell the patient to stop metamizole and contact a doctor straight away if fever, sore throat, mouth ulcers, bruising, bleeding or pallor appear (metamizole label, 4.4). If agranulocytosis is suspected, order a full blood count with differential and stop metamizole without waiting for the result. If agranulocytosis is confirmed, do not restart metamizole (metamizole label, 4.4). In older patients and in renal or hepatic impairment, give metamizole only after weighing benefit against risk (metamizole label, 4.4). Venlafaxine is not on the list of drugs whose levels metamizole lowers through enzyme induction, and the labels give no other guidance on the kinetics of this pair (metamizole label, 4.5).

Mechanism

Neither is an NSAID and their mechanisms do not overlap, so the pair is used to cover peaks of pain or fever by alternating doses. Metamizole induces CYP2B6 and CYP3A4, pathways that do not govern paracetamol metabolism, so the two do not alter each other.

Symptoms

The pair creates no distinct picture. The paracetamol ceiling stays at 4 g a day, and metamizole is limited by haematological risk: recurring fever, sore throat or mouth ulcers during treatment point to agranulocytosis rather than to the infection being treated.

Management

Alternate every 4-6 hours, counting each daily dose separately. Metamizole goes in short courses because of its haematological profile; paracetamol stays under 4 g, and lower with liver disease, low weight or regular alcohol use.