Metamizole
Metamizole is a highly effective non-opioid analgesic with spasmolytic properties that is frequently used in Switzerland. Despite its effectiveness, dispensing requires careful counselling about the rare but serious risks of agranulocytosis and drug-induced liver injury (DILI).
Key points
- Metamizole is a potent analgesic, antipyretic and spasmolytic indicated as a reserve agent when other therapies fail.
- The two most important risks are agranulocytosis and drug-induced liver injury (DILI), whose warning symptoms must be explained at every dispensing.
- Important interactions exist with methotrexate (increased haematotoxicity) and low-dose ASA (attenuated effect).
- As a List B+ substance, pharmacists may dispense metamizole for acute pain without a prescription after a documented consultation.
Profile
| Property | Description |
|---|---|
| Substance class | Pyrazolone derivative · non-opioid analgesic · not an NSAID |
| Swiss preparations | Novalgin® (sanofi-aventis (suisse) sa) · Minalgin® (Streuli Pharma AG, Uznach) · Metamizol Spirig HC® (Spirig HealthCare AG, Egerkingen) · Metamizol-Mepha® (Mepha Pharma AG) · Novaminsulfon Sintetica® (Sintetica AG, Mendrisio) |
| Galenic forms | Tablets 500 mg · drops 500 mg/ml (1 ml = 20 drops) · suppositories · injection/infusion (hospital) |
| Dispensing category | List B – with extension List B+ since 1.7.2021: pharmacists may dispense metamizole for the indication “acute pain” after consultation and documentation even without a medical prescription (Annex 2 TPLO). |
| Swiss Compendium prices | NOVALGIN film-coated tabs 500 mg, 10 units: List B, SL, increased co-payment 40 %, CHF 10.55 (generic alternative available) · NOVALGIN drops 0.5 g/ml, 20 ml: List B, SL, standard co-payment 10 %, CHF 11.40 |
| Onset of action | 30–60 min p.o. · half-life of active metabolites 2–4 h |
| Swiss position | Unlike in DK/FIN/F/S/N (banned): frequently prescribed in Switzerland and dispensed by pharmacies after consultation – as a reserve agent when NSAIDs/paracetamol fail or are contraindicated |
Mechanism of action
Complex and not conclusively clarified (as of 2025): metamizole is a prodrug that is rapidly hydrolysed in the gastrointestinal tract to the active metabolites 4-methylaminoantipyrine (MAA) and 4-aminoantipyrine (AA).
Mechanisms under discussion (acting synergistically):
- Central COX inhibition (not classical COX-1/COX-2 inhibition as with NSAIDs; central action on prostaglandin synthesis in the dorsal horn and hypothalamus → analgesia and antipyresis)
- Cannabinoid receptor activation (CB1/CB2 via arachidonic acid amide metabolites – presumably explains the spasmolytic effect)
- TRPA1 blockade and modulation of endogenous opioid and glutamatergic systems
Clinical consequence: metamizole is analgesically potent (comparable to tramadol), very strongly antipyretic, spasmolytic (the only non-opioid analgesic with this property) – but barely anti-inflammatory. It is therefore markedly less gastrotoxic than NSAIDs (no relevant peripheral COX-1 inhibition).
Indication in Switzerland
Swiss Compendium authorisation (reserve indication – “when other measures are insufficient or not tolerated”):
- Severe acute or chronic pain (postoperative, post-traumatic, tumour pain)
- Colic (renal, gallstones) – spasmolysis is a therapeutic advantage over NSAIDs here
- High fever that does not respond to other measures (paracetamol, ibuprofen, physical cooling)
List B+ indication “acute pain” (Annex 2 TPLO, since 1.7.2021): pharmacists may dispense metamizole after consultation and documentation even without a medical prescription. The indication covers acute (not chronic!) pain such as back pain, headache, postoperative pain outside the inpatient setting, premenstrual pain. Further B+ substances in this indication: diclofenac, ibuprofen, mefenamic acid, naproxen, ketoprofen, ASA, paracetamol – each available in higher doses than in self-medication (List D).
Swiss practice reality: frequent off-label use in migraine, musculoskeletal pain, headache – the Swissmedic DHPC of 02.04.2025 explicitly calls for a reduction of off-label use.
Adult dosage: tablets 500–1,000 mg per single dose, max. 4,000 mg/day · drops 20–40 drops single dose, max. 160 drops/day · always the lowest effective dose, shortest possible use.
Cave – safety signals 2025
▶ Agranulocytosis (MIA – metamizole-induced agranulocytosis) – the central and feared adverse effect. Swissmedic classification: “very rare” (up to 1:10,000). Idiosyncratic (not dose-dependent), can occur at any time during treatment and shortly after discontinuation, including after previously uncomplicated use.
Warning symptoms (mandatory counselling at every dispensing!): fever · chills · sore throat · painful mucosal changes (mouth, nose, throat, genital, anal area) · aphthae.
Procedure on suspicion: immediate interruption of therapy, differential blood count, medical consultation. On confirmed MIA: no resumption – lifelong contraindication.
Important update 2024/2025: routine blood count monitoring is no longer recommended – agranulocytosis is idiosyncratic and occurs between routine checks. Symptomatic approach instead of screening (EMA-CMDh decision 22.11.2024, Swissmedic DHPC 02.04.2025).
Masking risk: with a fever indication or concurrent antibiotic therapy, symptoms may be masked – active counselling is all the more important.
▶ Drug-induced liver injury (DILI) – the second major safety signal, established by the Swissmedic DHPC of 17.02.2021. Severe courses up to acute liver failure requiring liver transplantation have been described.
DILI symptoms: jaundice · upper abdominal complaints · nausea · vomiting · exhaustion · fatigue · rash, fever, eosinophilia (often as part of a hypersensitivity reaction).
Time window: a few days to months after the start of treatment · in suspected metamizole DILI: no resumption (lifelong contraindication, analogous to MIA).
New evidence 2025: Weber et al. (Liver International 2025) identified metamizole as the trigger in 18.8 % of a DILI cohort – with a characteristic clinical pattern (transaminase rise + early bilirubin rise) and 13.1 % fatal courses (death or liver transplantation).
▶ Severe cutaneous reactions: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalised exanthematous pustulosis (AGEP), fixed drug eruption.
▶ Anaphylactoid reactions and drop in blood pressure, particularly with overly rapid intravenous administration.
▶ Contraindications: pyrazolone allergy · analgesic asthma · bone marrow/blood count disorders · hepatic porphyria · third trimester of pregnancy · breastfeeding (do not breastfeed for 48 h after administration) · infants < 3 months or < 5 kg.
Top interactions
▶ Methotrexate ⚠️ (newly emphasised in the DHPC 04/2025): avoid concurrent use – increased haematotoxicity, especially in older patients. Ask about it actively in the pharmacy.
▶ Low-dose ASA (acetylsalicylic acid) (Aspirin Cardio®): metamizole can attenuate the platelet aggregation-inhibiting effect of ASA (competitive inhibition at platelet COX-1). Clinically relevant in cardiovascular secondary prevention. Practical recommendation: take ASA at least 30 min before metamizole.
▶ Ciclosporin: metamizole can reduce ciclosporin plasma levels (CYP induction) → risk of rejection in transplant patients. Level monitoring required.
▶ Other CYP3A4/CYP2B6 substrates: metamizole induces various cytochrome enzymes. Potentially relevant for bupropion, methadone, efavirenz, oral contraceptives, tacrolimus, sirolimus.
▶ Chlorpromazine and other phenothiazines: enhanced hypothermia possible.
▶ Other myelotoxic substances (cytostatics, sulfonamides, carbamazepine, captopril, antithyroid drugs): theoretically additive haematotoxicity – caution and individual risk assessment.
Pharmacy tip at the counter
List B+ consultation for “acute pain” (prescription-free dispensing by the pharmacist):
- Carry out careful triage and history-taking in the consultation room (distinguish acute from chronic pain, exclude red flags, check NSAID contraindications).
- Documentation is mandatory – use the question catalogue from the pharmaSuisse indication factsheet.
- Communicate the consultation fee transparently (a pharmacy consultation is a chargeable service).
- With chronic pain, treatment failure or red flags: triage to the physician – NO B+ dispensing.
Counselling at EVERY metamizole dispensing (DHPC obligation):
- Inform about agranulocytosis warning symptoms – ideally with a written factsheet.
- Explain liver symptoms (DILI): jaundice, persistent nausea, unusual fatigue – these too are stop indications.
- Clear message: “If you develop fever, a sore throat, aphthae, yellow eyes, unusual fatigue or upper abdominal complaints – stop the therapy immediately and go to your GP’s practice, even if you have been taking the medicine for a long time without problems.”
- Ask proactively about the methotrexate interaction (rheumatological, dermatological, oncological concomitant therapy).
- With low-dose ASA as secondary prevention: explain the dosing interval (ASA at least 30 min before metamizole).
- With drop prescriptions: state the dosing note explicitly (1 ml = 20 drops, daily maximum 160 drops).
- On repeat dispensing: critically question the reserve indication, consult the prescribing physician if necessary.
References
- Swissmedic: «DHPC – Novalgin®, Metamizol Spirig HC®, Minalgin®, Novaminsulfon Sintetica®, Metamizol-Mepha® (metamizolum). Wichtige Sicherheitsinformation zu metamizolhaltigen Arzneimitteln: Risikominimierende Massnahmen zur Früherkennung einer Agranulozytose, zur Reduktion des Off-Label-Use und zur Vermeidung der gleichzeitigen Anwendung von Methotrexat.» 02.04.2025, swissmedic.ch.
- Swissmedic: «DHPC – Metamizol: Risiko eines arzneimittelbedingten Leberschadens (Drug-Induced Liver Injury, DILI).» 17.02.2021, swissmedic.ch.
- BAG: Anhang 2 VAM «Liste der Indikationen und Arzneimittel, die von Apothekerinnen und Apothekern zur Behandlung häufig auftretender Krankheiten rezeptfrei abgegeben werden dürfen» (umgangssprachlich Liste B+), erweitert per 1.7.2021 um die Indikation «Akute Schmerzen» (Wirkstoffe: Diclofenac, Ibuprofen, Metamizol, Mefenaminsäure, Naproxen, Ketoprofen, ASS, Paracetamol). bag.admin.ch.
- pharmaSuisse: «Konsultation in der Apotheke (Liste B+) – Umsetzungshilfe und Indikationsmerkblätter», pharmasuisse.org.
- Schweizer Compendium: Fachinformationen Novalgin® / Minalgin® / Metamizol-Mepha® / Metamizol Spirig HC® / Novaminsulfon Sintetica®, Stand 2026, compendium.ch.
- EMA-PRAC / CMDh: Durchführungsbeschluss der Kommission vom 22.11.2024, C(2024) 8439 (final) – Aktualisierung der Produktinformationen metamizolhaltiger Arzneimittel.
- Weber S, Erhardt F, Allgeier J, et al.: «Drug-Induced Liver Injury Caused by Metamizole: Identification of a Characteristic Injury Pattern.» Liver International 2025, DOI 10.1111/liv.70012 (18.8 % Prävalenz in DILI-Kohorte, 13.1 % fatale Verläufe).
- Chatzimanouil MKT, Goppelt I, Zeissig Y, Sachs UJ, Laass MW: «Metamizole-induced agranulocytosis (MIA): A mini review.» Molecular and Cellular Pediatrics 2023; 10(1): 6.
- Arzneimittelkommission der Deutschen Ärzteschaft: «Interaktion von Metamizol und ASS: Reicht die Evidenz für klinische Konsequenzen?» Arzneiverordnung in der Praxis 2019; Kohortenstudie n=72 KHK-Patient:innen: OR 4.5 für kombinierten Endpunkt (Herzinfarkt/Schlaganfall/Tod), p=0.0028.