Flupirtine: Withdrawn Centrally Acting Analgesic (SNEPCO)

Flupirtine was a centrally acting non opioid analgesic, approved in Germany in 1986 and available under trade names such as Katadolon, Trancopal Dolo and flupirtine generics. It belonged to its own pharmacological class, the Selective Neuronal Potassium Channel Opener (SNEPCO). The EMA had flupirtine withdrawn from the European market in March 2018 because the risk of severe hepatotoxicity up to fulminant liver failure with fatal outcomes meant that the benefit risk balance was assessed as unfavourable.

This pillar page documents the historical importance and the background of the market withdrawal, for the information of patients who took the medicine in the past or who would like to learn about the disease history and the lessons from this pharmacovigilance process. A current prescription of flupirtine is no longer possible in the European Union.

Mechanism of Action

Flupirtine acted as a Selective Neuronal Potassium Channel Opener (KCNQ2/3, M current). Through activation of these specific potassium channels in central neurons, neuronal excitability was reduced. This stabilised the membrane potential, indirectly inhibited the activation of NMDA receptors and exerted analgesic action at the spinal level and in the brain.

Flupirtine also had muscle relaxant properties, which made it attractive for pain with muscular tension components (e.g. back pain). Unlike opioids, there was no addiction potential, and unlike NSAIDs, no gastrointestinal irritation or cardiovascular risks.

Pharmacokinetically, flupirtine was orally absorbed with bioavailability of about 90 percent, half life about 7 hours. Hepatic metabolism produced several metabolites, some of which act hepatotoxically. The formation of metabolites via cytochrome P450 partially explained the individually different liver toxicity profile.

Indications

• Acute pain with muscular component: back pain, muscular tension
• Tumour and chronic pain: in historical use as a non opioid analgesic with a muscle relaxant component
• Migraine and headache with muscular component
• Postoperative pain

Following market withdrawal in March 2018, these indications are no longer covered by flupirtine. Alternative therapies are paracetamol, ibuprofen, metamizole or, where appropriate, opioids for severe pain, always combined with non pharmacological measures.

Dosage and Administration

Historically (before market withdrawal): 100 mg three times daily, maximum daily dose 600 mg. The EMA had restricted the duration of use to a maximum of 2 weeks in 2013 and introduced mandatory liver monitoring. Despite this, cases of severe hepatotoxicity continued to occur.

Currently: no longer authorised in the EU, therefore no current dosing recommendation. Patients who took flupirtine in the past and who develop liver symptoms should seek medical clarification, since liver toxicity can also occur with delay after the end of therapy.

Adverse Effects

Common (in historical use): fatigue, dizziness, nausea, heartburn, dry mouth, greenish discolouration of urine (due to metabolites, clinically insignificant but confusing for patients).

Severe, the reason for the market withdrawal: hepatotoxicity up to fulminant liver failure with fatal outcomes or required liver transplantation. The incidence of severe liver toxicity was estimated at about 1 in 5,000 patients, an unacceptably high risk for an analgesic. Other adverse effects were hyperthermia, bone marrow suppression, allergic reactions.

EMA assessment 2018: after several safety assessments with increasing restrictions since 2013 (maximum duration of use 2 weeks, mandatory liver monitoring), it was decided in 2018 that the overall benefit risk balance was not acceptable. Flupirtine was withdrawn from the market across Europe.

Interactions

• Other hepatotoxic substances: additive liver toxicity, was a major risk factor
• Alcohol: additive liver toxicity
• Anticoagulants: possible INR increase
• Other CNS depressants: additive sedation
• Paracetamol: in combination, liver toxicity significantly increased

Special Considerations

Market withdrawal: flupirtine was withdrawn from the European market in March 2018. A prescription in the European Union is no longer possible. Alternative therapies for the indications are paracetamol, ibuprofen, naproxen, metamizole and non pharmacological measures.

Pharmacovigilance lesson: the history of flupirtine is an important example of how pharmacovigilance works: safety signals are collected, evaluated, initially restrictions are imposed, and if the profile remains unfavourable, market withdrawal follows. Patients and healthcare professionals are encouraged to actively report suspected adverse drug reactions.

For previous intake: patients who took flupirtine in the past and who develop unclear liver symptoms (jaundice, dark urine, fatigue, abdominal pain, nausea) should seek medical clarification.

Current pain relief: for chronic back pain, combined concepts of exercise therapy, manual therapy, behavioural therapy, NSAIDs or paracetamol as needed and, if appropriate, antidepressants (amitriptyline, duloxetine) for chronified pain are recommended today.

You may also be interested in

• Paracetamol, standard analgesic as alternative
• Ibuprofen, NSAID as alternative
• Metamizole, pyrazolone analgesic with spasmolytic action
• Tramadol, weak opioid for stronger pain
• Duloxetine, SNRI for chronified pain

Frequently Asked Questions

Sources

• EMA market withdrawal Flupirtine 2018, pharmacovigilance reports
• BfArM Red Hand Letter Flupirtine market withdrawal
• Gelbe Liste, Flupirtine active substance profile (historical)
• AWMF guidelines on pain therapy and back pain