Objectives: Acute drug-induced liver failure is a rare indication for liver transplant. There is only one case of flupirtine-induced liver failure requiring transplant in the literature. In February 2018, the European Medicines Agency issued a withdrawal of approval for flupirtine medication in European countries as a result of the risk of acute liver failure.
Materials and Methods: The aim of this study was a German-wide collection of data regarding patients with liver transplant as a result of flupirtine-associated liver failure.
Results: A total of 9 patients received transplants. All patients were women with a mean age of 43 years. Indication for flupirtine medication was musculoskeletal symptoms and migraine headache. The medication was taken over a period of approximately 3 months. All patients developed progressive acute liver failure, and no patient had previous chronic liver disease or cirrhosis. The mean laboratory Model for End Stage Liver Disease score for the patients was 31 ± 7 at time of transplant. Eight of the 9 patients were listed as “high urgency” for transplant. After transplant, they had an uneventful course with a prolonged mean intensive care unit stay of 13 ± 8.7 days. The whole hospitalization time was 43 ± 21 days.
Conclusions: This is the largest published series of patients who received liver transplant after a drug-induced acute liver failure from flupirtine medication.
Key words : Drug-induced acute liver failure, Idiosyncratic hepatotoxicity, Ethyl-2-amino-6-[(4-fluorbenzyl)amino]-3-pyridincarbamat (flupirtine), Transplantation
Acute drug-induced liver failure requiring liver transplant is a rare diagnosis. Paracetamol has played an important role in this context.1 But also other medications can cause liver function impairment.2 One of these has been flupirtine.
Flupirtine is a centrally acting, nonopioid analgesic with additional muscle relaxant properties, and it has been used to treat acute and chronic pain.3 Currently, it might be introduced in the treatment of multiple sclerosis.4 In addition to the commonly observed gastrointestinal and mild neurological side effects, in some cases the occurrence of drug-induced hepatitis, and even acute liver failure (ALF), was observed. Up to now, there has only been one reported case of flupirtine-induced liver failure requiring liver transplant.5
Since its approval in Germany in 1984, more than 12 million patients have been exposed to this drug. However, a growing number of reports of flupirtine-associated liver injury prompted its safety reevaluation by the European Medicines Agency (EMA) in 2013.6 Of nearly 600 case reports examined, there were 49 cases of liver failure and 15 cases resulting in liver transplant or fatal outcome (EMA/PRAC/310015/2013).6 In the statement issued in 2013, an admission restriction was imposed. In 2018, the EMA withdrew the approval for flupirtine so that further use was no longer possible in Germany.
Here, we report on 9 patients who required liver transplant as a result of flupirtine-induced ALF, which is the largest reported case series for this indication in the world.
Materials and Methods
All German liver transplant centers had been contacted to enable a comprehensive data collection. From these in 3 centers (Erlangen, Jena, Leipzig), we had a total of 9 patients who received transplants as a result of ALF induced by a flupirtine medication. Between 2004 and 2013, there were 1061 liver transplants (without living donation and combined organ transplant) performed at the University Hospitals of Jena, Leipzig, and Erlangen. In 84 cases (7.91% of all liver transplants), indication for liver transplant was ALF. Of these, 9 patients (0.85% of all, 10.71% of all ALFs) required liver transplant because of flupirtine-induced liver failure.
For patient analyses, the following data were included: patient medical history (with indication for medication, mono- or polymedication), status before liver transplant (United Network for Organ Sharing status, hemodialysis before liver transplant, mechanical ventilation before liver transplant, catecholamine application before liver transplant, laboratory chemistry), listing criteria (high urgency, time during listing and liver transplant), operation data (operation time, cold ischemia), donor data (donor risk index), and follow-up (intensive care unit stay, hospitalization time, complications).
For the literature research, we used the keywords: “acute liver failure,” “flupirtine,” “flupirtine induced liver failure,” and “liver transplantation” in various combinations.
All patients were women with a mean age of 43 ± 18 years. None of the patients had a known preexisting liver disease. Indication for flupirtine treatment was musculoskeletal pain (7/9 patients) or history of migraine headache (2/9 patients). The medication was taken over a period of approximately 3 months. The intake of flupirtine was done as a single medication or as a multiple drug therapy. Four of the 9 patients had monotherapy with flupirtine; the remaining patients had a preexisting “home” medication.
At the first clinical presentation, patients showed jaundice and a decrease in physical performance. The patients then developed progressive liver failure according to the King’s College Criteria. Seven of the 9 patients had to be transferred to an intensive care unit before liver transplant. One patient required mechanical ventilation, hemodialysis, and catecholamine therapy before operation. The laboratory chemistry before transplant revealed a mean laboratory Model for End Stage Liver Disease score of 31 ± 7. It was mainly a subacute, cholestatic liver failure. The additional laboratory parameters are shown in Table 1.
Eight of 9 patients were listed with the “high urgency” status according to the Eurotransplant Allocation System. The mean wait time between listing and transplant was 6.5 ± 6 days.
The mean operation was 270 ± 102 minutes with a cold ischemic time of 532 ± 109 minutes. Mean donor age was 43 ± 18.5 years. Of the 9 donors, 5 were men. The main cause of donor death was cerebrovascular accident (6/9 patients). The mean donor height was 169 ± 6.45 cm. The allocation procedure was national. One patient received an extended right lobe. The mean donor risk index was 1.75 ± 0.39.
The histopathological evaluation of the explanted livers did not reveal any preexisting liver disease in any of the patients. After transplant, the patients had a mean intensive care unit stay time of 13 ± 8.7 days. The whole hospitalization time was 43 ± 21 days. Of total patients, 1 patient died after transplant because of a complete mesenteric ischemia. All other patients did well over the long-term after transplant.
A search of the European database of suspected adverse reaction reports (EudraVigilance) identified a total of 800 individual case reports in which flupirtine was reported as a suspected or interacting drug. Of these case reports, 332 were assigned to the system organ class “liver diseases”. Of the total number of all case reports, 24 were fatal and 17 reported liver toxic reactions. As a result, a treatment restriction and monitoring was issued in 2013.7 In 2018, the approval was withdrawn in European countries; the main basis for this decision was the liver damage caused by flupirtine.
The case series we present here is, to the best of our knowledge, the largest one describing ALF requiring liver transplant after flupirtine intake. Liver transplant is a feasible option for the rare complication of flupirtine-induced liver failure and can have good long-term results.
Liver transplant and acute liver failure
Drug-induced liver injury is the leading cause of ALF in adults in Western countries, with a transplant-free survival rate of less than 50%.8
Fewer than 10% of drug-induced liver injuries progress to ALF, with an estimated incidence of only 1 to 2 cases per million people per year. However, up to 80% of patients who develop liver failure might die or require transplant.2 Women have been shown to be at higher risk of drug-induced livery injury, and patients who died were more likely older women.9 A similar predilection could be confirmed in this case series, since the only patient who died was the oldest of the transplanted patients (57 years vs mean of 43 years).
Outcomes of emergency transplant are consistently lower, with high early posttransplant mortality.2 According to the European Registry, ALF is the primary indication for liver transplant in 8% of cases, with a 5-year survival rate of 64% and an improving trend during the last 5 years.8,10
Acute liver failure
As analyzed by Canbay and colleagues, approximately 200 to 500 cases of ALF are diagnosed per year in Germany.11
Less than 10% of all liver transplants within Europe were performed as a result of ALF. Within this cohort, in 43% the cause of ALF was unknown, in 21% it was viral, in 11% it was paracetamol-associated, and in 10% it was induced by other drugs.10 Flupirtine-induced ALF has been described in only 1 case report. Therefore, our cohort describes a rare entity.
Non-paracetamol drug-induced ALF is mostly caused by idiosyncratic hepatotoxicity.8 Flupirtine has also been reported to cause liver injury of idiosyncratic type in rare instances.12 As stated by Biolato and associates, this liver injury is individual, unrelated to dosage, and unpredictable.8 Most examples of idiosyncratic drug hepatotoxicity occur within the first 3 months after drug initiation.8 This medication period can also be reconciled with our data. This was addressed in the pharmaceutical prescribing information, in which initially the length of drug intake was undetermined and later restricted to 14 days.
Often patients present with abrupt onset of jaundice and liver dysfunction, with subsequent development of encephalopathy and coagulopathy in patients with or without preexisting liver disease, as in our patient cohort.13
Flupirtine is neither an opioid nor a nonsteroidal anti-inflammatory drug; it produces analgesic action through blockade of glutamate N-methyl-D-aspartate receptor. It is used for the management of pain after surgery, trauma, musculoskeletal pain, cancer, and headache.14
In addition to the mentioned indications, the indication for multiple sclerosis has also been analyzed, but there is no further evidence for neuroprotective or disease-modifying effects of flupirtine in multiple sclerosis.4 The use of flupirtine for other indications has also been investigated. A study by Michel and associates analyzed the use of flupirtine in overactive bladder syndrome.15 However, this study was terminated prematurely because of frequent severe liver dysfunction; in 31% of the patients, who were exposed to flupirtine for at least 6 weeks, significantly increased liver values were observed.15
Flupirtine is metabolized in the liver to 4-fluorohippuric acid and the N-acetylated analogue D13223 by peroxidase enzymes, and these 2 metabolites are further oxidized and conjugated with glycine to form inactive metabolites.14,16
Although the mechanism of flupirtine-induced liver injury remains unclear, liver injury seems to be the result of a production of flupirtine-derived quinine diamine metabolites.6 In their in vitro analysis, Konishi and colleagues were able to identify the relevance of the reactive metabolite resulting in flupirtine-induced liver damage.17
The dose for adults is 300 to 400 mg/day and can be increased to 600 mg/day. The dose of flupirtine should be reduced to 50% in elderly patients and those with renal and hepatic impairment.14 In addition, it was found that flupirtine also increases the hepatotoxic potential of paracetamol, warfarin toxicity, and toxicity of other sedatives, including benzodiazepines.14 With regard to contraindications for flupirtine therapy, this medication should be avoided in patients with history of hypersensitivity to flupirtine; also, hepatic encephalopathy, cholestasis, myasthenia gravis, chronic alcoholism, primary biliary cirrhosis, and liver disease are mentioned as contraindications.14
With regard to co-medication with flupirtine, only limited information is available in the literature. However, Kreutzkamp and associates reported that patients with potentially hepatotoxic concomitant medication are considered to be at risk.18 Anderson and Borlak also identified that co-medication has a relevant role in the development of liver damage under flupirtine.19 Therefore, flupirtine should not be prescribed in patients with preexisting liver damage and/or alcohol abuse.5
As discussed by Puljak, flupirtine has indeed been shown to be an effective analgesic for acute pain; however, there may be a good reason that flupirtine should be abandoned.20 In contrast to the mentioned statements, Lawson stated that flupirtine is an effective analgesic that has potential for use in acute and chronic pain if managed with consideration.21 Therefore, all in all, the use of flupirtine has caused wide discussion in the literature.
In this report, we present the largest series of patients who received transplants as a result of flupirtine-induced liver failure. The Drug Commission of the German Medical Association has already written a statement in March 2013, which concerned hepatotoxicity due to flupirtine. In February 2018, the EMA issued a withdrawal of approval for medication with flupirtine, so that medication with flupirtine can no longer be carried out or should be avoided in some countries.
Volume : 18
Issue : 4
Pages : 481 - 484
DOI : 10.6002/ect.2019.0297
From the 1Department of General, Visceral and Vascular Surgery, Jena University
Hospital, Jena, Germany; the 2Department of General, Visceral, Vascular, and
Surgery, Magdeburg University Hospital, Magdeburg, Germany; the 3Department of
Surgery, Erlangen University Hospital, Erlangen, Germany; and the 4Department of
Visceral, Transplant, Thoracic, and Vascular Surgery, Leipzig University
Hospital, Leipzig, Germany
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no potential declarations of interest.
Corresponding author: Felix Dondorf, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
Table 1. Laboratory Chemistry Before Transplant