Abstract
Petadolex®, a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4–730 days) nine developed severe HILI (average time-to-onset 103 days, ALT-range 3–153; AST 2–104-fold ULN). HILI cases resolved after medication withdrawal though two patients required liver transplantation. Liver biopsies revealed an inconsistent injury pattern, i.e. necrosis, macrovesicular steatosis, inflammation, cholestasis, and bile duct proliferation. Causality assessment rated 3 cases likely, 13 possible, 8 unlikely and 24 as unclassifiable/unclassified. Note, 22 patients reported hepatotoxic co-medications especially during periods of pain. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At >45 and 90-fold MCD bile duct hyperplasia was observed but could not be confirmed in an explorative minipig study at 218-fold MCD. Human hepatocyte studies at 49-fold Cmax serum petasins (=active ingredient) and therapeutic Ibuprofen, Paracetamol and Naratriptan concentrations evidenced liver transaminase and CYP-monooxygenase changes. Collectively, Petadolex® HILI cases are rare, idiosyncratic and frequently confounded by co-medications. A physician-supervised self-medication plan with herbs and pain relief medication is needed to minimize risk for HILI.
Highlights
Herbal and Dietary Supplements (HDS) are a multi-billion dollar enterprise and are considered to be safe by the public
We report the case of Petadolex®, a defined Petasites hybridus extract used as migraine preventive treatment in adults
There was no clear pattern in the temporary alterations of serum biochemistries during the six-month chronic toxicity study with very slight but statistically insignificant changes of AST and ALT (Supplementary Table S2)
Summary
Herbal and Dietary Supplements (HDS) are a multi-billion dollar enterprise and are considered to be safe by the public. The U.S Drug-Induced-Liver Injury-Network reported HDS related liver injury to be on the rise accounting for about 20% of all DILI cases [1]. We report the case of Petadolex®, a defined Petasites hybridus (butterbur) extract used as migraine preventive treatment in adults. The extract is primarily composed of sesquiterpene esters, mainly of the petasin and the furanopetasin chemotype [2] and constitutes a mixture of petasin, isopetasin, neopetasin as well as furanoeremophilanes and eremophilanlactones. In the following this mixture is referred to as ‘petasin’. In 2012, the American Academy of Neurology concluded butterbur to be effective for migraine prevention [7]
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