Severe adverse reactions caused by Kampo formulas from the viewpoint of cases relieved by the Adverse Drug Reaction Relief System in 2021

Although most adverse reactions to Kampo formulas are mild, there have been reports of serious adverse reactions, such as interstitial pneumonia caused by Shosaikoto [1] and mesenteric phlebosclerosis caused by Kampo preparations containing gardenia fruit (Gardeniae fructus) [2]. Although some previous reports [3, 4] on the incidence of adverse reactions to Kampo medicines are known, there are no reports on the actual number of patients with serious adverse reactions that resulted in hospitalization or death, excluding mild and moderate cases, in Japan. The ‘Adverse Drug Reaction Relief System’ aims to provide relief benefits for patients who experienced adverse drug reactions, required hospitalization, or died due to the adverse reaction [5]. Relief cases under the Adverse Drug Reaction Relief System are cases of severe adverse reactions to drugs. This study aimed to observe the recent trend of severe adverse reactions caused by Kampo formulas by examining the data on relief cases from the Adverse Drug Reaction Relief System, published on the website of the Pharmaceuticals andMedical Devices Agency (PMDA) in 2021 [6]. Data of 72 cases (24 males and 48 females), in which Kampo formulas were identified as the causative drug, out of the 1442 relief cases recorded in the 2021 Adverse Drug Reaction Relief System, available on the PMDA website, were examined [4]. The age range of the patients was from 20 to over 80 years old (20–29 years: 5 cases; 30–39 years: 5 cases; 40–49 years: 14 cases; 50–59 years: 14 cases; 60–69 years: 13 cases; 70–79 years: 15 cases; and ≥80 years: 6 cases). Adverse drug reactions caused by Kampo medicines included drug-induced liver injury (38 cases, 14 of which were in combination with modern medicines), interstitial pneumonia (32 cases, 9 of which were in combination with modern medicines), pseudo-aldosteronism or hypokalemia (four cases), generalized drug rash (three cases, all in combination with modern medicines), and one case of erythema multiforme type drug eruption (one case). In five cases, two Kampo prescriptions were combined. One case experienced two adverse reactions (drug-induced liver injury and generalized drug rash). The most common Kampo formula was saireito (18 cases), followed by saikokaryukotsuboreito (10 cases); bofutsushosan (six cases); seishinrenshiin, saikokeishikankyoto, and shin’iseihaito (four cases); shosaikotokakikyosekko and kakkonto (three cases); and nyoshinsan, shakuyakukanzoto, saibokuto, and hangeshashinto (two cases) (Table 1). Of these, five experienced adverse reactions to over-the-counter drugs (two cases of bofutsushosan), while one experienced an adverse reaction to a decoction. Kampo formulas causing drug-induced liver injury included saireito (eight cases); bofutsushosan (five cases); saikokaryukotsuboreito (three cases); shosaikotokakikyosekko (three cases); kakkonto, saikokeishikankyoto, shakuyakukanzoto, seishinrenshiin, and nyoshinsan (two cases); and nine other Kampo prescriptions (one case) (Table 1). Thirty-one (81.6%) patients with drug-induced liver injury were prescribed Kampo formulas containing Scutellariae radix. Kampo formulas causing interstitial pneumonia included saireito (nine cases); saikokaryukotsuboreito (seven cases); shin’iseihaito (three cases); saikokeishikankyoto (two cases); and 11 other Kampo prescriptions (one case) (Table 1). Twenty-nine (90.6%) patients with interstitial pneumonia were prescribed Kampo formulas containing S. radix. There was one case of death due to interstitial pneumonia while taking shosaikoto. In conclusion, the most severe adverse reactions caused by Kampo formulas included drug-induced liver injury and interstitial pneumonia. We could confirm that the most common serious adverse reactions by Kampo formulas that required hospitalizations or funerals in Japan were drug-induced liver injury and interstitial pneumonia, and that most of these adverse reactions were due to the use of Kampo formulas containing S. radix. More than 80% of the patients experienced drug-induced liver injury, and more than 90% of the patients experienced interstitial pneumonia caused by the Kampo formula containing S. radix. These adverse reactions have been reported to be caused by an allergic reaction to S. radix [7]. Although adverse reactions due to immunoallergic reactions could occur even with Kampo formulas not containing S. radix, these severe adverse reactions should be carefully monitored in patients receiving Kampo formulas containing S. radix. Over-the-counter drugs Received: 7 February 2023 Revised: 10 May 2023 Accepted: 21 May 2023