Serious adverse events (AEs) of Kampo-medicines, Japanese traditional herbal medicines, have been described in the package insert as the additional side effects, currently. The feature of the Kampo-induced AEs, however, has remained unclear. To characterize the patients who suffered from liver dysfunction (LD) and interstitial pneumonia (IP), the most common AEs of Kampo-medicines, we investigated the case series for additional side effects in package insert of Kampo-medicines and compared with those for Japanese adverse drug event report database (JADER) and relief aid system for adverse drug events (RASAD) reported by pharmaceutical and medical devices agencies in Japan.

Methods: Fifty five kampo-medicines, in which the serious AEs including LD and IP have been added for the revision of package insert (RPI) since 1999, were investigated. The cases for LD/IP in RPI (n=90/22) were compared with those in JADER (n=853/621) and RASAD (n=231/96) data.

Results: Ninety three AEs were added to the package insert of 55 kampo-medicines in 1999-2016. Among them, 51(54.8%) and 20 (21.5%) were responsible for LD in 47 and IP in 20 kampo-medicines, respectively. RPI cases for LD were younger than those for IP (50: 20-90 vs. 70: 40-80 yrs). The ratio of female in LD was higher than that in IP (71% vs. 59%). Median (range) for occurrence date of LD and IP were 61 (3-850) and 45 (10-1119) days after starting the administration, respectively. Similar results were observed in JADER and RASAD data, though the difference in female ratio between LD and IP was remarkable (JADER: 75% vs. 46%, RASAD: 74% vs. 30%). Positive rate for drug-induced lymphocyte stimulation test (DLST) in LD were lower than that in IP (48% vs. 80%).

Conclusion: Kampo-induced LD are found in the younger female patients regardless DLST status. On the other hand, IP should be paid attention for elderly male patients with DLST positive. Since both AEs are frequently occurred within 3 months after administration of Kampo-medicines, intensive monitoring for the corresponding symptoms and laboratory test is recommended for the patients with risk factors in this periods.