Appendix 1.Summary of Herb-Drug Interactions of Xiaoke Pill and Anti-diabetic Drugs
Patent herbal medicines / Anti-diabetic drugs / Clinical result of interactions / Severity level of interaction / Design of study / Level of evidence / Modified Jadad scale / Referen-ces / Adverse effects/events / Clinical
recommendation / Comments
Xiaoke pill / _ / Increased hypoglycemic effect / B / RCT / 2b / 2 / (38) / Not reported / Dose adjustment or patient monitoring / The beneficial effect was reported using TCM symptoms, FBG and urine glucose as parameters.
_ / Uncertain interaction effect / A / RCT / 2b / 2 / (50) / No side effect / Unlikely to be clinically significant / The interaction effect could not be assessed since the drugs for control group were different from the intervention group.
_ / Hypoglycemia / D / Case report / 4 / _ / (16) / Hypoglycemia / Dose adjustment or patient monitoring / The adverse events occurred in two elderly diabetic patients.
_ / Hypoglycemic coma / D / Case report / 4 / _ / (17) / Hypoglycemic coma / Dose adjustment or patient monitoring / The adverse events occurred in 5 elderly diabetic patients.
_ / Hypoglycemic coma / D / Case report / 4 / _ / (18) / Hypoglycemic coma / Dose adjustment or patient monitoring / The adverse event occurred in an elderly diabetic patient.
_ / Hypoglycemic coma then death / E / Case report / 4 / _ / (19) / Hypoglycemic coma then death / Contraindicated / The adverse event with 3 episodes of hypoglycemia occurred in an elderly diabetic patient.
1.Gliclazide
2.Glipizide / Increased hypoglycemic effect / B / Case series / 4 / _ / (39) / Hypoglycemia / Unlikely to be clinically significant / 1.Lower incidence rate of hypoglycemia in patients with Xiaoke pill in combination with AD with doses reduced;
2. Significantly improved lipid profile and indexes of hemorrheology.
_ / Uncertain interaction effect / A / Case series / 4 / _ / (14) / No adverse events / Unlikely to be clinically significant / Uncertain interaction effect due to unclear drug used in the control group.
_ / Uncertain interaction effect / A / Case series / 4 / _ / (15) / No adverse events / Unlikely to be clinically significant / 1. Uncertain interaction effect in the study due to unclear drug used in the control group;
2. Well-controlled blood pressure under the combination use of Xiaoke pill and captopril.
Biguanides (details unknown) / Hypoglycemic coma / D / Case report / 4 / _ / (20) / Hypoglycemic coma / Dose adjustment or patient monitoring / Three adverse events induced by Xiaoke pills occurred in 3 of 11 hypoglycemic cases.
Phenformin / Hypoglycemia / D / Case report / 4 / _ / (21) / Hypoglycemia / Dose adjustment or patient monitoring / Two adverse events reported in the study were due to self-medication.
_ / Hypoglycemia / D / Case report / 4 / _ / (22) / Hypoglycemic coma / Dose adjustment or patient monitoring / The adverse events induced by Xiaoke pills occurred in 3 of 8 elderly diabetic patients.
_ / Hypoglycemic coma and death / D and E / Case report / 4 / _ / (23) / Hypoglycemic coma and death / Contraindicated / All hypoglycemic coma with death in 1 case occurred in elderly diabetic patients.
_ / Hypoglycemia with hemiplegia / D / Case report / 4 / _ / (24) / Hypoglycemia with hemiplegia / Dose adjustment or patient monitoring / The adverse events occurred in 2 elderly patients.
_ / Hypoglycemia and hypoglycemic coma / D / Case report / 4 / _ / (25) / Hypoglycemia and hypoglycemic coma / Dose adjustment or patient monitoring / Most cases in the report were elderly and suffered diabetic nephropathy.
Glibenclamide / Hypoglycemic coma / D / Case report / 4 / _ / (26) / Hypoglycemic coma / Dose adjustment or patient monitoring / The adverse events occurred in two elderly cases with self-medication in 1 case.
Phenformin / Hypoglycemic coma / D / Case report / 4 / _ / (27) / Hypoglycemic coma / Dose adjustment or patient monitoring / The adverse event occurred in an elderly patient.
_ / Hypoglycemic coma / D / Case report / 4 / _ / (28) / Hypoglycemic coma / Dose adjustment or patient monitoring / The adverse events occurred in three diabetic patients.
AD co-used in 2 of 8 patients (drug names unknown) / Hypoglycemic coma / D / Case report / 4 / _ / (29) / Hypoglycemic coma / Dose adjustment or patient monitoring / The adverse events occurred in 8 diabetic patients with average age 65 years and other complications including nephropathy, cerebral infarction, hypertension, CHD and hepatic disease.
_ / Hypoglycemic coma / E / Case report / 4 / _ / (30) / Hypoglycemic coma / Contraindicated / The adverse events occurred in six elderly diabetic patients with cerebral infarction
_ / Hypoglycemic encephalopathy (cerebral infarction) / D / Case report / 4 / _ / (31) / Hypoglycemic encephalopathy / Dose adjustment or patient monitoring / The adverse event occurred in a 51 years woman with nephropathy, taking lower dose of Xiaoke pill
Phenformin co-used in 1 of 5 patients / Hypoglycemic coma with death / E / Case report / 4 / _ / (32) / Hypoglycemic coma with death / Contraindicated / All adverse events occurred in elderly patients with large doses of Xiaoke pills.
_ / Hypoglycemic coma with death / E / Case report / 4 / _ / (33) / Hypoglycemic coma with death / Contraindicated / The adverse event occurred in a 74 years man with low dose of Xiaoke pills.
Phenformin / Hypoglycemia with mental disorder / D / Case report / 4 / _ / (34) / Hypoglycemia with mental disorder / Dose adjustment or patient monitoring / The adverse event occurred in a 63 years woman with diabetic nephropathy, taking even low dose of Xiaoke pills.
_ / Anaphylactic shock / D / Case report / 4 / _ / (36) / Anaphylactic shock / Dose adjustment or patient monitoring / The anaphylactic shock without hypoglycemia occurred in a 49 years woman with single dose of Xiaoke pills (5 pills).
_ / Severe hair loss / D / Case report / 4 / _ / (37) / Severe hair loss / Dose adjustment or patient monitoring / 3 episodes of severe hair loss occurred in a 57 years man after taking Xiaoke pills.
_ / Hypoglycemic coma and death / D or E / Case report / 4 / _ / (35) / Hypoglycemic coma and death / Contraindicated / 1.2 of 20 patients died due to long duration of hypoglycemia;
2.3 patients with self-medication only suffered impaired glucose tolerance.
List of abbreviations used
ADs: anti-diabetic drugs; CCT: controlled clinical trial; DM: diabetes mellitus; PCM: proprietary Chinese medicine; RCT: randomized controlled trial; TCM: traditional Chinese medicine