Postmarketing safety evaluation: depside salt injection made from Danshen (Radix Salviae Miltiorrhizae)

Transcription

1 Online Submissions: J Tradit Chin Med 2014 December 15; 34(6): info@journaltcm.com ISSN JTCM. All rights reserved. REVIEW TOPIC Postmarketing safety evaluation: depside salt injection made from Danshen (Radix Salviae Miltiorrhizae) Yanpeng Chang, Wen Zhang, Yanming Xie, Xiangyang Xu, Rendi Sun, Zheng Wang, Ruihua Yan Yanpeng Chang, Wen Zhang, Yanming Xie, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing , China Yanpeng Chang, Intensive Care Unit of Shenyang Orthopedic Hospital, Shenyang , China Xiangyang Xu, Rendi Sun, Zheng Wang, Ruihua Yang, Shanghai Green Valley Pharmaceutical Ltd., Shanghai , China Supported by National Science and Technology Major Projects for "Major New Drugs Innovation and Development": Study on Key Technologies of Postmarketing Evaluation for Chinese Medicine (No. 2009ZX ) Correspondence to: Prof. Yanming Xie, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing , China. datamining5288@ 163.com Telephone: Accepted: June 19,2014 Abstract OBJECTIVE: To systematically examine the postmarketing safety of depside salt injection made from Danshen (Radix Salviae Miltiorrhizae), identify the potential risk factors, and ensure its clinical safety. METHODS: We examined a comprehensive series of studies on the production process, quality standards, pharmacology, population pharmacokinetics, and safety evaluation of depside salt injection made from Danshen (RadixSalviaeMiltiorrhizae). Data from Ⅰ-Ⅳ clinical drug trials, hospital information systems (HIS), and spontaneous reporting systems (SRS) were also analyzed. RESULTS: The effective components of salvianolic acid salt content reached almost 100%, and the magnesium lithospermate B content reached more than 80%. The median lethal dose (LD50) calculated by the Bliss method was 1.49 g/kg, with 95% confidence intervals of g/kg. Long-term tests on Beagle dogs indicated that doses of less than 80 mg/kg were safe and doses of 320 mg/kg were toxic. Adverse drug reactions (ADRs) included digestive disorders; drug-induced erythrocyte deformation in lung, liver, spleen, kidney, bone marrow, intestinal mucosa, lymph nodes, and other tissues; megakaryocytes in lung, liver, and spleen resulting from mild hemolysis; and mild hyperplasia in bone marrow hematopoietic tissue. Other studies indicated no irritative effect of the injection on local tissues and blood vessels, and no allergic reactions, erythrocyte coagulation, or hemolysis. SRS data showed that the most common ADRs were headache, head distention, dizziness, facial flushing, skin itching, thrombocytopenia, and the reversibility of elevated Aspartate transaminase. HIS data indicated no damage to renal function from using depside salt injection made from Danshen (Radix Salviae Miltiorrhizae) at a dosage higher than the recommended dose. CONCLUSION: This study analyzes the clinical characteristics of ADRs from depside salt injection made from Danshen (Radix Salviae Miltiorrhizae), and discusses the factors influencing such reactions. It provides scientific reference and recommendations for clinically safe medication of the Danshen injection JTCM. All rights reserved. Key words: Product surveillance, postmarketing Chinese medicine; Safety; Danshen (Radix Salviae Miltiorrhizae); Depside salt injection JTCM www. journaltcm. com 749

2 INTRODUCTION The depside salt injection made from Danshen (Radix Salviae Miltiorrhizae) manufactured by Shanghai Green Valley Pharmaceutical Co., Ltd., (Shanghai, China) is prepared from salvianolate compound extracted and refined from Danshen (Radix Salviae Miltiorrhizae), with magnesium lithospermate B (>80%) as the main active ingredient. It activates blood, removes blood stasis, and dredges the channels. It is used to treat patients with stable angina pectoris Classes Ⅰand Ⅱ, associated with coronary heart disease (CHD), whose symptoms are mild or moderate chest pain, chest tightness and palpitations, and who are diagnosed with the Traditional Chinese Medicine (TCM) syndrome of heart blood stasis. MEDICINE QUALITY CONTROL Quality control of raw herbal medicinal material The injection is made from salvianolate compound produced by Shanghai Green Valley Life Pharmaceutical Co., Ltd., and extracted from Danshen (Radix Salviae Miltiorrhizae) grown in Linyi, Shandong Province. This growing area contains the highest salvianolic acid B content (4.5%-9.0%) in the world, and indicators of moisture, total ash, acid-insoluble ash, total metals, harmful elements, extract, and Tanshinone Ⅱ-A satisfy the requirements of the Chinese Pharmacopoeia (2010). 1 Linyi enjoys favorable environmental conditions, such as good soil, water, and air quality to relevant national standards. The development of mountain areas, comprehensive management, and constant adjustment of the growing environment has made this area highly conducive to the cultivation and growth of Danshen (Radix Salviae Miltiorrhizae), producing a medicinal material that has a high concentration of active ingredients in the water-soluble phenolic acids and is especially suitable for the extraction of salvianolate. The chemical compositions of salvianolate include the active ingredient magnesium lithospermate B (80%-90%), as well as purple oxalate and rosemary acid homologues (10%-20% ). These active ingredients can protect the cardiovascular system, 2-4 and together form the effective part of the injection. An effective system has been established for studying and controlling the quality of the injection. Quality control of the production process The injection is manufactured in accordance with process specifications and relevant production quality control requirements, and the balance and deviation in composition are managed to ensure quality, stability, and consistency of products. In addition, the manufacturer has specified the principles and main technical parameters of key production equipment, formulated quality standards for the solvents, adsorbents, decolorizing agents, and clarifying agents to be used in production, and controlled the production process and levels of bacteria and endotoxins generated. Quality control was performed using three levels of fingerprints for raw materials, drug substances (extracts), and final products. Internal control was established over the quality indicators of process water, raw materials, intermediate products, and finished products, such as property, identification, visible foreign objects, variations in amount of packaging, heavy metals, harmful elements, pyrogens, hemolysis and coagulation, abnormal toxicity, antihypertensive substances, allergic reactions, fingerprints, proteins, tannins, resins, oxalates, and potassium ions. The shelf-life stability of the product and its quality within 1 year of the expiration date were examined by accelerated testing, long-term tests, key inspections, and appearance inspections. Product variety was inspected yearly; accelerated tests and long-term stability trials were also conducted when changing drafted quality standards into regular quality standards, commissioning product production, changing raw materials suppliers, and changing packaging materials. All the results showed that the stability of the quality of the product was good. NON-CLINICAL SAFETY AND PHARMACOLOGICAL STUDIES Toxicity tests In September 1997, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, performed acute toxicity tests on mice and long-term toxicity tests on rats and Beagle dogs. Mice received single doses of 1.3, 1.45, 1.61, and 1.79 g/kg of Danshen (Radix Salviae Miltiorrhizae) depside salt injection intravenously. Autopsies revealed no abnormality in the organs of dead mice, and there were no lesions in autopsies of surviving mice conducted 2 weeks after administration. The lethal median dose (LD50) calculated by the Bliss method was 1.49 g/kg, with 95% confidence intervals of g/kg. Sprague Dawley (SD) rats were divided into four groups of 50, 200, and 400 mg/kg dose, and a saline control group. Rats received the injection intraperitoneally for 30 consecutive days. Doses less than 50 mg/kg (about twice as much as the optimal effective dose for rats) were non-toxic; doses of 200 mg/kg or more were toxic. This could cause drug-induced peritonitis to some local tissues, but without obvious damage to the heart, liver, kidneys, and other solid organs. Beagle dogs in the dose groups received 20, 80, and 320 mg/kg injections intravenously, and the animals in the control group received saline intravenous injections, for 30 days. The 20 mg/kg dose (about six times as much as the optimal effective dose for dogs) was non-toxic, doses less than 80 mg/kg (about 24 times as much as the optimal effective dose for dogs) were safe, and doses of 320 mg/kg (about JTCM www. journaltcm. com 750

3 100 times as much as the optimal effective dose for dogs) were toxic. The toxic and side reactions of the 320 mg/kg dose included digestive disorders; drug-induced erythrocyte deformation in the lung, liver, spleen, kidney, bone marrow, intestinal mucosa, lymph nodes, and other tissues; megakaryocytes in the lung, liver, and spleen resulting from mild hemolysis; and mild hyperplasia in bone marrow hematopoietic tissue. Other toxicity studies showed that the injection exerted no irritative effect on local tissues and blood vessels, no allergic reactions, and did not produce any erythrocyte coagulation or hemolysis. In 2013, the detection limit of "abnormal toxicity" as specified in existing product quality standards was revised in accordance with the guideline requirements and approved by the State Pharmacopoeia Commission. The expression was modified to read "Take this product, dissolve and dilute it with sterile water for injection to make a solution of 15 mg/ml, check it by the method (Appendix XIIIE of Volume Ⅱ of Chinese Pharmacopoeia 2010), administer slowly through intravenous injection for at least 30 seconds; all requirements are to be fulfilled." (The National Drug Standards of China Food and Drug Administration, YBZ Z-2013) Pharmacological evaluation of the injection In cardiovascular pharmacodynamic tests, the Pharmacology Lab of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, found that the drug had an anti-myocardial ischemic effect, an effect on cardiac hemodynamics and oxygen consumption of the heart, and inhibited platelet aggregation and thrombosis. Cerebrovascular pharmacodynamic tests indicated a therapeutic effect on the rat model of focal cerebral ischemia arising from cerebral artery occlusion, on the gerbil model of total cerebral ischemia arising from bilateral carotid artery ligation reperfusion, an effect on mice hypobaric hypoxia ability, and on rabbit basilar artery vascular ring tension and PC-12 cell injury induced by hypoxia-reoxygenation. Studies indicated the pharmacological mechanism underlying the injection to be the migration of vascular endothelial cells and tube formation, the regulation of the Ca 2+ channel, regulation of immune/inflammatory physiological processes, anti-platelet aggregation, and the inhibition of Na + / K + ATP enzymes through its anti-oxidative stress effect. As a result, this drug can protect myocardial and endothelial cells and improve blood circulation. PREMARKETING CLINICAL SAFETY STUDIES A Phase Ⅰ human tolerance clinical trial was conducted by Xiyuan Hospital of China Academy of TCM from December 16 to 29, 2002; 36 healthy volunteers (men and women) aged from 18 to 50 participated in the trial. No adverse reactions were found. A Phase Ⅱ clinical safety trial was conducted as a preliminary evaluation of the safety and efficacy of the drug for the treatment of angina pectoris in CHD (heart blood stasis syndrome). After 14 days of treatment, one patient in the experimental group experienced distending pain in full head. In a Phase Ⅲ clinical safety trial on angina pectoris, some subjects experienced mild abnormality in routine blood tests, renal, and hepatic functions, as well as distending pain in full head and dizziness, but no serious ADRs. POSTMARKETING CLINICAL SAFETY STUDIES Postmarketing Phase Ⅳ trials (Randomized Controlled Trials [RCTs]) A multi-center Phase Ⅳ clinical trial evaluated the efficacy and safety of the injection in the treatment of chronic stable angina pectoris in CHD from April 9, 2006 to May 17, Co-led by Huashan Hospital, affiliated with Fudan University, and Ruijin Hospital, affiliated with Shanghai Jiaotong University, the trial incorporated 40 Class Ⅲ hospitals and 10 Class Ⅱ hospitals, with a large sample of ADR incidence rate was 0.56%, mainly involving the digestive, nervous, and cardiovascular systems; ADR symptoms included vomiting, headache, head distention, dizziness, chest distress, palpitations, flushing and thermal discomfort, pruritus, hypotension, insomnia, and thrombocytopenia. 5 Evaluation of clinical applications and therapeutic value A large number of clinical studies indicate that, in addition to cardiovascular [angina pectoris, postoperative coronary stent intervention, postoperative cardiopulmonary bypass (CPB) valve replacement, heart failure, myocardial infarction] and cerebrovascular (ischemic stroke, cerebral infarction) diseases, the injection can treat lung diseases, thoracic obstruction, kidney diseases, lumbar disc herniation, sudden deafness with vertigo, pancreatitis, liver cirrhosis, postoperative anticoagulation, coronary slow flow, tuberculosis, disseminated intravascular coagulation, and other diseases. 6 Because the drug improves microcirculation and resists oxidative stress injury, it was predicted to improve microcirculation of the heart, protect against ischemic-reperfusion injury, and prevent no-reflow restenosis after percutaneous coronary intervention (PCI) and diabetes microvascular pathological changes in clinical applications. Additionally, because it can inhibit thromboxane A2 (TXA 2), and elevate Prostacyclin (PGI 2), it was predicted to treat thrombotic diseases with aspirin and clopidogrel resistance; and because it promotes the proliferation and differentiation of neural stem cells and the formation of neuron axons, it was predicted to treat ischemic cerebrovascular diseases. In Phase Ⅱ JTCM www. journaltcm. com 751

4 and Ⅲ trials, the injection was effective in the treatment of angina pectoris, abnormal electrocardiogram (ECG), TCM symptoms, and exercise tolerance tests (based on pre- and post-treatment comparison). The Phase Ⅳ postmarketing clinical trial showed that the drug was effective in treating patients with angina of varying severity; the ADR incidence rate was low (0.56%), and all ADRs were mild or moderate. Moreover, findings indicated that the drug could be safely applied to elderly CHD patients or those with mild hepatic and renal dysfunction. Pharmacokinetic evaluation On the basis of the Phase Ⅰ clinical pharmacokinetic trial, two other studies were completed after the injection was introduced to the market. A multi-ingredient in vivo and pharmacokinetic study examined the injection's three main ingredients: magnesium lithospermate B, rosemary acid and lithospermic acid. After Beagle dogs received a 6 mg/kg intravenous injection, the average half-lives (T 1/2) of magnesium lithospermate B, rosemary acid, and lithospermic acid were 0.05, 0.04, and 0.07 h respectively; after SD rats received a 60 mg/kg intravenous injection, the average elimination half-lives (T 1/2) of magnesium lithospermate B, rosemary acid, and lithospermic acid were 1.04, 0.75, and 2.00 h, respectively. Another pharmacokinetic study was conducted examining magnesium lithospermate B in selected typical patients with angina pectoris (CHD), who received the injection intravenously. The terminal elimination half-life (T 1/2) was (1.71 ± 0.78) h, much lower than that of healthy people. 7 The role of magnesium lithospermate B in impairing blood circulatory function might be one of the pathological mechanisms reducing drug distribution, thereby shortening the half-life. For CHD patients with blood stasis syndrome, it may be advisable to increase the dose, extend the infusion time, or increase the frequency of administration. Evaluation results showed that the price of the product was reasonable; a single course of treatment costs RMB 2492, which is moderate compared with similar cardiovascular and cerebrovascular therapeutic products. The product showed significant treatment effect, and good safety and reliability. Registry-based postmarketing clinical safety monitoring study As a Chinese medicine parenterally-administered medication under clinical safety monitoring, the injection is covered by the research from a major national science and technology project for "Major New Medicine Development," titled Research on Key Technologies for Evaluation of Postmarketing Traditional Chinese Medicines (No. 2009ZX ), presided over by Xie Yanming, a researcher from the Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences. In December 2012, the project passed a review by the Ethics Committee of the Institute of Basic Research in Clinical Medicine (Approval document No. 16), and completed protocol registration in clinicaltrials.gov (ID: NCT ). The project is currently underway. Spontaneous Reporting System (SRS) data analysis An analysis of the SRS data on ADRs reported for Danshen (Radix Salviae Miltiorrhizae) depside salt injection from the State Adverse Drug Reaction Monitoring Centre revealed 739 ADR case reports involving 1310 adverse reactions of 106 types. Overall, there were 24 cases of serious ADRs, accounting for 3.25% of the total, and 251 new ADR cases, accounting for 33.96% of the total. Among all new ADR cases, there were 238 general cases, accounting for 32.20% of the total and 13 serious cases, accounting for 1.76% of the total; no patients died. In the SRS reports, the proportion of severe ADRs and new severe ADRs was high, and mainly included anaphylactoid reaction, chilling, rash, and abnormal liver function. Among the reported ADRs, abnormal liver function was mentioned in the specification of the solution. In 19 ADR cases, the solution was used to treat the indications, and used for different diseases in the other cases. The severe ADRs could have been caused by super indications medication and clinical use not in accordance with TCM syndrome differentiation and treatment. The 10 most common ADR symptoms were rash, dizziness, itching, headache, chills, difficulty breathing, nausea, palpitations, anaphylactoid reaction, and fever. Proportional reporting ratio (PRR) analysis showed that dizziness, headache, nausea, and itching were early warning signals, while Bayesian confidence propagation neural network method (BCPNN) analysis showed that dizziness and headache were early warning signals. The propensity score analysis indicated that the PRR and BCPNN results were equivalent, and both the headache and dizziness were early warning signals before and after matching. 8 Hospital Information System (HIS) data analysis An analysis was carried out on the clinical safety and effectiveness of the injections using HIS data from 14, 191 patients in 20 Grade Ⅲ, Level A hospitals around China. Most patients were middle-aged or elderly. The injection was mostly used to clinically treat hypertension, atherosclerosis, and ischemic encephalopathy. Most patients received a single dose of mg with a treatment cycle of 1-3 days; the solvent was 0.9% sodium chloride solution. When it was used to treat coronary heart disease, the injection was usually used in combination with clopidogrel hydrogen and isosorbide esters. 9 In patients who stopped administration of the injection within 24 h after commencement of treatment, the potential risk factors were cefazolin, dopamine, mannitol, and epinephrine compared with the control group; however, for patients who stopped administration over 24 h but less than or equal to 48 h after commencement, the potential risk factors were ambroxol, JTCM www. journaltcm. com 752

5 levamlodipine, and papaverine. The propensity score method was used to analyze the confounding factors reflecting the patient's four hepatic and renal function indicators; i.e., alanine aminotransferase, aspartate aminotransferase, serum creatinine, and blood urea nitrogen. The results indicated that the injection might impact alanine aminotransferase and blood urea nitrogen. A dose higher than the recommended one was more likely to lead to abnormal changes in levels of creatinine and blood urea nitrogen than a recommended dose, but the difference was not statistically significant. Use in a treatment cycle longer than that recommended in the medicine specification did not seem to exert a significant effect on hepatic and renal functions. 10 RISK CONTROL A risk management evaluation and necessity of risk minimization action plan has been carried out for the injection, and an action plan has been developed to control the origin of raw medicinal material in accordance with Good Agricultural Practice standards, improve the production process and quality standards, strengthen studies on the material basis of the pharmacological effects and allergic reactions, conduct drug metabolism studies, carry out well-targeted drug safety publicity and education, amend the medicine specification, conduct postmarketing pharmacoepidemiologic studies, and improve corporate internal drug quality and ADR monitoring systems. FUTURE POSTMARKETING EVALUATION PLAN The postmarketing evaluation plan for future use of the depside injection will focus on evaluating the following three areas over the next 3-5 years: pharmacology, indications, and clinical application. The pharmacology evaluation includes more rigorous and advanced evaluation of the production process, quality, and stability. The indications evaluation system will be established by standardizing literal expression, conducting mechanism studies, strengthening pharmacological and toxicological tests and studies, and improving the medicine specification. The clinical evaluation studies, including population and individual evaluation studies, will follow the methodology adopted by the Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences in the "Research on Key Technologies for Evaluation of Postmarketing Traditional Chinese Medicines-Clinical Safety Monitoring of Postmarketing Parenterally Administered Chinese Medicines." Safety monitoring and safety evaluations will be conducted. Additionally, it is imperative to establish a postmarketing safety monitoring network for the injection. In summary, this is the first study to demonstrate that salvianolate and its dominant ingredient magnesium lithospermate B are the most important active ingredients of Danshen (Radix Salviae Miltiorrhizae), and it proposed magnesium lithospermate B as the quality control indicator of Danshen (Radix Salviae Miltiorrhizae) depside salt injection and its powder injection. Our study indicates that the preparation process is original; the fingerprint-based quality standards for the raw medicinal material, drug substances, and finished products have been established; and that the original bottle freeze-drying technology has been adopted in the solution production. Both pharmacological and toxicological studies indicate that Danshen (Radix Salviae Miltiorrhizae) depside salt injection is a high-efficacy and low-toxicity cardiovascular drug. REFERENCES 1 National Pharmacopoeia Committee. Chinese Pharmacopoeia Beijing: China Medical Science Press, 2010: Wu XJ, Wang YP, Wang W, et al. Free radical scavenging and inhibition of lipid peroxidation by magnesium lithospermate B. Acta Pharmacol Sin 2000; 21(9): Wang W, Wang YP, Sun WK, et al. Effects of magnesium lithospermate B on aggregation and 5-HT release in rabbit washed platelets. Acta Pharmacol Sin 2000; 21(9): Luo WB, Wang YP. Effect of magnesium lithospermate B on calcium and nitric oxide in endothelial cells upon hypoxia/reoxygenation. Acta Pharmacologica Sinica 2002; 23 (10): Miao Y, Gao ZY, Xu FQ, et al. Clinical observation on salvianolate for the treatment of angina pectoris in coronary heart disease with heart-blood stagnation syndrome. Zhong Yao Xin Yao Yu Lin Chuang Yao Li 2006; 17(2): Song YQ, Xu XY, Sun RD. A summary of clinical application of salvianolate injection. Chin J Pharmacoepidemiol 2012; 21(8): Zhang Y, Gao R, Liu JX, et al. Pharmacokinetic study of lithospermata B on patients with blood-stasis syndrome of CHD. Zhong Yao Yao Li Yu Lin Chuang 2010; 26(6): Lu PF, Xiang YY, Xie YM, et al. Pharmacovigilance of parenterally administered salvianolate based on analysis of spontaneous reporting system data. Zhong Guo Zhong Yao Za Zhi 2013; 38(18): Chang YP, Zhang H, Xie YM, et al. Analysis of salvianolate injection combined with usual drugs in treatment of coronary heart disease in real world. Zhong Guo Zhong Yao Za Zhi 2013; 38(18): Chang YP, Huo J, Xie YM, et al. Real world study of affect on liver function of overdose of salvianolate extract injection. Zhong Guo Zhong Yao Za Zhi 2013; 38(18): JTCM www. journaltcm. com 753