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Salvia polyphenolic acid for injection

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Indications: Huoxuetongluo. It is used for the symptoms of blood stasis and obstruction in the meridian (mild to moderate cerebral infarction) during the recovery period of stroke, and symptoms include hemiplegia, skewed tongue, strong tongue numbness, and numbness.

Approval date: April 02, 2011

Modification date: January 28, 2016

Please read the instructions carefully and use under the guidance of a physician

Warning: Although there is no case of anaphylactic shock in the pre-marketing clinical trials, it should still be used in medical institutions with rescue conditions. The user should be qualified or have accepted the treatment of severe allergic reactions such as anaphylactic shock. Physicians who are trained for rescue of anaphylactic shock, those who have serious adverse reactions such as allergic reactions after taking the drug should immediately stop the drug and treat it in time.

【Drug Name】

Common name: Salvia polyphenolic acid for injection

Phonetic script: Zhusheyong Danshen Duofensuan

[Ingredients] Salvia polyphenolic acid; the auxiliary material is mannitol.

[Character] This product is light brown to brown powder or loose substance; it is hygroscopic.

[Specifications] 0.13g per container (containing 100mg of salvia polyphenolic acid)

[Usage and Dosage] Intravenous drip. One at a time (100mg), just before use, dissolve with an appropriate amount of 0.9% sodium chloride injection, and then dilute it with 250ml of 0.9% sodium chloride injection, once a day. During the medication, the drip rate should be strictly controlled, not higher than 40 drops per minute. The course of treatment is 14 days.

【Adverse reactions】

1. Allergic reactions: Individual patients develop local rashes, erythema, itching, or flushing of the skin, flushing, sweating, etc., and the relevant symptoms should be promptly discontinued and observed.

2. A few patients have symptoms such as eye swelling, head swelling, headache, dizziness, etc.

3. One of the 544 patients developed conscious general fever after administration, but the temperature did not increase.

4. A few patients showed elevated liver function (ALT) and myocardial enzymes (CK, CK-MB).

5. Few patients experience fluctuations in blood pressure (lower or higher) after taking the drug.

[Taboo]

1. People with a history of allergies or severe adverse reactions to this product or salvia drugs are contraindicated.

2. Banned for pregnant and lactating women.

【Precautions】

1. Patients should be carefully inquired about their medication history and allergies before administration, and those with allergies or those with allergies, asthma, and pulmonary insufficiency should be used with caution.

2. Carefully check the prepared infusion solution before using the medicine. If the solution is found to be cloudy, precipitated, discolored, or crystallized, it should not be used.

3. Drug dilution should be formulated strictly according to requirements, and the type, dosage and dilution concentration of the diluted solution must not be changed. Use it immediately after dispensing.

4. This product has no safety and effectiveness information for use in combination with other injections, this product should be used alone, and infusion with other injections is prohibited; this product has no safety and effectiveness information for use in combination with other drugs, Be careful in combination.

5. Strictly follow the dosage, dosing rate and dosage course specified in the instructions, and do not use too fast infusion and overdose or over course of medication.

6. During the medication, you should closely observe the medication response, especially the first 30 minutes. When abnormality is found, the drug should be stopped immediately and active treatment measures should be adopted; after the end of the drug treatment, it should be observed in a medical institution for at least 30 minutes.

7. Patients who have allergic reactions after taking the drug should immediately stop the drug and promptly perform anti-allergic treatment.

8. Patients with severe diseases such as heart, liver and kidney should be used with caution.

9. Those with bleeding tendency should use with caution.

10. The liver function (ALT, etc.), renal function (BUN, SCr), electrocardiogram, and myocardial enzymes (CK, CK-MB) should be regularly reviewed during the medication period.

11. This product should not be used with medicines containing veratrum.

12. The clinical trial patients of this product are aged 30 to 70 years, and have not been clinically tested in pregnant women, nursing women, children and the elderly over 70 years old. Therefore, in pregnant women, nursing women, children and 70 years of age or older The effectiveness and safety of medication in the elderly cannot be determined. It is not recommended to use this product in the above groups.

[Drug Interactions] There are no related studies on drug interactions with this product.

[Clinical trials] This product was approved for clinical research by the State Drug Administration in March 2003, and Phase I, II, and III clinical trials were conducted from September 2003 to February 2005.

The phase Ⅰ clinical trial was to observe the tolerance of the human body to salvia polyphenolic acid for injection and to determine the safe range of clinical administration. There are five dose groups in the single-stage tolerability test of Phase I, which are administered with 0.5, 1, 2.25, 3, and 4 drugs, respectively, for a total of 28 people; the continuous dose tolerance test is divided into 1 and Two groups of two doses, a total of 12 people, once a day, continuous administration for 14 days. The single-dose and continuous-dose tolerance test methods are: intravenous injection of danshen polyphenolic acid and 0.9% sodium chloride injection 250ml, the drip rate is 30-40 drops / minute. The results of the phase Ⅰ clinical trial recommended that the proposed clinical dosage of this product is 1-2 per time / day.

Phase Ⅱ and Ⅲ clinical trials are to observe the effectiveness and safety of stasis and blood clotting syndrome in the recovery period of stroke disease (mild to moderate atherosclerotic thrombotic cerebral infarction) for salvia polyphenolic acid for injection. The design of clinical trials were multi-center, randomized, blinded, double-dose, and positive control. The control drug was Xuesaitong for injection. Method of administration: Test group (low-dose group): one salvia polyphenolic acid for injection, diluted with 0.9% sodium chloride injection, and then intravenously, once a day. Test group (high-dose group): 2 injections of salvia polyphenolic acid for injection, diluted with 0.9% sodium chloride injection, intravenously, once a day. Control group: 200mg Xuesaitong for injection, diluted with 0.9% sodium chloride injection, and then intravenously, once a day. During the medication, the drip rate is strictly controlled, and it is required to be no higher than 40 drops / min. The course of treatment is 14 days.

There were 234 cases of Phase II clinical observations, including 78 cases of Xuesaitong for injection, 77 cases of low-dose polyphenolic acid (1) group for injection, and 79 cases of high-dose polyphenolic acid (2) group for injection; The number of clinical observation cases in stage Ⅲ was 521 cases, of which 173 were Xuesaitong for injection, 173 were in low-dose (1) salvia polyphenolic acid group, and 175 were in high-dose (2) salvia polyphenolic acid injection group. . The cases included in phase Ⅱ and phase Ⅲ clinical trials were mainly patients with blood stasis and obstruction due to stroke recovery during the meridian recovery period. Western medicine diagnosed patients with mild to moderate atherosclerotic thrombotic cerebral infarction. Age 30-70 years. The analysis of the main factors influencing the evaluation of the efficacy of the experimental group and the control group before treatment suggested comparability.

Results of Phase Ⅱ clinical trials: In terms of the comprehensive efficacy of stroke, the total efficacy of the low-dose salvianolate group was better than that of Xuesaitong group, the low-dose salvia polyphenolate group and the high-dose salvia polyphenolic group, and There was no significant difference between the high-dose group and the Xuesaitong group. There was no significant difference in the efficacy and total effective rate of TCM syndromes in each group. There was no statistically significant difference in the efficacy of neurological deficit score improvement in each group. Analysis of the efficacy of related symptoms and signs showed no difference between the groups.

Results of phase Ⅲ clinical trials: In terms of comprehensive efficacy of stroke, the high-dose salvia polyphenolic acid group and the low-dose salvia polyphenolic acid group were better than the Xuesaitong group. In terms of the efficacy of TCM syndromes, the high-dose salvia polyphenolic acid group was superior to the Xuesaitong group, and the differences between the other groups were not statistically significant. The clinical neurological deficit score scores improved curative effect: Danshen polyphenolic acid high dose group and Danshen polyphenolic acid low dose group were better than Xuesaitong group.

In terms of the individual symptom recovery rate of TCM syndromes, the scores of TCM syndromes in the three groups during the treatment showed that the high-dose salvia polyphenolic acid group and the low-dose salvia polyphenolic acid group could significantly improve the hemiplegia caused by stroke. The symptoms of skewed tongue, astringent or silent speech, headache, limb pain, numbness, irritability and irritability were statistically analyzed. The test group was better than the control group.

Compared with the high-dose salvia polyphenolic acid group and the low-dose salvia polyphenolic acid, the clinical cure rate, marked recovery rate and total effective rate were not statistically significant. Only a few high-dose groups were better than low-dose groups.

In terms of safety: During the clinical trial, 40 patients in the phase I clinical trials had undergone relevant safety checks before and after treatment, and the number of cases in the treatment group before and after treatment in the phase II and III clinical trials: blood routine 498 There were 496 cases of routine urine, 459 cases of routine urine, 459 cases of liver function (ALT497, AST496 cases), renal function (BUN498 cases, Cr498 cases), myocardial enzymes (CK482 cases, CK-MB477 cases) and electrocardiogram 496 cases. Most of the treatments were normal before and after treatment, and some patients had abnormalities after normal treatment before treatment and abnormalities before treatment. Most of the abnormalities worsened after treatment. Most of the abnormalities or changes were minor, and most were considered to have no clinical significance and had nothing to do with the test drug. However, a small number of changes are more obvious, which may be related to the test drug.

In the single-stage tolerant administration in the first-stage clinical trial, 3 cases of high-dose group (4 sticks / day / person) had dizziness symptoms after treatment, and no other complaints were reported. The symptoms lasted for about 20 minutes, and the dizziness symptoms resolved on their own. The investigator determined that the relationship with the test drug was suspicious; in the low-dose group (0.5 sticks / day / person), one patient had a myocardial enzyme CK elevation of 648 U / L and a CK-MB elevation of 26 U / L 24 hours after administration, and a review was performed after 1 day CK was 1549U / L, CK-MB was 40U / L, and after 7 days, CK was 261U / L, and CK-MB was 25U / L. The researchers thought that it may be related to cold after exercise and has nothing to do with the test drug. The patient experienced a slight decrease in diastolic blood pressure, which was not ruled out as related to the drug. In the continuous-dose small-dose group (1 stick / day / person), 4 subjects felt mild head and eye fullness after taking the drug, which the researchers thought may be related to the drug.

Phase Ⅱ clinical trial: 1 patient in the low-dose salvia polyphenolic acid group (1 stick / day) had a blood pressure of 150 / 100mmHg and numbness in the lips after 1 day of administration, and the blood pressure did not decrease after using antihypertensive drugs. 110mmHg, drug withdrawal, blood pressure returned to normal, it is not ruled out that it is related to the test drug. One case of the salvia polyphenolic acid high-dose (2 sticks / day) group for 7 days after the administration showed a large amount of erythema, pimples, pruritus, and pruritus on the face and behind the ear. It disappeared for several hours without treatment. The patient had eaten shrimp and crab the night before, and the researchers did not rule out that it had nothing to do with the test drug.

In the low-dose group, ALT and AST increased from 30U / L and 30U / L before treatment to 127U / L and 86U / L after treatment, and 1 case increased from 48U / L and 38U / L before treatment. After treatment, 78U / L and 45U / L are considered to be related to the test drug. Phase Ⅲ clinical trial, high-dose salvia polyphenolic acid injection group (2 sticks / day), 1 case was treated on the 3rd day, 40 minutes after infusion, skin flushing, sweating, mild symptoms, slower drip rate, no After stopping the drug, the symptoms disappeared after 30 minutes, and similar symptoms did not appear after continued administration. The researchers determined that it may be related to the test drug; high dose (2 sticks / day), 1 case after the drug was administered for 1 day, conscious body fever, but the body temperature was normal (36.8 ° C), no facial flushing, no skin rash, no cough and other symptoms, disappeared after 1 hour, and withdrew from the test. The researchers thought it might be related to the test drug. One patient received a low dose (1 stick / day). On the third day of medication, he experienced headache and eye swelling for 2 hours, which resolved on his own. Similar symptoms did not appear after continued administration.

In the high-dose group, 2 cases of CK and CK-MB increased slightly after treatment, and 1 case of CK and CK-MB increased from 144.95 U / L, 28.8 U / L to 284.9 U / L, and 34.35 U before treatment, respectively. / L, 1 case of CK, CK-MB increased from 153U / L, 5U / L before treatment to 560U / L, 31U / L, and returned to 53U / L, 13U / L after review, which is considered to be possible with the test drug Related; 1 case in the high-dose group increased CK-MB from the original 17U / L to 43U / L after treatment, and was rechecked to 20U / L after 1 week, which was considered to be related to the drug; 1 case in the low-dose group was ALT, AST Increased from 36.8U / L and 37.2U / L before treatment to 79.1U / L and 81U / L after treatment, respectively, and the post-treatment review was 37.6U / L and 39.2U / L, which were considered to be related to the test drug. ALT and AST in the high-dose group increased from 38.9 U / L and 37.3 U / L before treatment to 103 U / L and 85 U / L after treatment, respectively, and the post-treatment review was 32.7 U / L and 30.6 U / L, respectively. L, think it may be related to the test drug.

TXA 2的比值,抑制血小板聚集;离体试验结果显示,本品有一定的抗脑微粒体脂质过氧化和清除自由基的作用,可增加超氧化物歧化酶活性及调节缺血后一氧化氮合酶活性。 [Pharmacology and toxicology] The results of non-clinical pharmacodynamic tests show that this product can reduce the area of cerebral infarction in rats with focal cerebral ischemia, improve behavioral disorders and neurological symptoms caused by cerebral ischemia, and reduce ischemic cerebral edema; Inhibit cerebral thrombosis in rats with middle cerebral artery thrombosis model, reduce ischemic brain tissue damage caused by thrombosis; improve cerebral cerebral cortex blood flow in rats caused by middle cerebral artery combined with common carotid ligation on the same side; inhibit Thrombosis, regulating the ratio of PGI 2 / TXA 2 and inhibiting platelet aggregation; in vitro test results show that this product has a certain effect on anti-brain microsome lipid peroxidation and scavenging free radicals, which can increase the activity of superoxide dismutase And regulate nitric oxide synthase activity after ischemia.

The results of the toxicology test showed that in the long-term toxicity test of Beagle dogs for 8 consecutive weeks, 300mg / kg intravenous infusion of this product can cause severe nausea, vomiting and slow weight gain. One (1/6) dogs Death, histopathological examination results in obvious myocardial damage, manifested as myocardial fibrosis and myocardial rupture, T wave inversion appeared on the electrocardiogram when the drug was discontinued; T wave inversion also occurred during administration of 100 mg / kg. Wistar rats were continuously administered for 8 weeks in a long-term toxicity test. This product was administered by intraperitoneal injection at 600 or 200 mg / kg. Blood biochemical examination showed a significant increase in creatinine (Cr). The results of toxicological tests suggest that a larger dose of this product may have certain cardio- and renal toxicity.

This product has not completed all reproductive toxicity tests and has not observed its safety to offspring.

[Storage] Sealed and kept in cool and dark place (not more than 20 ℃).

[Packaging] Low borosilicate glass controlled injection package. 1 stick / box.

[Validity] 30 months.

[Executive Standard] YBZ00252011

[Approval number] National Medicine Standard Z20110011

【manufacturer】