Insert of Butylphthalide and Sodium Chloride Injection
【Medicine Name】
Generic Name: Butylphthalide and Sodium Chloride Injection
Trade Name: En bi pu (NBP)                                                                                                                                                              

English Name: Butylphthalide and Sodium Chloride Injection
Chinese Pinyin: Dingbentai lühuana Zhusheye
【Ingredients】The main active of NBP is Butylphthalide and its chemical name is dl-3-butylphthalide-isobenzofuran-1(3H)-ones

 
 

Structural Formula:
Molecular formula: C12H14O2              
Molecular weight: 190.24
Excipient: Sodium Chloride(for injection), hydroxypropyl-β-cyclodextrin, Injection water
【Description】The product is colorless transparent liquid
【Indication】Butylphthalide can improve the injured nerves function in patients with acute ischemic stroke.
【Specification】100ml: 25 mg Butylphthalide and 0.9g Sodium Chloride
【Usage and Dosage】This product should be injected within 48 hours. Intravenous drip,2 times per day,25 mg(100ml) per time, not less than 50 minutes every time. Intervals between 2 times not less than 6 hours. 14 days as a treatment course. PVC infusion set has obvious adsorption effect of butylphthalide, so only allow use PE or PP elastomer infusion set. There is no efficacy and safety research data on 48 hours after onset.
【Adverse Reactions】Adverse events
In clinical trials, adverse reactios rate of patients in Butylphthalide and Sodium Chloride Injection group(n=606) is 24.59% and Control group (n=243) is 26.75%,The researchers believed the relationship between adverse events and experimental drugs mostly irrelevant or may have nothing to do. Among them, the erythema multiforme drug eruption may be related to test drug, there was no serious adverse events related to the test drug.
Adverse events related to the drug are as follows:
 
Adverse Reactions Butylphthalide and Sodium Chloride Injection group(n=606) Control group(n=243)
case number odds ratio case number odds ratio
ALT Abnormality 20 3.30% 9 3.70%
Respiratory tract infection 14 2.31% 4 1.65%
symptom aggravate 13 2.15% 3 1.23%
Urinary System Infection 8 1.32% 1 0.41%
high fibrinogen 7 1.16% 5 2.06%
descent of heart rate 6 0.99% 0 0.00%
rash 5 0.83% 2 0.82%
diarrhea 5 0.83% 0 0.00%
blood glucose elevation 5 0.83% 1 0.41%
relapsed cerebral infarct 4 0.66% 2 0.82%
Headache 4 0.66% 0 0.00%
hemorrhagic infarction 4 0.66% 1 0.41%
Electrocardiogram Changes 4 0.66% 1 0.41%
fever 3 0.50% 2 0.82%
dizziness 3 0.50% 0 0.00%
chest distress 3 0.50% 0 0.00%
Urine RBC count abnormal 3 0.50% 1 0.41%
Urine WBC count abnormal 2 0.33% 1 0.41%
abnormal platelet 2 0.33% 1 0.41%
occult blood 2 0.33% 0 0.00%
Myocardial infarction 2 0.33% 0 0.00%
DBIL increased 2 0.33% 0 0.00%
cerebral hernia 2 0.33% 0 0.00%
 the tension on the left side of the head 1 0.17% 0 0.00%
Somnolence 1 0.17% 0 0.00%
 
 
 
 
Adverse Reactions Butylphthalide and Sodium Chloride Injection group(n=606) Control group(n=243)
case number odds ratio case number odds ratio
Chronic otitis media 1 0.17% 0 0.00%
Dyspnea 1 0.17% 0 0.00%
renal inadequacy 1 0.17% 1 0.41%
Urine protein abnormality 1 0.17% 0 0.00%
Creatinine/Urea nitrogen elevation 1 0.17% 1 0.41%
Infusion site local skin redness 1 0.17% 0 0.00%
itchy skin 1 0.17%        2 0.82%
allergic dermatitis 1 0.17% 1 0.41%
left-handed numbness 1 0.17% 0 0.00%
left ankle wrench 1 0.17% 0 0.00%
sjogren syndrome and aggravated 1 0.17% 0 0.00%
eye swelling 1 0.17% 0 0.00%
Muscle weakness upper limb 1 0.17% 1 0.41%
cold 1 0.17% 1 0.41%
zoster 1 0.17% 0 0.00%
stomach discomfort 1 0.17% 0 0.00%
prostatic hyperplasia 1 0.17% 0 0.00%
Nausea 1 0.17% 1 0.41%
heart failure 1 0.17% 1 0.41%
rheumatic heart valve disease 1 0.17% 0 0.00%
unstable angina 1 0.17% 0 0.00%
Hypokalemia 1 0.17% 0 0.00%
Periodontitis 1 0.17% 0 0.00%
gum-pain 1 0.17% 0 0.00%
Glaucoma 1 0.17% 0 0.00%
 
Adverse reactions related to the drug are as follows:
The phaseⅠclinical trial(n=84): Adverse reaction occurs only in a single given butylphthalide larger doses, in 80 mg group a subject feel eyes discomfort(1/6); in 100 mg group a subject feel somnolence(1/4);2 subjects feel limb lassitude(2/4);one subjects feel head heavy(1/4); 6 subjects descent of heart rate in 120 mg group and 100 mg group(6/10) the slowest heart rate was 42 times/min and mostly gradually returned to normal after drug withdrawal. Among 10 cases of subjects in medication for many times, 50 mg each time, 2 times per day,2 cases of subjects AST elevation ,1 case of subjects ALT elevation and 1 case of subjects limb weakness.
In the phase IIand IIIclinical trials: Butylphthalide group(n=522) adverse reactions rate is 7.47 and Control group(n=229) is 6.99%. According to the system classification, incidence of adverse reactions and laboratory examination between the two groups had no statistical difference. Incidence of adverse reactions according to the following method: very common(≥1/10), common(≥1/100,<1/10), less common(≥1/1000,< 1/100),rare(≥1/10000,<1/1000),very rare(<1/1000)
Nervous system: Less common, including dizzy(Butylphthalide group 0.19%,Control group 0.00%) ,headache(Butylphthalide group 0.57%,Control group 0.44%), coma and cerebral hernia(Butylphthalide group 0.38%,Control group 0.00%)
Respiratory: Less common, including chest distress(Butylphthalide group 0.57%,Control group 0.00%), dyspnea(Butylphthalide group 0.19%,Control group 0.00%)
Gastrointestinal system: Less common, including diarrhea(Butylphthalide group 0.57%,Control group 0.00%),
Skin and its appendages: Less common, including Pruritus(Butylphthalide group 0.19%,Control group 0.44%),allergic dermatitis(Butylphthalide group 0.19%,Control group 0.44%), infusion site local redness(Butylphthalide group 0.19%,Control group 0.00%), rash(Butylphthalide group 0.57%,Control group 0.87%)
Systemic anomaly: Less common, including weakness limb(Butylphthalide group 0.19%,Control group 0.00%),symptom aggravate(Butylphthalide group 0.19%,Control group 0.00%).
Abnormal laboratory examination:
ALT elevation(≥ 2 times),Butylphthalide group 2.49%( Recovery after the drug was stopped),Control group 1.32%)
Creatinine increase:Butylphthalide group 0.38%,Control group 0.00%
Urea Nitrogen increase: Butylphthalide group 0.19%,Control group 0.44%
Hemorrhage and Coagulation obstacles: platelet count increase, Butylphthalide group 0.19%,Control group 0.44%
platelet count decrease, Butylphthalide group 0.19%,Control group 0.44%.
 
【Contraindications】
This drug should never be used in case of hypersensitivity to any one of the product's constituents
【Precaution】
1.This drug should be used with caution when patient in sick sinus syndrome and bradycardia.
2. This drug should be used with caution when patients’ liver function is damaged
3. Patients with significant bleeding tendency should pay attention to use it.
4.Hydroxypropyl-β- cyclodextrin clear by glomerular filtration, thus patients’ creatinine clearance less than 30 ml/min should be caution in with this product.
【Pregnant women and nursing patients’ administration】
The safety of the product for pregnant and nursing women isn’t definitive now.
【Children’s administration 】The safety and efficacy of the product for children now isn’t definitive.
【Senior citizen’s administration】Please refer to 【Usage and Dosage】.
【Mutual impact between drugs】Now is not definitive.
【Overdose】There is not overdose report until now. Single drug resistance test tip of this product in overdose can cause bradycardia,should pay attention to that.
【Clinical Research】
Phase II
Phase IIclinical trails (multi-center, randomized, double-blind and multi-dose parallel controlled trial)which involving 199 patients showed that the efficacy of 25 mg per time bid group is better than others.
Phase III
Phase III clinical trails (multi-center, randomized, double-blind double dummy positive controlled trial) involved 552 patients(Acute cerebral infarction in Territory of ICA within 48hr after first onset,NIHSS 6-25) treated with Butylphthalide (n=370) or Ozagrel Sodium Injection (n=182) .After consecutive 14 days, patients in tested group divided into two groups treated with Butylphthalide soft capsule or aspirin(as Control).
The result of FAS statistical analysis (n=552)
Compare with data before treatment, on the 15th day of Butylphthalide sodium chloride injection treatment group, the NIHSS score reduces by 3.65±3.29,Ozagrel Sodium Injection group is 3.25±2.66,difference between two groups has statistical sense(P=0.034). NIHSS variation rate before and after treatment of Butylphthalide sodium chloride injection treatment group is 44.05±40.90%,Ozagrel Sodium Injection group is 41.24±34.22%,difference between two groups has no statistical sense(P=0.088).Use NIHSS score before treatment as covariant, the analysis of NIHSS score covariance before and after treatment shows that on the 15th day after treatment the difference has statistical sense(P=0.035).
Compare with data before treatment, on the 15th day of Butylphthalide sodium chloride injection treatment group, the BI score increases by 18.51±20.44,Ozagrel Sodium Injection group is16.15±18.10,difference between two groups has no statistical sense(P=0.065); BI variation rate before and after treatment of Butylphthalide sodium chloride injection treatment group is 53.12±70.21%,Ozagrel Sodium Injection group is 43.85±58.37%,difference between two groups has statistical sense(P=0.041); Use BI score before treatment as covariant, the analysis of BI score covariance before and after treatment shows that on the 15th day after treatment the difference has no statistical sense.
There was no significant difference between before and after 90th day treatment for the Barthel score change value.
There was significant difference between control group and treatment groups for the rate of patients’ mRs 0-1 after 90th treatment, and Butylphthalide sodium chloride injection was more effective.
In line with the result of PPS(n=489,treatment group 324,control group 165) statistical analysis
On the 15th day after treatment, NIHSS variation rate before and after treatment of Butylphthalide sodium chloride injection is 49.14±39.90%,Ozagrel Sodium Injection group is 44.88±33.54%,the difference had statistical sense(P=0.024); BI variation rate before and after treatment of Butylphthalide sodium chloride injection is 20.42±20.84,Ozagrel Sodium Injection group is 17.52±18.33,the difference has statistical sense(P=0.024).
The analysis result of other index is in accordance with FAS.
【Pharmacology and Toxicology】
Pharmacology and Toxicology of Butylphthalide
Pharmacological action: The product is dl-3-butylphthalide and its structure is same with natural butylphthalide. The clinical studies show that the product has obvious treatment effect on ischemic cerebrovascular diseases and can improve the recovery of patients’ damaged neurological function. Study on animal pharmacodynamics shows that the product has stronger anti-brain ischemia effect, obviously improve micro cycle and rate of the blood stream in the cerebral ischemic area, increase the amount of capillary vessels in the ischemic area, reduce brain edema, decrease the cerebral Infarction volume of rats, improves the brain energy metabolism, reduce the fading of nerve cell, inhibit the formation of thrombosis and so on. The product can reduce the content of arachidonate, enhance the level of NO and PGI2 of endothelium in blood vessel of brain, reduce the concentration of inner cellular calcium, inhibit glutamate release, scavening radicals and increase the activities of antioxidases, and is effecitive on the multi- pathological links of ischemic stroke.
 Toxicology Study: The toxicology study of repeat administration: rats were intraperitoneal injection of 20 mg/kg, 40 mg/kg, 80 mg/kg Butylphthalide and Sodium Chloride Injection for consecutive 2 months. Pathological changes included alveolar epithelial damage, including alveolar epithelial hyperplasia, swelling, abscisic and so on. In 80 mg/kg groups, the capsules of liver thickened, cellulose membrane hyperplasia, chronic inflammation proliferation. Each dosage group and excipient visible renal tubular injury obviously, characterized by increased renal tubule swelling, increased volume, cytoplasm light dye, recover gradually after drug stopped. Consecutive 2 months injection administration with different doses of Butylphthalide to beagle dogs(2, 6 and 18 mg.kg-1), Pathological changes were included local cerebral flake alveolarepithelial hyperplasia in lung, swlling, abscisic, bronchitis inflammatory lesion in 6 and 18 mg/kg groups. Mild cloud edema ofrenal tubular epithelial cells, swelling, cytoplasm light dye, karyopyknosis, Interstitial expansion and hyperemia were appear in 6 and 18 mg/kg groups and recovery after the drug was stopped.
Hereditary toxicity: The results of Ames test, CHL chromosomal aberration test and mice’s micro–nuclear test are all negative.
Reproductive toxicity: In general reproduction toxicology trials, female and male animals are given drug orally(for female animal, give drug for two weeks before mating, continue to give drug for 15 days after fertilization; for male animal, give drug for consecutive 8 weeks) 80mg/kg, 200mg/kg and 500mg/kg, the result is have no obvious impact on parental animals’ fertility, no obvious embryo toxicity and teratogenesis effect. Only animals’ drinking in high dosage group obviously increases, in the beginning days after drug giving have slavering and creeping symptoms. In the reproductive toxicity trials of surrounding puerperium, give drug orally 80mg/kg,200 mg/kg and 500 mg/kg, animals in high dosage group have the tendency of pregnancy period prolonging. One of pregnant rats dystocia(anatomy test is dead fetus). Few animals have no milk secretion and find that baby rats (4 days) have lower rate of survival. Baby rats’ weight (4 days to 3 weeks) falls obviously. F1 generation big rats in high dosage group have lower scores of ramp test and suspension test (reflecting coordinate and balance ability). F2 generation baby rats’ skeleton development delay a little. Middle and low dosage groups haven’t found any abnormal phenomenon.
【Pharmacokinetics】
Single-dose pharmacokinetics: Give Chinese healthy testee intravenous infusion of 100 ml Butylphthalide sodium chloride injection respectively containing 20 mg, 40 mg and 80 mg Butylphthalide. Tmax is respectively 0.84 hour, 0.84 hour and 1 hour; T1/2 average is respectively 6.10±3.13 hour, 8.84±2.98 hour and 9.63±2.59 hour; Cmax average is respectively 199.5 ±76.7, 378.7±134.1 and 847.4±356.6 ng/ml; AUC0-t average is respectively 246.5±65.5, 591.2±126.0 and 1261.8±259.0ng·hr/ml. The result of statistics analysis shows that Cmax, AUC0-t and AUC0-∞ increase in proposition to dose increase.
Multiple-dose pharmacokinetics: Continuously give Chinese healthy testee were intravenous injected of Butylphthalide sodium chloride injection: on day 1 and day 8 for 50 mg per time qd, from day 3to day 7 injected for 50 mg per time bid. Take blood after single dose on the day 1 and day 8, Butylphthalide plasma’s average Tmax respectively is 1hour; Average clearance half life is respectively 9.16±3.76 and 16.70±7.20 hour; Average Cmax is respectively 1319.5±703.0 and 635.8±226.2ng/ml;Average AUC0-t is respectively 907.4±192.2 and 1363.5±326.6 ng·hr/ml;Average AUC0-∞ is respectively 942.5±186.6 and 1700.3±689.9ng·hr/ml. Kidney excretion total is 18.81±8.95ug and kidney clearance rate is 21.2±10.4ml/hr,Kidney excretion percentage is 0.04±0.02%,which shows that there is lesser percentage of excretion of unchanged drug in the urinary and most of the drug has become metabolites in the body. Steady Cavg is 78.50±12.50 ng/ml, and drug %F is 779.98±286.30%. If give Butylphthalide sodium chloride injection 100ml which contains 50mg Butylphthalide for once every 12 hours, the trough concentration of Butylphthalide will not increase any more from the 5th administration on and keep steady. Ro is 1.19±0.32,Rs is 1.02±0.18,and there is few accumulation.
 
 
【Storage】Seal save
【Package】Glass bottle,100 ml/bottle
【Shelf Life】2 years
【Specification No.】SFDA Standard YNH01342010
【Approval No.】国药准字H20100041
【Manufacturer】
Company Name: Shijiazhuang Pharma Group NBP Pharmaceutical Co., Ltd.
Address: No.88 Yangzi Road, Economic and Technological Development Zone, Shijiazhuang City, Hebei Province, China
Zipcode: 052160
Tel: 0311-83092888
Fax: 0311-83092777
Website: www.nbp.com.cn
 Free medical consulting telephone: 800-803-8825