Analysis on Common Compatibility Contraindications of Breviscapine for Injection

Chenggen ZHAO, Hongbo ZHANG, Fei HOU

Kunming Longjin Pharmaceutical Co., Ltd., Kunming 650503, China

Abstract [Objectives] To analyze the common compatibility contraindications of breviscapine for injection, and to provide references for clinical rational drug use. [Methods] The pH distribution of the combined drugs in the report on the compatibility contraindications of breviscapine for injection and was analyzed. [Results] Breviscapine for injection may become turbid or precipitated when mixed with drugs whose pH are lower; it can make the liquid discoloration in a strong alkaline solution. [Conclusions] Breviscapine for injection should not be combined with drugs whose pH are lower, especially drugs with pH lower than 4.2. Breviscapine for injection should not be used with drugs with strong alkaline. It is recommended to use Breviscapine for injection separately.

Key words Breviscapine for injection, Compatibility contraindications, pH, Raditional drug use, Analysis

1 Introduction

Breviscapine is a flavonoid compound isolated from the Compositae plant Erigeron breviscapus (Vant.) Hand-Mazz. It contains Apigenin-7-O-glucuronide and scutellarin, mainly scutellarin. Breviscapine has the effects of promoting blood circulation, removing blood stasis, dredging collaterals and relieving pain, and is widely clinically applied in the treatment of stroke and its sequelae, coronary heart disease, and angina pectoris. With its widespread clinical application, there occurs compatibility contraindications from time to time. In this study, we summarized common compatibility contraindications of breviscapine for injection in clinical application, and analyzed reasons for compatibility contraindications, to provide references for its clinical rational use.

2 Data source

In China National Knowledge Infrastructure (CNKI), Wanfang database, and CQVIP database, we searched using such key words as "breviscapine+contraindications", "breviscapine+clinical application", "breviscapine+safe drug use", "breviscapine+rational drug use", and "breviscapine+safety assessment". We obtained 46 papers on the compatibility contraindications of breviscapine, involving 31 drugs. We searched the pH of compatible drugs, and summarized the compatibility contraindications and verification tests according to the acid-base classification of the drugs. Combined with the adverse reactions of breviscapine for injection reported by patients, we analyzed the reasons for the compatibility contraindications and the risks caused by the contraindications.

3 Results and analysis

3.1 Contraindications for compatibility with common solventsBreviscapine and the solvent with a lower pH can cause the drug to precipitate (Table 1), and there is a contraindication between breviscapine and the solvent.

Table 1 Contraindications for compatibility of breviscapine with common solvents

3.2 Contraindications for compatibility with low pH drugs

Breviscapine and the acid solution with a lower pH can cause the drug to precipitate (Table 2), and there is a compatibility contraindication between breviscapine and such drugs.

Table 2 Contraindications for compatibility of breviscapine with low pH drugs

Compatible drugClinical application compatibility situations and resultsTest verificationDrug pHGlycerol fructose and sodium chloride injection[21]Patient given with 75 mg breviscapine for injection+250 mL glycerol fructose and sodium chloride injec-tion, turbidity appeared in 20-30 min, and then flocs formedN/A3.0-6.0Pefloxacin meiodate injec-tion[22]Patient given with continuous intravenous infusion of pefloxacin meiodate injection and breviscapine for injec-tion, light brown precipitate appeared in the infusion tubeMixed 2 mL pefloxacin meiodate injection+2 mL breviscapine for injection, the drug solution turned into a milky yellow turbid liquid, and a dark brown precipitate appeared after 10 min3.5-4.5Ambroxol hydrochloride in-jection[23]Patient given with 40 mL breviscapine for injection+50 mL 0.9% NS, and added 30 mg ambroxol hydrochlo-ride injection, white flocs appeared immediatelyTook 30 mg ambroxol hydrochloride injection+5 mL 0.9% NS, 40 mL breviscapine for injection+250 mL 0.9% NS, mixed 1 mL separately, white flocs appeared3.5-5.5Sulfotanshinone sodium in-jection[24]Patient given with 50 mg sulfotanshinone sodium injec-tion+250 mL 5% GS, then 80 mg breviscapine for in-jection+250 mL 5% GS, red flocs appeared in the in-fusion tubeTook 10 mg breviscapine for injection and 10 mg sulfotanshinone sodium injection, dissolved with 5% GS, mixed 1 mL separately, red flocs appeared3.5-5.5[25]Isosorbide mononitrate injec-tion[26]Patient given 100 mg breviscapine for injection+250 mL 5% GS, then given 25 mg isosorbide mononitrate injection+250 mL 0.9% GS, yellow granular precipi-tate and flocs appeared after 5 minN/A4.0-6.0Cefotaxime sodium for injec-tion[27]N/ATook 2 g cefotaxime sodium for injection, breviscap-ine for injection, dissolved with 100 mL 0.9% NS, mixed 5 mL separately, white turbidity appeared4.5-6.5

3.3 Contraindications for compatibility with high pH drugs

Breviscapine and the alkaline solution with a high pH can cause the drug to change color (Table 3), and there is a compatibility contraindication between breviscapine and such drugs.

Table 3 Contraindications for compatibility of breviscapine with high pH drugs

Compatible drugClinical application compatibility situations and resultsTest verificationDrug pHFurosemide injection[32]Patient given with 40 mg breviscapine for injection+250 mL 5% GS, then added 40 mg furosemide injec-tion, the drug solution became turbidN/A8.5-9.5Aminophylline injection[33]Patient firstly given with 50 mg breviscapine for injec-tion+5% GS, then with 250 mg aminophylline injec-tion+100 mL 5% GS, the solution in the infusion bot-tle changed from light yellow to dark yellowTook 50 mg breviscapine for injection+250 mL 0.9% NS dissolved, and then 250 mg aminophylline injection+100 mL 5% GS dissolved, mixed them a little, the drug solution changed from slightly yellow to dark yellow≤ 9.6Pantoprazole sodium for in-jection[34-35]Patient firstly given with 50 mg breviscapine for injec-tion+250 mL 0.9% NS, then with 60 mg panto-prazole sodium for injection+100 mL 0.9% NS, the the infusion tube drug solution changed from light yellow to bright yellowTook 80 mg pantoprazole sodium for injection+0.9% NS dissolved, 50 mg breviscapine for injection+250 mL 5% GS dissolved, mixed 2 mL separately, the mixed solution changed from transparent to dark yellow, and a yellow precipitate appeared after 24 h9.5-11.0Aciclovir for injection[36]Patient firstly given with 40 mg breviscapine for injec-tion+250 mL 0.9% NS, then 0.5 g aciclovir for injec-tion+250 mL 0.9% NS, dark yellow turbid and yellow fine powder appeared in the drug solutionTook 0.5 g aciclovir for injection, 40 mg breviscap-ine for injection, then dissolved with 20 mL 0.9% NS separately, mixed these two kinds of drug solu-tion, dark yellowish brownish turbidity and yellow fine powder appeared immediately, and yellow pre-cipitate appeared after 30 min10.5-11.5Ganciclovir for injection[37]Patient firstly given with 0.25 g ganciclovir for injec-tion+250 mL 0.9% NS, then given with 50 mg bre-viscapine for injection+250 mL 0.9% NS, the drug solution changed from clear to dark orangeTook 0.25 g ganciclovir for injection, 50 mg brevis-capine for injection, dissolved with 0.9% NS, mixed 2 mL separately, the mixed solution turned into dark orange, and turbidity, precipitation and flocs appeared after 2 min10.5-11.5Omeprazole sodium for in-jection[38-39]Patient firstly given with 50 mg breviscapine for injec-tion+250 mL 5% GS, then with 40 mg omeprazole sodium for injection+250 mL+0.9% NS, drug solu-tion turned into dark yellowTook omeprazole sodium for injection+100 mL 0.9% NS dissolved, then breviscapine for injection+250 mL 0.9% NS dissolved, mixed these two kinds of drug solution, 6 h later, the color of the mixed solution darkened, the pH decreased, and the insol-uble particles increased10.1-11.1

3.4 Contraindications for compatibility with protein drugs

Jiang Qionghua[41]reported 1 case of contraindication of breviscapine for injection and cerebroprotein hydrolysate: the patient was firstly given with 20 mg breviscapine for injection+250 mL 5% GS, then given with 20 mL cerebroprotein hydrolysate+250 mL 5% GS, milky white flocs appeared immediately in the infusion tube; through consulting the relevant standards, the pH of the cerebroprotein hydrolysate was 10.5-12.5[42].

3.5 Compatibility contraindications and unexpected adverse drug reaction (UADR)In the historical data of adverse reactions of breviscapine for injection, among 8 611 cases, 2 082 cases (24.18%) involved the above compatibility contraindicated drugs; unexpected adverse reactions/symptoms occurred in 275 cases, accounting for 11.17% of the total number of unexpected reports; 231 cases had serious adverse reactions/symptoms, accounting for 37.62% of the total number of serious reports; 51 cases had turbidity/precipitation, as indicated in Table 4.

Table 4 Compatibility contraindications and statistics of unexpected adverse drug reactions (UADR)

Compatible drugNumberof ADRcases∥casesType of ADR∥casesPrecipitation/turbidityUnexpectedseriousExpectedseriousUnexpectedgeneralExpectedgeneralUADR∥casesGC-NS62042551Feeling cold (3), anaphylactic shock (2), local numbness (1), tremor (1), dermatitis (1), and muscle pain (1)Pantoprazole sodium for injection46032635Hypokalemia (2), eczema (1), anaphylactic shock (1), hypoglycemia (1), gastrointestinal bleeding (1), fear of cold (1), joint swelling (1), and abnormal tearing (1)Cerebroprotein hydrolysate injection390011028Fear of cold (2), dry mouth (2), myalgia (1), tremor (1), eczema (1), urticaria (1), tongue numbness (1), and nasal congestion (1)Omeprazole sodium for injection32 003 326Frequent urination (1), eyelid edema (1), and tachycardia (1)Ambroxol hydrochloride injection1402039Abnormal stool (3), and anaphylactic shock (2)Isosorbide mononitrate injection13000 310Joint pain (1), dry mouth (1), and swelling of hands (1)Salviae miltiorrhizae and ligus-trazine hydrochloride injection100 00 010No UADRFructose injection93 0006No UADRLigustrazine hydrochloride injection7 0 0 016Epistaxis (1)Cefotaxime sodium for injection700124Blurred vision (2)Lansoprazole for injection70001 6Abnormal stool (1)Amoxicillin sodium for injection610 1 1 3Mouth numbness (1)Furosemide injection61 00 05No UADRAminophylline injection400 1 0 3No UADRAciclovir for injection3 0 001 2Night sweats (1)Ornidazole Injection3 1 000 2No UADRInvert sugar and electrolytes injection310 01 1Tachycardia (1)Ganciclovir for injection2 0 00 0 2No UADRSodium bicarbonate injection20 0 011Loss of appetite (1)Tiopronin for injection1 0 0 00 1No UADRTotal2 08251421892331 567

4 Discussion

According to the historical data of adverse reactions of breviscapine for injection, 24.18% of the patients used the above compatibility contraindicated drugs, of which 231 cases had serious adverse symptoms, and 51 cases had turbidity or precipitation. These indicate that the contraindicated drugs will undergo oxidation, hydrolysis and polymerization due to the physical and chemical properties of the drug and the interaction of the pharmacokinetics, which will cause the effective components of the drug to be precipitated or change the structure, which will cause the drug to change color, precipitate or reduce the efficacy of the drug, may also induce adverse reactions and increase the risk of drug use[43].

There is a compatibility contraindication between breviscapine for injection and drugs with lower or higher pH due to physical and chemical properties of the drug itself. Breviscapine contains such flavonoids as scutellarin (5, 6, 4’-trihydroxyflavone-7-O-glucuronide) and apigenin-7-O-glucuronide (4’, 5-Dihydroxy-7-[(β-D-glucopyranuronosyl)oxy] flavone), with the latter as the main active component. The structure contains acidic groups such as carboxyl and phenolic hydroxyl groups, and its physical and chemical properties determine that it is difficult to dissolve in water and soluble in weakly alkaline solutions, but its properties are extremely unstable and easily converted into other flavonoids and accordingly lose efficacy[44-45]. In order to increase the solubility and stabilize the properties of the drug, breviscapine is made into easily soluble and more stable glucuronate (breviscapine for injection) during the production process, which is weakly alkaline (pKa 3.35)[46]. When breviscapine glucuronate is combined with a solution with a low pH, the salt ions on the 4’ carbon atom will be replaced by H+ and reduced to scutellarin glucuronide, which is insoluble in water, resulting in turbidity or precipitation. According to the study of Li Yu[47], the turbidity of breviscapine for injection in a solution with a pH lower than 4.2 will increase with the decrease of pH; according to the study of Jiang Sanyuanetal.[48], the time for breviscapine for injection to appear turbid in a solution with a pH lower than 4.0 decreases with the decrease of pH. Therefore, the drug instructions clearly stipulate that breviscapine for injection shall not be used after being diluted with a solution with a pH lower than 4.2. The pH of glucose injection is 3.2-6.5, so the current version of the drug instructions deletes the use of glucose injection as a solvent for breviscapine for injection.

Combined drug use will increase the number of insoluble particles in the drug solution due to the difference in the chemical components of the drug and the pH change, resulting in the precipitation of the effective components and discoloration of the drug solution[49]. The basic structure of flavonoids is that the second carbon atom of chromone is connected to a phenyl group. Chromone is colorless, but after introducing the benzene ring at the second carbon atom, it will form a cross-conjugated system. Through electron transfer and rearrangement, the conjugated chain is extended to produce color, so breviscapine is generally light yellow to yellow. A study[50]has indicated that the stability of breviscapine aqueous solution decreased rapidly with the increase of pH. With the increase of pH, the 7-glucuronide on the breviscapine glucuronate is cleaved to generate 4′,5,6-trihydroxyflavonoid, which promotes electron displacement and rearrangement, and darkens the color of the solution.

In addition, some study[51]indicates that breviscapine for injection contains sterols, tannins, resins, gums, volatile oils, catechols, sugars and other compounds. The tannin components can combine with proteins to form precipitates. Therefore, when breviscapine for injection is used in combination with protein drugs, it may cause precipitation.

Therefore, when clinically using breviscapine for injection, it should be used after sodium chloride injection is dissolved and used alone as much as possible. It is strictly forbidden to mix with other drugs, and it should be used with great caution when combined with other drugs. If it is necessary to use other drugs in combination, the interval between drug use, the nature of the drugs, and drug interactions should be carefully considered, and the infusion tube should be flushed appropriately and monitoring should be strengthened.