Tigrilol, chemical name: (1S, 2S, 3R, 5S) - 3 - [7 - [[(1R, 2S) - 2 - (3,4-difluorophenyl) cyclopropyl] amino] - 5-propylthiotriazolo [4,5-d] pyrimidin-3-yl] - 5 - (2-hydroxyethoxy) - 1,2-cyclopentanediol, molecular formula: Ctwenty-threeHtwenty-eightFtwoNsixOfourS，It is an inhibitor of platelet aggregation.
The clinical efficacy and safety of tegrilol have been verified and supported by the platelet inhibition and patient outcomes study (PLATO study) and several subgroup studies.The PLATO study also showed that the efficacy of tegrilol was significantly better than that of clopidogrel, so it was listed as a first-line recommendation by several domestic and foreign guidelines. In addition, the European guidelines listed the recommended level of tegrilol before clopidogrel in the past two years, and clopidogrel can only be used in patients who cannot use tegrilol.Because Tigrilol and thiophene pyridine drugs (clopidogrel) are drugs with different chemical classifications, the Chinese name "ticagrel" was replaced by "Tigrilol".
1. Reference value of drainage parameter calculation (XlogP): 2
2. Number of hydrogen bond donors: 4
3. Number of hydrogen bond receptors: 12
4. Number of rotatable chemical bonds: 10
5. Number of tautomers: 4
6. Topological molecular polar surface area: 164
7. Number of heavy atoms: 36
8. Surface charge: 0
9. Complexity: 736
10. Number of isotope atoms: 0
11. Determine the number of atomic structure centers: 6
12. Number of uncertain atomic structure centers: 0
13. Determine the number of chemical bond structural centers: 0
14. Number of indeterminate chemical bond structure centers: 0
15. Number of covalent bond units: 1[2]
medical aircraft
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The trade name of Tigrilol is Beilinda. It is a round, double convex, yellow coated tablet. One side is engraved with "T", the upper side is engraved with "90", and the other side is smooth, containing 90 mg of Tigrilol.Tegralol is a platelet aggregation inhibitor. Its clinical efficacy and safety have been verified and supported by the platelet inhibition and patient outcomes study (PLATO study) and several subgroup studies.The PLATO study also showed that the efficacy of tegrilol was significantly better than that of clopidogrel, so it was listed as a first-line recommendation by several domestic and foreign guidelines. In addition, the European guidelines listed the recommended level of tegrilol before clopidogrel in the past two years, and clopidogrel can only be used in patients who cannot use tegrilol.Because Tigrilol and thiophene pyridine drugs (clopidogrel) are drugs with different chemical classifications, the Chinese name "ticagrel" was replaced by "Tigrilol".
Drug name
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Common name: Tegrillo
Trade name: Beilinda (Tigrilol Tablets)
English name: Ticagelor
English product name: BRILINTA (Ticagelor Tablet)
Molecular formula: C23H28F2N6O4S
Molecular weight: 522.57
Ingredient: The active ingredient of this product is Tigrilol, and its chemical name is: (1S, 2S, 3R, 5S) - 3 - [7 - {[(1R, 2S) - 2 - (3,4-difluorobenzene) cyclopropyl] amino} - 5 - (propylthiouracil) - 3H - [1,2,3] - triazophos [4,5-d] pyrimidin-3-yl] - 5 - (2-hydroxyethyl) cyclopentane-1,2-diol[3]
Brief Introduction to Drugs
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Today, with the continuous growth of acute coronary syndrome (ACS), antiplatelet therapy is still one of the important treatment measures for ACS.Tegrelol is a new oral antiplatelet drug of cyclopentyl triazole pyrimidine (CPTP), ATC code is B01AC24.Tegralol is a non precursor drug that can act directly without hepatic metabolic activation and can reversibly bind to P2Y12 ADP receptor.The PLATO study results showed that after 12 months of treatment, Tigrilol further significantly reduced the risk of cardiovascular death/myocardial infarction/stroke composite endpoint event in ACS patients by 16% compared with clopidogrel without increasing major bleeding, and significantly reduced cardiovascular death by 21%.Based on the benefits of Tigrilol treatment for ACS patients, relevant guidelines at home and abroad recommend that Tigrilol be used for antiplatelet therapy for ACS patients.In the two authoritative guidelines of the European Heart Association (the 2011 ESC NSTE-ACS Guidelines and the 2012 STEMI Guidelines), it is pointed out that clopidogrel can only be used in patients who cannot accept tegrilol treatment, which fully shows the recognition of new drugs to further reduce mortality.
Pharmacology and toxicology
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Pharmacodynamic characteristics
Tigrilol, a member of the chemical classification of cyclopentyl triazole pyrimidine (CPTP), is a selective adenosine diphosphate (ADP) receptor antagonist that acts on the P2Y12ADP receptor to inhibit ADP mediated platelet activation and aggregation. Its mechanism is similar to that of thienopyridine drugs (such as clopidogrel).However, the difference is that the interaction between tegrenol and platelet P2Y12 ADP receptor is reversible, without conformational change and signal transmission, and the platelet function in the blood also recovers rapidly after drug withdrawal.Based on the fact that Tigrenol and thiophene pyridines are drugs of different chemical classifications, the Chinese name "ticagrel" is replaced by "Tigrenol".
In the ONSET/OFFSET study, among patients with stable coronary heart disease who received aspirin treatment, Tigrenol showed a rapid onset of pharmacological action. The average platelet aggregation inhibition (IPA) of Tigrenol was 41% after 0.5 hours of 180 mg load dose administration, and the maximum IPA effect was 89% after 2-4 hours of administration. This effect can be maintained for 2-8 hours.[3]
Clinical trials
The validation of the clinical efficacy and safety of tegrilol mainly comes from the PLATO study.This study is an international multicenter, randomized, double-blind, double simulation, parallel, event driven clinical phase III study. 18624 ACS patients included in the study cover all ACS patient types (unstable angina, non ST segment elevation myocardial infarction and ST segment elevation myocardial infarction), as well as initial drug treatment or percutaneous coronary intervention (PCI),Or patients treated with coronary artery bypass grafting (CABG).The efficacy and safety of antiplatelet therapy for ACS patients were compared head to head between tegrilol (loading dose 180 mg, then 90 mg twice a day) and clopidogrel (loading dose 300 ～ 600 mg, then 75 mg, once a day).
The results showed that, in the context of daily aspirin use, compared with clopidogrel, tegrenol significantly reduced the risk of cardiovascular death/myocardial infarction/stroke composite endpoint event by 16% after 12 months of treatment, and the benefits mainly occurred in cardiovascular death and myocardial infarction, with the relative risk reduced by 21% and 16% respectively.In addition, the effect appeared at the early stage of treatment (absolute risk decreased by [ARR] 1.0% and relative risk decreased by [RRR] 12% at 30 days), and the effect persisted throughout the 12 months.This suggests that it is appropriate to treat ACS patients with tegrilol for up to 12 months.On the basis of the PLATO study, a number of subgroup analyses were also carried out, including weight, gender, diabetes history, transient ischemic attack or non hemorrhagic stroke, or revascularization, combined drug treatment, final diagnosis of indicative events, and treatment routes to be carried out at random.The results of these studies consistently demonstrate that the therapeutic effect of Tigrilol is superior to that of clopidogrel.In terms of safety, the incidence of major bleeding was similar in the Tigrilol group and the clopidogrel group (11.6% and 11.2%, respectively, P=0.43).[3]
Toxicological data
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Genotoxicity:
The results of Tigrilol Ames test, mouse lymphoma test and rat micronucleus test were negative.The results of Ames test and mouse lymphoma test of O-demethylation metabolite of Tigrilol activity were negative.[3]
Reproductive toxicity:
Male and female rats were orally administered with tegrenol at doses of 180 and 200 mg/kg/day respectively (calculated according to AUC, equivalent to 90 mg of the maximum recommended human dose for 60 kg people, and>15 times the exposure at MRHD twice a day), and no significant impact on fertility was found.The incidence of abnormal estrous cycle in female rats increased when the dose was ≥ 10 mg/kg/day (calculated according to AUC, equivalent to 1.5 times the exposure amount in MRHD).
In the fetal development toxicity test of pregnant rats, 20 ～ 300 mg/kg/day (calculated by mg/m2, 20 mg/kg/day is equivalent to MRHD) was administered orally.In the 300 mg/kg/day (calculated by mg/m2, equivalent to 16.5 times of MRHD) dose group, abnormal offspring can be seen, including increased liver lobes and ribs, incomplete sternal ossification, pelvic joint dislocation and sternal deformity.Pregnant rabbits were given Tigrilol for 21 ～ 63 mg/kg/day. At high doses (calculated in mg/m2, equivalent to 6.8 times of MRHD), gallbladder development was delayed and hyoid, pubic and sternal ossification was incomplete.[3]
Perinatal toxicity
In the experiment, pregnant rats were given tigrilol at a dose of 10-180 mg/kg/day, and at a high dose (calculated by mg/m2, equivalent to 10 times of MRHD), the death of the young and the effect on the growth of the young could be seen.10 and 60 mg/kg/day (calculated in mg/m2, equivalent to 1.5 and 3.2 times of MRHD) can see relatively slight effects, including ear opening and eye opening time delay.[3]
Carcinogenicity:
In mice and male rats, the oral doses of tegrenol were 250 mg/kg/day and 120 mg/kg/day respectively (calculated according to AUC, equivalent to 19 times and 15 times of the exposure during MRHD, respectively), and there was no increase in the incidence of tumor related to administration.In female rats, the incidence of uterine cancer, uterine adenocarcinoma and hepatocellular adenoma increased when the dose was 180 mg/kg/day (calculated according to AUC, equivalent to 29 times of the exposure amount in MRHD), while the incidence of tumor did not increase when the dose was 60 mg/kg/day (8 times of AUC in MRHD).[3]
Pharmacokinetics
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General characteristics:
The pharmacokinetics of tigrenol is linear, and the exposure of tigrenol and its active metabolite (AR-C124910XX) is roughly proportional to the dosage.[3]
Absorption:
Tegrelot absorbed rapidly, and the median Tmax was about 1.5 hours.Tigrilol can rapidly produce its main circulating metabolite AR-C124910XX (also active substance), with a median Tmax of about 2.5 hours (1.5~5.0).In the dose range studied (30 ～ 1260 mg), the Cmax and AUC of tigrenol and its active metabolite increased roughly in proportion to the dosage.
The average absolute bioavailability of Tigrilol was about 36% (range 25.4% to 64.0%).The intake of high-fat food can increase AUC of tegrilol by 21% and decrease Cmax of active metabolite by 22%, but has no effect on Cmax of tegrilol or AUC of active metabolite.It is generally believed that these minor changes are of little clinical significance, so Tigrilol can be taken before or after meals.[3]
Distribution:
The steady-state distribution volume of Tigrilol is 87.5L.Tegralol and its metabolites are extensively bound to human plasma proteins (>99%).[3]
Metabolism:
Tegrelot is mainly metabolized by CYP3A4, and a small part is metabolized by CYP3A5.
The main metabolite of Tigrilol is AR-C124910XX, which is also active in vitro and can bind to P2Y12ADP receptor of platelet.The systemic exposure of active metabolites is about 30-40% of that of Tigrilol.[3]
Excretion:
Tegralol is mainly eliminated through liver metabolism.The average recovery rate of radiation measured by using Tegrelot radioactive tracer is about 84% (57.8% in feces, 26.5% in urine).The recovery rate of tegrenol and its active metabolites in urine was less than 1% of the dosage.The main elimination pathway of active metabolites is bile secretion.The average t1/2 of tigrilol is about 7 hours, and the active metabolite is 9 hours.[3]
Special population:
aged:Population pharmacokinetic analysis showed that, compared with young subjects, the exposure of tigrenol in elderly patients with ACS (>75 years old) increased (Cmax and AUC were about 25%), and the exposure of active metabolites also increased.These differences have no clinical significance.
Children patients:Tigrilol has not been evaluated in a child population.[3]
Gender:
Compared with male patients, female patients had higher exposure to tegrenol (Cmax and AUC were 52% and 37%, respectively) and its active metabolites (Cmax and AUC were about 50%).These differences have no clinical significance.[3]
Kidney damage:
Compared with subjects with normal renal function, the exposure of tigrenol and its active metabolites in patients with severe renal damage (creatinine clearance rate<30ml/min) was 20% lower.[3]
Liver damage:
Compared with healthy subjects, the Cmax and AUC of Tigrenol in patients with mild liver damage were 12% and 23% higher respectively.Tigrilol has not been studied in patients with moderate or severe liver damage.[3]
Race:
The average bioavailability of Asian patients was 39% higher than that of Caucasian patients.The bioavailability of tegrenol in self identified black patients was 18% lower than that in Caucasian patients.In the clinical pharmacology study, the exposure (Cmax and AUC) of tegrenol in Japanese subjects was about 40% higher than that in Caucasians (about 20% after weight adjustment), and the exposure of tegrenol in healthy Chinese subjects was 40% higher than that in Caucasians.[3]
indication
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This product is used for patients with acute coronary syndrome (unstable angina, non ST segment elevation myocardial infarction or ST segment elevation myocardial infarction), including patients receiving drug treatment and percutaneous coronary intervention (PCI), to reduce the incidence of thrombotic cardiovascular events.Compared with clopidogrel, this product can reduce the incidence of cardiovascular death, myocardial infarction or stroke composite endpoint. The difference between the two treatment groups comes from cardiovascular death and myocardial infarction, but there is no difference in stroke.
In ACS patients, the combination of this product and aspirin was studied.The results showed that the maintenance dose of aspirin greater than 100 mg would reduce the clinical efficacy of tegrenol in reducing composite endpoint events. Therefore, the maintenance dose of aspirin should not exceed 100 mg per day.[3]
contraindication
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one
Allergic to Tigrilol or any auxiliary ingredient of this product.
two
Patients with active pathological bleeding (such as peptic ulcer or intracranial hemorrhage).
three
History of intracranial hemorrhage
four
Patients with moderate to severe liver damage
five
Because the combined use of tegrenol can lead to a significant increase in the exposure of tegrenol, it is prohibited to use tegrenol tablets in combination with powerful CYP3A4 inhibitors (such as ketoconazole, clarithromycin, nefazodone, ritonavir and azanavir).[3]
Usage and dosage
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Oral.This product can be taken before or after meals.
The initial dose of this product is 180 mg (90 mg × 2 tablets) for a single load, and then one tablet (90 mg) for each time, twice a day.
Unless there is a clear contraindication, this product should be used in combination with aspirin.After taking the first dose of loaded aspirin, the maintenance dose of aspirin is 75-100 mg once a day.
Patients with ACS who have received an overload dose of clopidogrel can begin to use tegrilol.
During treatment, try to avoid leakage.If a patient misses a dose, a 90 mg tablet (the patient's next dose) should be taken at the scheduled time for the next dose.
The treatment time of this product can be up to 12 months, unless there are clinical indications to stop the treatment of this product.
Early termination of any antiplatelet drugs (including this product) in patients with acute coronary syndrome may increase the risk of cardiovascular death or myocardial infarction caused by underlying diseases. Therefore, early termination of treatment should be avoided.[3]
Adverse reactions
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The safety of tegrenol tablets was evaluated in 10000 patients, including more than 3000 patients who had been treated for more than one year.Among the patients treated with tegrilol, the most frequently reported adverse reactions were dyspnea, contusion and epistaxis, and the incidence of these events was higher than that of patients in the clopidogrel group.
Other common adverse reactions are gastrointestinal bleeding, subcutaneous or dermal bleeding, ecchymosis and bleeding at the operation site. Occasional adverse reactions are: intracranial bleeding, dizziness and headache, eye bleeding, hemoptysis, hematemesis, gastrointestinal ulcer bleeding, hemorrhoid bleeding, gastritis, oral bleeding, vomiting, diarrhea, abdominal pain, nausea, indigestion, pruritus, rash, urethral and vaginal bleedingBleeding after operation;The rare adverse reactions were hyperuricemia, confusion, paresthesia, ear hemorrhage, dizziness, retroperitoneal hemorrhage, constipation, joint hematocele, elevated serum creatinine, wound hemorrhage, and traumatic hemorrhage.In the PLATO study, 6.0% of patients with ventricular intermittence in the acute phase in the Tigrilol group;One month later, the incidence of ventricular intermission was 2.2%.Details of relevant adverse reactions are as follows:
CABG related bleeding:In the PLATO study, 1584 patients (12% of the cohort) underwent coronary artery bypass grafting (CABG) surgery, of which 42% had major fatal/life-threatening bleeding in PLATO, and there was no difference between the two treatment groups.Fatal CABG bleeding occurred in 6 patients in each group.
Non CABG related bleeding and non procedure related bleeding:There was no difference in the incidence of major fatal/life-threatening bleeding defined by PLATO -, which was not associated with CABG, between the tegrilol and clopidogrel groups, but the overall major bleeding, TIMI major bleeding, and TIMI major+minor bleeding defined by PLATO were more common in the tegrilol group.Similarly, after removing all procedure related bleeding, more bleeding occurred in the tegrilol group than in the clopidogrel group (Table 2).The incidence of discontinuation of treatment due to non procedure related bleeding in the tigrilol group (2.9%) was higher than that in the clopidogrel group (1.2%; p<0.001).
Intracranial hemorrhage:The number of intracranial non operational bleeding in the tegrilol group (26 patients had 27 bleeding, 0.3%) was more than that in the clopidogrel group (n=14 bleeding, 0.2%), of which 11 bleeding in the tegrilol group and 1 bleeding in the clopidogrel group were fatal.There was no difference in overall fatal bleeding between the two groups.
dyspnea:Dyspnea (feeling shortness of breath) was reported in patients treated with tegrenol.In the PLATO study, 13.8% and 7.8% of patients in the Tigrilol group and clopidogrel group reported adverse reactions of dyspnea (including dyspnea, dyspnea at rest, exertional dyspnea, paroxysmal nocturnal dyspnea and nocturnal dyspnea).The researchers believe that the dyspnea of 2.2% of patients in the Tigrilol group and 0.6% of patients in the Clopidogrel group has a causal relationship with the treatment received, and a few of them are serious adverse reactions (0.14% in the Tigrilol group and 0.02% in the Clopidogrel group).The symptoms of dyspnea are mostly mild to moderate, and most of them occur in a single attack at the early stage after treatment.
Compared with clopidogrel, patients with asthma/COPD treated with tegrilol have an increased risk of non severe dyspnea (3.29% in the tegrilol group and 0.53% in the clopidogrel group) and severe dyspnea (0.38% in the tegrilol group and 0.00% in the clopidogrel group).In terms of absolute value, the risk of this group is higher than that of the general PLATO population.
About 30% of these dyspnea events were eliminated within 7 days.PLATO includes patients with congestive heart failure, chronic obstructive pulmonary disease or asthma at baseline, and more of these patients and elderly patients report dyspnea.0.9% of the patients in the Tigrilol group stopped the study drug due to dyspnea, and 0.1% in the clopidogrel group.The higher incidence of dyspnea in the Tigrilol group was not associated with new or worsening cardiopulmonary disease.Tegralol had no effect on pulmonary function test.[3]
laboratory examination
Creatinine levels rise:In the PLATO study, the serum creatinine concentration of 25.5% and 21.3% patients in the Tigrilol group and clopidogrel group increased significantly by more than 30%;The serum creatinine concentration of 8.3% and 6.7% patients increased significantly by more than 50%.The increase of creatinine>50% was more significant in patients>75 years old (13.6% of Tigrilol compared with 8.8% of clopidogrel), patients with severe renal injury at baseline (17.8% of Tigrilol compared with 12.5% of clopidogrel), and patients receiving ARB combined with medication (11.2% of Tigrilol compared with 7.1% of clopidogrel).In these subgroups, renal related serious adverse events and adverse events leading to discontinuation of the study drug were similar in both groups.The total number of renal adverse events reported by the Tigrilol group was 4.9%, and that of the Clopidogrel group was 3.8%. However, the researchers believed that the incidence of events related to the treatment was similar between the two groups: 54 (0.6%) in the Tigrilol group and 43 (0.5%) in the Clopidogrel group.
Elevated uric acid level:In the PLATO study, the serum uric acid concentration of 22% and 13% patients in the Tigrilol group and the clopidogrel group respectively increased beyond the normal upper limit. The average serum uric acid concentration in the Tigrilol group increased by about 15%, and that in the clopidogrel group was about 7.5%. After stopping the treatment, the serum uric acid concentration in the Tigrilol group decreased to about 7%, while that in the clopidogrel group did not decrease.The incidence of adverse events of hyperuricemia reported by Tigrilol group was 0.5%, and that of clopidogrel group was 0.2%.Among these adverse events, 0.05% in the Tigrilol group and 0.02% in the clopidogrel group were considered to be cause and effect related to the treatment.The adverse events of gouty arthritis reported by Tegrelot group were 0.2%, and those reported by clopidogrel group were 0.1%. The investigator assessed that these adverse events were not causal related to the treatment.
Bradycardia:Clinical studies have shown that tegrenol can increase the slow arrhythmia (including ventricular interval) detected by Holter.PLATO excluded patients with increased risk of bradycardia events (such as patients with sick sinus syndrome, 2nd or 3rd degree AV block or syncope due to bradycardia without pacemaker protection).In the PLATO study, 1.7% and 1.5% of patients treated with tegrenol and clopidogrel reported syncope, presyncope and loss of consciousness, respectively.
In the Holter subgroup (about 3000 patients) of the PLATO study, in the acute phase, the number of patients (6.0%) with ventricular intermittence in the Tigrenol group was more than that in the clopidogrel group (3.5%);One month later, the incidence of ventricular intermittence was 2.2% in the Tigrilol group and 1.6% in the clopidogrel group.
Male mammary gland development:The PLATO study showed that 0.23% of male patients in the Tigrilol group reported male breast development, while 0.05% in the clopidogrel group.The PLATO study showed that there was no difference in other sex hormone related adverse reactions (including malignant tumors of sexual organs) between the two treatment groups.
Post IPO experience:Some adverse reactions were reported during the post marketing use of this product.Since these reactions are all spontaneous reports from people with uncertain sample size, it is impossible to reliably estimate the incidence of these adverse reactions.
Immune system diseases – allergic reactions, including vascular edema.[3]
matters needing attention:
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Bleeding risk
In the phase 3 key test (PLATO [Platelet inhibition and patient results], 18624 patients), the key exclusion criteria included increased risk of bleeding in the past 6 months, clinically significant thrombocytopenia or anemia, previous intracranial hemorrhage, gastrointestinal bleeding, or major surgery in the past 30 days.In patients with acute coronary syndrome treated with tegrilol and aspirin, the risk of non CABG major bleeding is increased, and bleeding requiring clinical attention (non lethal or life-threatening "major+secondary PLATO bleeding") is also more common.
Therefore, we should measure the balance between the known increase in bleeding risk of patients treated with tegrilol and the benefits of preventing atherothrombotic events.If there is clinical evidence, the following patients should be cautious in using tegrenol:
1. Patients with bleeding tendency (such as recent trauma, recent surgery, coagulation dysfunction, active or recent gastrointestinal bleeding) should use this product with caution.This product is prohibited for patients with active pathological bleeding, patients with a history of intracranial hemorrhage, and patients with moderate to severe liver damage.
2. Patients who use other drugs that may increase the risk of bleeding (such as non steroidal anti-inflammatory drugs (NSAIDS), oral anticoagulants and/or fibrinolytic solvents) within 24 hours after taking Tigrilol tablets should use this product with caution.
At present, there is no data about the hemostatic effect of tegrenol on platelet component transfusion;Circulating tegrenol may inhibit transfused platelets.Since the combination of tegrenol and desmopressin does not reduce the bleeding time of template method, desmopressin may have no effect on clinical bleeding events.
Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may enhance hemostasis.After determining the cause of bleeding and controlling the bleeding, Tigrilol tablets can be reused.[3]
operation
Every patient should be informed that they are using Tigrilol before they are about to undergo any scheduled surgery and before taking any new drugs.
In the PLATO study, for patients undergoing coronary artery bypass grafting (CABG), tegrenol caused more bleeding events than clopidogrel when the drug was stopped one day before surgery, but when the drug was stopped two or more days before surgery, the incidence of major bleeding events was similar between the two groups.For patients undergoing elective surgery, if antiplatelet drug treatment is not necessary, Tigrilol should be stopped 7 days before surgery.[3]
Patients at risk of bradycardia events
Since asymptomatic ventricular intervals are often observed in early clinical studies, patients with high risk of bradycardia events (such as patients with sick sinus syndrome, 2nd or 3rd degree atrioventricular block or bradycardia related syncope but without pacemaker) were excluded from the main study PLATO to evaluate the safety and effectiveness of tegrilol.Due to the limited clinical experience in these patients, Tigrilol should be used with caution.
In addition, care should also be taken when tegrenol is used in combination with drugs known to cause bradycardia.However, in the PLATO test, when combined with one or more known drugs that can cause bradycardia (such as 96% beta receptor blocker, 33% calcium channel blocker diltiazem and verapamil, and 4% digoxin), no clinically significant adverse events were observed.
During the Holter subgroup study of PLATO, in the acute phase of ACS, there were more patients with ventricular intermission>3 seconds in the tegrilol group than in the clopidogrel group.In the acute phase of ACS, Holter monitoring found that the increase of ventricular intermittence in patients with chronic heart failure (CHF) was higher than that in the overall study population in the Tigrilol treatment group, but this situation did not occur after one month of treatment with Tigrilol or compared with clopidogrel.In this patient population, there were no adverse clinical outcomes associated with this imbalance, including syncope and pacemaker implantation.[3]
dyspnea
13.8% of patients treated with tegrilol reported dyspnea, and 7.8% of patients treated with clopidogrel.The researchers believe that there is a causal relationship between the dyspnea of 2.2% of patients and Tigrilol.It is usually mild to moderate dyspnea and can be relieved without stopping the medicine.Patients with asthma/COPD may have an increased absolute risk of dyspnea during the treatment of tegrilol. Patients with asthma and/or COPD history should use tegrilol with caution.The mechanism of dyspnea caused by this product is still unclear.If the patient reports new, persistent or aggravated dyspnea, it should be carefully studied. If it is intolerable, the treatment of this product should be stopped.
In a subgroup study, 199 patients in the PLATO trial (whether or not they reported dyspnea) were examined for pulmonary function, and there was no significant difference in FEV1 between the two treatment groups.There is no adverse effect on pulmonary function measured after long-term treatment for 1 month or at least 6 months.[3]
Drug withdrawal
Discontinuation of Tigrilol treatment should be avoided.If it is necessary to temporarily stop Tigrilol (such as treating bleeding or elective surgery), treatment should be restarted as soon as possible.Discontinuation of tegrenol will increase the risk of myocardial infarction, stent thrombosis and death.[3]
Increased creatinine level
Creatinine levels may increase during tegrilol treatment, but the pathogenesis is still unclear.After one month of treatment, the renal function should be checked. Later, the renal function should be checked according to the needs of routine treatment. Special attention should be paid to patients ≥ 75 years old, patients with moderate/severe renal damage, and patients receiving ARB combined treatment.
Increased blood uric acid
In the PLATO study, the risk of hyperuricemia in patients treated with tegrenol was higher than that in patients treated with clopidogrel.Tigrilol should be used with caution for patients with previous hyperuricemia or gouty arthritis.To be cautious, Tigrilol is not recommended for patients with uric acid nephropathy.[3]
other
Based on the relationship between the maintenance dose of aspirin observed in the PLATO test and the efficacy of tegrenol compared with clopidogrel, the combination of tegrenol and aspirin with a maintenance dose>100 mg is not recommended (see [Clinical Trial]).
The combined use of tigrilol and CYP3A4 strong inhibitors (such as ketoconazole, clarithromycin, naftazolone, ritonavir and azanavir) should be avoided, because the combined use may significantly increase the exposure of tigrilol (see [Drug Interaction]).
It is not recommended to use tegrilol in combination with CYP3A4 strong inducers (such as rifampicin, dexamethasone, phenytoin, carbamazepine and phenobarbital), because combined use may lead to decreased exposure and effectiveness of tegrilol.
It is not recommended to use tegrilol in combination with CYP3A4 substrates with narrow therapeutic index (i.e. cisapride and ergot alkaloids), because tegrilol may increase the exposure of these drugs.
It is not recommended to use tegrenol in combination with simvastatin or lovastatin greater than 40 mg.
Close clinical and laboratory monitoring is recommended when digoxin is used in combination with tegrenol.There is no data on the possible increase of tegrenol exposure in combination with powerful P-glycoprotein (P-gp) inhibitors (such as verapamil, quinidine, cyclosporine).If the combination of drugs cannot be avoided, the drug should be administered with caution.[3]
Impact on ability to drive and operate the machine
At present, there is no research on the influence of Tigerlot on driving and mechanical operation ability.Tegrello has no or only minor impact on driving and mechanical operation ability.
It is reported that dizziness and confusion may occur during the treatment of acute coronary syndrome. Therefore, patients with these symptoms should be very careful when driving or operating machinery.
Drugs for pregnant and lactating women
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gestation
There is no control study on the use of tegrenol in pregnant women.Animal studies have shown that when the mother receives about 5 to 7 times the maximum recommended dosage (MRHD, according to the body surface area), tegrenol will cause fetal malformation.Tigrilol should only be used during pregnancy if the potential benefits outweigh the risks to the fetus.[3]
lactation
Whether tegrenol or its active metabolites will be secreted into human milk is still unknown.Tigrilol can be secreted through rat milk.Since many drugs can be secreted into human milk, and Tigrilol may have potentially serious adverse reactions to breast-feeding infants, it is necessary to decide whether to stop breast-feeding or discontinue the drug after considering the importance of Tigrilol to mothers.[3]
Children's medication
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The safety and effectiveness of this product for children under 18 years of age have not been established.
Medication for the elderly
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Elderly patients do not need to adjust the dose.See [Usage and Dosage].
In the PLATO study, 43% of patients were ≥ 65 years old and 15% were ≥ 75 years old.The relative risk of bleeding was similar across treatment and age groups.
There was no difference in safety or effectiveness between elderly patients and young patients.However, according to clinical experience, it cannot be determined that the difference in efficacy between the elderly and young patients is consistent, and some elderly patients are more sensitive to drugs cannot be excluded.
Drug interaction
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Tegrelot is mainly metabolized by CYP3A4, and a small part is metabolized by CYP3A5.[3]
Effects of other drugs on Tigrilol:
CYP3A inhibitor:Combined use of ketoconazole could increase the Cmax and AUC of telogrello by 2.4 and 7.3 times respectively, and decrease the Cmax and AUC of active metabolites by 89% and 56% respectively;Other strong inhibitors of CYP3A4 will have similar effects.The combination of this product with CYP3A potent inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nefenavir, indinavir, azanavir and telithromycin) should be avoided (see [Contraindications] and [Pharmacokinetics]).
CYP3A inducer:Combined use of rifampicin reduced the Cmax and AUC of telogrello by 73% and 86%, respectively. The Cmax of active metabolite did not change, and the AUC decreased by 46%.Other CYP3A4 inducers (such as dexamethasone, phenytoin, carbamazepine and phenobarbital) are also expected to reduce the exposure of tegrilol.This product should not be used in combination with CYP3A potent inducer.
aspirin:When combined with aspirin at a maintenance dose greater than 100 mg, the clinical efficacy of tegrenol in reducing composite endpoint events will be reduced.Others: clinical pharmacological interaction studies show that when Tigrenol is used in combination with heparin, enoxaparin, aspirin or desmopressin, compared with Tigrenol alone, it has no effect on platelet aggregation induced by PK and ADP of Tigrenol or its active metabolite.[3]
Effects of Tegralol on other drugs:
Tegrelot is an inhibitor of CYP3A4/5 and P-glycoprotein transporter.
Simvastatin, Lovastatin:Because it is metabolized by CYP3A4, tegrenol can increase its serum concentration.Tegrelol increased Cmax of simvastatin by 81%, AUC by 56%, Cmax of simvastatin acid by 64%, AUC by 52%, and some patients increased to 2-3 times.Simvastatin had no effect on the plasma concentration of tegrenol.Tigrilol may have a similar effect on lovastatin.When used together with tegrilol, the dosage of simvastatin and lovastatin should not be more than 40 mg.
Atorvastatin:The combination of atorvastatin and tegrenol can increase the Cmax of atorvastatin acid by 23% and AUC by 36%.AUC and Cmax of all atorvastatin acid metabolites will also show a similar increase.Considering these increases is not clinically significant.
Drugs metabolized by CYP2C9:The plasma concentration of tegrenol and tolbutamide did not change when they were used together, suggesting that tegrenol is not an inhibitor of CYP2C9 and is unlikely to change the metabolism of drugs mediated by CYP2C9 (such as warfarin and tolbutamide).
Oral contraceptives:Tegrelol combined with levonorgestrel and ethinylestradiol will increase the exposure of ethinylestradiol by about 20%, but will not change the PK of levonorgestrel.When Tigrilol is used in combination with levonorgestrel and ethinylestradiol, it is not expected to have a clinically significant impact on the effectiveness of oral contraceptives.
Digoxin (P-gp substrate):The combination of tegrenol and digoxin can increase the Cmax and AUC of the latter by 75% and 28% respectively.Therefore, it is recommended that appropriate clinical and/or laboratory monitoring should be carried out when Tigrilol is used in combination with P-gp dependent drugs with a narrow treatment index (such as digoxin and cyclosporine).
Combined treatment with other drugs:
Drugs known to induce bradycardia:Since asymptomatic ventricular intermittence and bradycardia were observed, it should be used with caution when tegrenol is combined with drugs known to induce bradycardia.
In PLATO research, Tegrelot is often used in combination with aspirin, proton pump inhibitors, statins, beta blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers for long-term treatment of concomitant diseases, and heparin, low molecular weight heparin and intravenous GpIIb/IIIa inhibitors for short-term treatment of concomitant diseases.No clinically significant adverse effects related to these drugs were observed.The combination of tigrenol with heparin, enoxaparin or deamopressin had no effect on the determination of activated partial thrombin time (aPTT), activated coagulation time (ACT) or factor Xa content.However, due to the potential pharmacodynamic interaction, care should be taken when Tigrenol is used in combination with drugs known to change hemostasis.
As abnormal bleeding was reported in SSRI treatment (such as paroxetine, sertraline and citalopram), it is recommended that SSRI should be used with caution in combination with tegrilol, which may increase the risk of bleeding.[3]
Overdose
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At present, there is no antidote to reverse the effect of tegrenol, and it is expected that tegrenol cannot be cleared through dialysis (see [Precautions]).Overdose should be disposed of in accordance with local standard medical practice.Hemorrhage is an expected pharmacological effect of drug overdose. If bleeding occurs, appropriate supportive treatment measures should be taken.
Tigrilol tablets were well tolerated at a single dose up to 900 mg.The results of single dose incremental study show that the dose limiting reaction of this product is gastrointestinal toxicity, including nausea, vomiting, diarrhea, etc.Other adverse reactions with clinical significance that may be caused by drug overdose include dyspnea and ventricular arrest. ECG monitoring should be carried out.[3]
