Pradaxa

[Drug name]

Common name: Dabigatran Etexilate capsules

Trade name: Pradaxa

English name: Dabigatran Etexilate Capsules

Chinese Pinyin: dabijiaqunzhijiaonang

[Ingredients]

Dabigatran etexilate. Molecular formula: C34H41N7O5CH4O3S Molecular weight: 723.86 (methanesulfonate), 627.75 (free substance)

[Properties]

This product is a capsule, and the content is yellow granules.

[Indications]

Prevention of stroke and systemic embolism (SEE) in adult patients with non-valvular atrial fibrillation who have one or more of the following risk factors: Previous stroke, transient ischemic attack or systemic embolism; left ventricular ejection fraction = grade 2; age >= 75 years old; age >= 65 years old, and accompanied by any of the following diseases: diabetes, coronary heart disease or hypertension

[Dosage and Dosage]

Take with water, with or after meals. Do not open capsules. The recommended dose for adults is 300 mg taken orally daily, i.e. one 150 mg capsule twice daily, and should be maintained for life-long treatment.

Special groups:

(1) Patients with bleeding risk

The factors that increase the risk of bleeding are listed below: For example, age ≥75 years old, moderate renal insufficiency [creatinine clearance (CrCL) 30~ 50ml/min], or receiving combined treatment with a potent P-glycoprotein (P-gp) inhibitor (see Special Populations in "Pharmacokinetics"), combined treatment with antiplatelet drugs, or previous gastrointestinal bleeding (see "Precautions"), etc. For patients with one or more of the above risk factors, physicians may consider reducing the patient's daily dose to 220 mg, i.e., one 110 mg capsule twice daily.

(2) Patients with renal insufficiency

Before starting treatment with this product, renal function should be evaluated by calculating creatinine clearance, and patients with severe renal insufficiency (i.e. CrCL <30ml/min) should be excluded from use; treatment with this product is not recommended in these groups (see "Contraindications").

Patients with mild or moderate renal insufficiency do not need to adjust the dose. For patients with moderate renal insufficiency (creatinine clearance 30-50ml/min), renal function evaluation should be performed at least once a year. Renal function should be assessed during treatment when there are clinical conditions that may decrease or worsen renal function (e.g., volume depletion, dehydration, and certain concomitant medications).

Dabigatran is cleared by dialysis; clinical experience with this approach in clinical trials is limited.

(3) Elderly patients

The treatment dose for patients aged 80 and above is 220 mg per day, that is, one 110 mg capsule each time, twice a day.

Pharmacokinetic studies in the elderly have shown increased drug exposure in patients with age-related decreases in renal function.

Because renal function impairment is common in elderly patients (>75 years old), renal function should be evaluated by calculating creatinine clearance before starting treatment with this product, and patients with severe renal insufficiency (i.e., CrCL <30ml/min) should be excluded. See Dosage in Patients with Renal Impairment.

(4) Switching therapy with other drugs

Switching from this product to parenteral anticoagulant therapy

Switching from this product to parenteral anticoagulant therapy should be performed 12 hours after the last administration of this product.

Converting from parenteral anticoagulation therapy to this product

This product should be taken within 2 hours before the next treatment time. If the patient is receiving maintenance therapy (such as intravenous unfractionated heparin), this product should be taken when the drug is stopped.

Switching from vitamin K antagonists to treatment with this product

Vitamin K antagonists should be discontinued. When the INR (international normalized ratio of prothrombin) is <2.0, this product can be treated immediately.

Switching from this product to vitamin K antagonist treatment:

The decision to start vitamin K antagonist (VKA) treatment should be based on the patient's creatinine clearance rate:

·When CrCL ≥ 50 ml/min, start VKA treatment 3 days before stopping dabigatran etexilate;

·When 30 ml/min ≤ CrCL < 50 ml/min, give VKA treatment 2 days before stopping dabigatran etexilate.

(5) Others

Cardioversion: During the process of cardioversion, the treatment with this product can be maintained.

Missed dose: If it is more than 6 hours before the next dose, you can still take the missed dose of this product. If it is less than 6 hours before the next dose, the missed dose should be ignored. Do not give a double dose of a medicine to make up for a missed dose.

[Adverse Reactions]

In the key study examining the effect of dabigatran etexilate in preventing stroke and SEE in patients with atrial fibrillation, a total of 1209 people were randomly enrolled. 1 patient, 12,042 patients received dabigatran etexilate, 6,059 patients received dabigatran etexilate 150 mg twice a day, and 5,983 patients received 110 mg twice a day. A total of 22% of patients with atrial fibrillation who received stroke or SEE prophylaxis (long-term treatment for up to 3 years) experienced adverse effects. The most commonly reported adverse reaction was bleeding, which occurred in approximately 16.5% of patients with atrial fibrillation receiving stroke and SEE prophylaxis. Although infrequent in clinical trials, major or severe bleeding can occur, and bleeding from any location can lead to disabling, life-threatening, or fatal outcomes. Major bleeding is defined as meeting one or more of the following criteria: bleeding accompanied by a drop in hemoglobin level of at least 20g/L, or bleeding requiring blood transfusion or bleeding of at least 2 units of blood cells. Symptomatic bleeding in critical areas or organs: intraocular, intracranial, spinal canal or intramuscular bleeding with compartment syndrome, retroperitoneal bleeding, intraarticular bleeding or pericardial bleeding. Major bleeding that meets one or more of the following criteria is called life-threatening bleeding: fatal bleeding, symptomatic intracranial hemorrhage; bleeding accompanied by a drop in hemoglobin of at least 50g/l; bleeding requiring blood transfusion or blood cells of at least 4 units; bleeding accompanied by hypotension requiring intravenous vasopressors; bleeding requiring surgical treatment. Patients randomized to receive dabigatran etexilate 110 mg twice daily had a significantly reduced risk of overall inadvertent, life-threatening bleeding and intracranial hemorrhage compared with those receiving warfarin (P<0.05). Compared with warfarin, subjects randomized to receive dabigatran etexilate 110 mg twice daily had a significantly lower risk of major bleeding (hazard ratio 0.80, [P=0.0026]). Compared with warfarin, subjects randomized to receive dabigatran etexilate 150 mg twice daily had a significantly increased risk of major gastrointestinal bleeding (hazard ratio 1.47, [p=0.0008]), primarily in patients ≥75 years of age. All subgroups (e.g., renal impairment, age, combined use of antiplatelet drugs or P-gp inhibitors) showed benefits of dabigatran compared with warfarin in preventing stroke and SEE, as well as a reduced risk of intracranial hemorrhage (ICH). In specific patient subgroups with an increased risk of major bleeding when treated with anticoagulants, the excess bleeding risk with dabigatran is due to gastrointestinal bleeding, which generally occurs in the first 3 to 6 months after initiation of dabigatran etexilate therapy. Myocardial infarction In the RE-LY study, the annualized event rate of myocardial infarction was 0.82% for dabigatran etexilate 110 mg twice daily and 0.81% for dabigatran etexilate 150 mg twice daily, and 0.64% for warfarin (see Clinical Trials).

【Taboo】

People who are known to be allergic to the active ingredients or any excipients of this product. ·Patients with severe renal insufficiency (CrCL <30ml/min) (see "Dosage and Dosage"). ·Clinically significant active bleeding. ·Diseases or conditions that pose a significant risk of major bleeding, such as current or recent peptic tract ulcers, malignant growths with a high risk of bleeding, recent brain or spinal cord injury, recent brain, spinal cord, or eye surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities. ·Combined application of any other anticoagulant drugs, such as unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux sodium, etc.), oral anticoagulants (warfarin, rivaroxaban, apixa classes, etc.), except in situations where there is a switch from that therapy to FUNA or vice versa (see "Dosage and Administration"), and at doses necessary to maintain patency of central venous or arterial catheters (see "Drug Interactions"). ·Hepatic insufficiency or liver disease that is expected to affect survival time. Coadministration of cyclosporine, systemic ketoconazole, itraconazole, tacrolimus, and dronedarone (see Drug Interactions). · Mechanical prosthetic valve (see "Precautions").

[Notes]

Patients with elevated liver enzymes ≥2ULN (upper limit of normal) were excluded from clinical trials of atrial fibrillation-related stroke and SEE prevention in hepatic insufficiency. There is no experience in treating this patient subgroup, so this product is not recommended for this population. Bleeding risk As with all other anticoagulants, dabigatran etexilate should be used with caution when the risk of bleeding is increased. Bleeding can occur anywhere during treatment with dabigatran etexilate. If there is an unexplained decrease in hemoglobin and/or hematocrit, attention should be paid to searching for the site of bleeding. The following factors are related to increased plasma concentrations of dabigatran: Decreased renal function (CrCL 30-50ml/min), age ≥75 years, low body weight <50kg, or combined use of strong P-gp inhibitors (such as amiodarone, quinidine or verapamil) (see "Dosage and Dosage", "Drug Interactions" and "Pharmacokinetics".) In a study to prevent non-valvular disease In studies of stroke and SEE in adults with atrial fibrillation, dabigatran was associated with a higher incidence of major gastrointestinal (GI) bleeding. Dabigatran etexilate 150 mg twice daily was associated with a statistically significant increase in the incidence of major bleeding. This increased risk was seen in older patients (≥75 years of age). The risk of gastrointestinal bleeding is increased with use of acetylsalicylic acid (ASA), clopidogrel, or nonsteroidal anti-inflammatory drugs (NSAIDs) and the presence of esophagitis, gastritis, or gastroesophageal reflux requiring treatment with proton pump inhibitors (PPIs) or histamine 2 (H2)-blockers. In these patients with atrial fibrillation, a dose of dabigatran etexilate 220 mg daily as one 110 mg capsule twice daily should be considered (see Dosage and Administration). Consider using PPIs to prevent GI bleeding. The risk of bleeding may be increased in patients taking concomitant selective serotonin reuptake inhibitors (SSRIs) or selective serotonin norepinephrine reuptake inhibitors (SNRIs) (see Drug Interactions). Close clinical monitoring (monitoring for signs of bleeding or anemia) is recommended throughout the treatment period, especially if concomitant risk factors are present (see Pharmacology and Toxicology). Table 3 summarizes factors that may increase the risk of bleeding. Please also see contraindications under "Contraindications".

[Drug use in special populations]

Children's precautions:

There is no relevant application in children for the following indications of this product; prevention of stroke and SEE in patients with non-valvular atrial fibrillation. Due to the lack of safety and efficacy data on the use of this product in patients under 18 years of age, this product is not recommended for use in patients under 18 years of age.

Precautions during pregnancy and lactation:

Pregnancy There are insufficient data on the exposure of pregnant women to this product. Animal studies have shown reproductive toxicity (see Toxicological Studies in Pharmacology and Toxicology). Whether there is a potential risk to humans is unknown. Pregnancy should be avoided in women of childbearing potential receiving dabigatran etexilate. Pregnant women should not receive this product unless necessary. Breastfeeding There are no clinical data on the effects of dabigatran on the nursing infant. Breastfeeding should be stopped during treatment with this product. Fertility No human trial data available. In animal studies, effects on female fertility were manifested by decreased implantation numbers and increased preimplantation losses at 70 mg/kg (a level 5 times higher than patient plasma exposure levels). No other effects on female animal fertility were observed. Has no effect on male animal fertility. At maternally toxic doses (levels 5 to 10 times higher than patient plasma exposure levels), reduced fetal weight and embryonic viability and increased fetal variability were observed in rats and rabbits. In prenatal and postnatal studies, increased fetal mortality was observed at maternally toxic dose levels (levels 4 times greater than patient plasma exposure levels).

Precautions for the elderly:

The treatment dose for patients aged 80 and above is 220mg per day, that is, one 110mg capsule each time, twice a day. See Special Populations under Dosage and Administration.

[Drug interactions]

There is little or limited experience with the following anticoagulants and antiplatelet aggregation drugs that may increase the risk of bleeding when used in combination with this product; anticoagulant drugs such as unfractionated heparin (UFH), low molecular weight heparin (LMWH), and heparin derivatives (fondaparinux sodium, desirudin), thrombolytic drugs drugs, vitamin K antagonists, rivaroxaban or other oral anticoagulants (see "Contraindications"), and antiplatelet aggregation drugs such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, sulfinpyrazone (see "Precautions"). Limited data collected from patients with atrial fibrillation from the phase III RE-LY study observed that the combined use of other oral or injectable anticoagulants, regardless of dabigatran etexilate or warfarin, increased the incidence of major bleeding by approximately 2.5-fold, primarily when switching from one anticoagulant to another (see Contraindications and Precautions). UFH may be used at doses necessary to maintain central venous or arterial catheter patency (see Contraindications). Data collected from patients with atrial fibrillation from the phase III RE-LY study (see "Clinical Trials") observed that combined use of the antiplatelet drugs ASA or clopidogrel resulted in a doubling of the incidence of major bleeding, regardless of whether dabigatran etexilate or warfarin was used (see "Precautions"). Clopidogrel: In a phase I study in healthy young male volunteers, coadministration of dabigatran etexilate and clopidogrel did not result in a further prolongation of capillary bleeding time compared with clopidogrel monotherapy. In addition, compared with monotherapy of the two, indicators such as dabigatran AUCτ,ss and Cmax,ss, coagulation indicators used to evaluate the effect of dabigatran, or indicators such as platelet aggregation inhibition, used to evaluate the effect of clopidogrel, remained essentially unchanged when used in combination. Dabigatran AUCτ,ss and Cmax,ss increased by 30% to 40% (see Precautions) with loading doses of 300 mg or 600 mg clopidogrel (see ASA paragraph below). ASA: There was a clinical phase II study that examined the impact of the combined use of dabigatran etexilate and ASA on the bleeding risk in patients with atrial fibrillation. In this study, ASA was randomly used in combination. Based on logistic regression analysis, coadministration of ASA 81 mg or 325 mg and dabigatran etexilate 150 mg twice daily may increase the risk of bleeding from 12% to 18% and 24%, respectively. (See "Notes"). NSAIDs: Coadministration of NSAIDs used for short-term analgesia in the perioperative period with dabigatran etexilate has not been shown to be associated with an increased risk of bleeding. In the RE-LY study, long-term use of NSAIDs increased the bleeding risk with dabigatran etexilate and warfarin by approximately 50%. Therefore, due to the risk of bleeding, especially when using NSAIDs with elimination half-lives >12 hours, close observation for signs of bleeding is recommended (see Precautions). LMWH: The combined use of LMWH (such as enoxaparin) and dabigatran etexilate has not been specifically studied. When switching from enoxaparin 40 mg subcutaneously for 3 days to dabigatran etexilate, dabigatran exposure 24 hours after the last enoxaparin dose was slightly lower than after dabigatran etexilate alone (220 mg alone). Greater anti-FXa/FIIa activity was observed when dabigatran etexilate was administered after enoxaparin pretreatment than when dabigatran etexilate was administered alone. This may be due to residual effects of enoxaparin treatment and is not considered clinically relevant. Pretreatment with enoxaparin did not produce significant changes in other dabigatran-related anticoagulant tests.

[Pharmacological effects] Pharmacological effects Dabigatran etexilate is a small molecule prodrug and has not shown any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran via esterase-catalyzed hydrolysis in plasma and liver. Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor and the main active ingredient in plasma. Since thrombin (serine protease) converts fibrinogen into fibrin in the coagulation cascade, inhibition of thrombin prevents thrombosis. Dabigatran also inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation. Animal-based and in vitro tests have shown that the antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and oral administration of dabigatran etexilate have been confirmed in different animal models of thrombosis. According to the results of the phase II study, dabigatran plasma concentration and anticoagulant effect are closely related. Dabigatran prolongs thrombin time (TT), ECT, and aPTT. The calibrated diluted TT (dTT) assay provides an estimate of dabigatran plasma concentration and therefore can be compared with expected dabigatran plasma concentrations. ECT provides direct measurement of direct thrombin inhibitor activity. The aPTT test is widely used and can provide an approximate indication of the mild degree of anticoagulation produced by dabigatran therapy. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of the anticoagulant effect, especially when the plasma concentration of dabigatran etexilate is high. High aPTT values ​​should be interpreted with caution. In summary, it is speculated that these detection methods of anticoagulant activity can reflect the therapeutic level of dabigatran and provide guidance for the assessment of bleeding risk. For example, anticoagulation indicators such as aPTT measured at dabigatran trough concentrations or trough values ​​exceeding the 90th percentile are considered to be associated with an increased risk of bleeding. The steady-state geometric mean peak dabigatran plasma concentration measured 2 hours after twice daily administration of 150 mg dabigatran etexilate was 175 ng/ml, with a range of 117 to 275 ng/ml (25th to 75th percentile range). The geometric mean trough concentration of dabigatran measured in the morning at the end of the dosing interval (i.e., 12 hours after the 150 mg dabigatran evening dose) was 91.0 ng/ml, with a range of 61.0 to 143 ng/mg (25th to 75th percentile range). For the prevention of stroke and SEE in patients with non-valvular atrial fibrillation using dabigatran etexilate 150 mg twice daily. ·The plasma concentration of dabigatran measured at the trough of the 90th quantile (10 to 16 hours after the previous dose) was approximately 200ng/ml. ·Trough ECT (10 to 16 hours after the previous dose) was approximately 3 times the upper limit of normal. This increase was equivalent to the observed 90th percentile ECT prolongation of 103 seconds. ·The aPTT ratio at trough (10 to 16 hours after the previous dose) is greater than 2 times the upper limit of normal, which is equivalent to the observed 90th [sup]th[/sup] quantile aPTT prolongation, which is approximately 80 seconds. Toxicological studies Based on routine studies of safety pharmacology, repeated dose toxicity and genotoxicity, non-clinical data indicate that this product has no special hazard to the human body. The effects observed in repeated-dose toxicity studies were due to amplified pharmacodynamic effects of dabigatran. Effects on female animal fertility were manifested by a decrease in implantation numbers and an increase in pre-implantation losses at 70 mg/kg (equivalent to 5 times the patient's plasma exposure level). At maternally toxic doses (corresponding to 5 to 10 times the patient's plasma exposure levels), reduced fetal weight and embryonic viability, and increased fetal variability were observed in rats and rabbits. In prenatal and postnatal studies, increased fetal mortality was observed at maternally toxic dose levels (higher than 4 times the plasma exposure levels observed in patients). In lifetime toxicology studies in rats and mice, no evidence of tumorigenic potential was found at doses up to 200 mg/kg of dabigatran.

[Storage]

Seal and store dry below 25C.

[Specifications]

110 mg, 75 mg, 150 mg

[Packaging specifications]

Double aluminum blister packaging, 10 capsules/box.

[Validity period]

36 months