Lixiana medicine 60mg Daiichi-sankyo prevents stroke and blood clots (2 blisters x 14 tablets)

ATC code: B01AF03.

Mechanism of action

Edoxaban inhibits high, direct and recovery, the protease serin is at the end of the common path of blood clotting. Edoxaban inhibits the element of freedom and prothrombinase activity. Inhibiting the distant factor in the series of blood clotting reactions reduces thrombin formation, prolonging the time to create blood clots and reducing the risk of thrombotic formation.

Pharmacological effects

Edoxaban onset works quickly within 1-2 hours corresponding to the peak concentration of Edoxaban CMAX. Pharmacological effects are measured by anti -resistant testing test that can be predicted and correlated with dosage and Edoxaban level. Due to far -up inhibition, Edoxaban also extends the time to create blood clots in tests such as prothrombin (PT) time and partial activity time of thromboplastin (APTT). The changes are recorded in these blood clotting tests expected in the treatment dose, however, these changes are small, have a high level of oscillation and have no benefits in monitoring EDOXABAN's anticoagulant effects.

affect blood clotting points when moving from Rivaroxaban, Dabigatran or Apixaban to Edoxaban

In clinical pharmacological studies, healthy volunteers use Rivaroxaban 20 mg once a day, dabigatran 150 mg 2 times/day or Apixaban 5 mg 2 times/day, followed by a single dose of 80 mg Edoxaban on the 4th. Effects on the prothrombin period (PT) and other copper biological indicators (such as distant anti -APTT) have been identified. After switching to Edoxaban on the 4th, prothrombin time corresponds to the 3rd day of using Rivaroxaban and Apixaban. In the case of dabigatran, the higher APTT activity has been recorded after using Edoxaban with previous Dabigatran treatment compared to the lone Edoxaban treatment. This is considered due to the treatment effect of Dabigatran, but does not prolong the bleeding time.

Based on these data, when switching from these anticoagulants to Edoxaban, Edoxaban can begin to be used at the next time of the previous anticoagulant drug as scheduled (see the dose, usage section).

Clinical efficiency and safety

Systemic stroke and embolism

Clinical research Edoxaban in the atrial fibrillation has been designed to prove the effectiveness and safety of two levels of Edoxaban compared to Warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation due to a heart valve and a risk of stroke at an average to high level and body embolism (See).

In the key study of Engage AF-Timi 48 (research in the event group, phase 3, multi-center, random, double blind over 21,105 patients with congestive heart failure, hypertension, age ≥ 75, diabetes, stroke with an average ChADS2 score of 2.8, randomly subdivided into EDOXABAN treatment group 30 mg 1 time/day, EDOXABANR treatment Warfarin. Patients in both EDOXABAN treatment groups are reduced by half a dose if there are the following clinical factors: Average renal failure (CRCL 30 - 50 ml/min), light weight (≤ 60 kg) or simultaneous use

The evaluation criterion is a combination of stroke and body embolism. The extra assessment criteria include: combining stroke, systemic embolism and cardiovascular death (CV); Main adverse events on the heart (MACE), combined with non -fatal myocardial infarction, non -fatal stroke, body embolism does not cause death and death from cardiovascular disease or bleeding; Combining stroke, body congestion and death due to all causes.

Research has a medium Edoxaban treatment time with both 60 mg and 30 mg groups of 2.5 years. The average tracking time of both groups of Edoxaban 60 mg and 30 mg is 2.8 years. The average annual treatment period per patient is 15,471 and 15,840 corresponding to the group of 60 mg and 30 mg; The average annual monitoring time per patient is 19.191 and 19,216 corresponding to the group 60 mg and the group 30 mg.

In the group using warfarin, the average ttr (the time in the treatment range, Inr 2.0 to 3.0) is 68.4%.

The main analysis of efficiency aims to indicate the equivalent of Edoxa-Ban compared to Warfarin on the first stroke or body embolism that appears during a stroke or within 3 days after the last dose in the complex that changes the trend of treatment (mitt). Edoxaban 60 mg is not inferior to Warfarin in terms of criteria for evaluating the main efficiency related to stroke or systemic embolism (the upper limit of HR's 97.5% trust is below the amplitude of not lower than that is 1,38).

Please see more information about drugs in the instructions for the use of drugs attached.

Safety level in patients with atrial fibrillation is not due to the cause of the heart valve in the study of AF-TIMI 48

The main price to evaluate safety is the massive bleeding event.

In the 60 mg Edoxaban, the risk of massive bleeding and other types of bleeding are significant compared to the group using warfarin (corresponding to 2.75% and 3.43% per year) [HR (95% confidence interval): 0.80 (0.71; 0.91); P = 0.0009], Ich (equivalent 0.39% and 0.85% per year) [HR (95% trust range): 0.47 (0.34; 0.63); P

In the 60 mg Edoxaban EDOXABAN treatment group, the bleeding event leads to a decrease in death compared to the warfarin treatment group (0.21%and 0.38%) [HR (95%confidence interval): 0.55 (0.36; 0.84); P = 0.0059 in terms of superiority], mainly due to reduced mortality due to ICH bleeding [HR (95 %trust range): 0.58 (0.35; 0.95); P = 0.0312].

In the analysis under the group, for patients in the 80 mg Edoxa-Ban group, the dose must be reduced to 30 mg in the study of AF-TIMI 48 due to body weight ≤ 60 kg, average renal failure or simultaneous use with P-GP inhibitors, 104 (3.05% per year) in the group of patients who use the dose of 30 mg and 166 (4.85%/year) Massive hemorrhage [HR (95%confidence interval): 0.63 (0.50; 0.81)].

In the study of Engage AF-Timi 48, there has been a significant improvement in clear clinical results (the first regulation, the body embolism, massive bleeding, or death due to all causes; mitt population, overall research period) in favor of the group using Edoxaban, HR (95%trust range): 0.89 (0.83; 0.96); P = 0.0024 when comparing the EDOXABAN treatment group 60 mg compared to Warfarin.

Please see more information about drugs in the instructions for the use of drugs attached.

Deep vein embolism, treatment of pulmonary embolism and prevention of deep vein embolism and pulmonary embolism (venous thrombosis)

Edoxaban clinical research program in the treatment of deep veins are designed to prove the effect and safety of Edoxaban in the treatment of deep veins and pulmonary embolism, prevent recurrence of deep veins and pulmonary obstruction.

In the key Hokusai-VTE study, 8292 patients were randomly subcclosed to initially treated with heparin (enoxaparin or heparin without segment), then used Edoxaban 60 mg once a day or reference medicine. In the group of reference drugs, heparin treatment rings at the beginning simultaneously with Warfarin, adjusted to INR target from 2.0 to 3.0, then used solitary war-farin. Treatment period is from 3 months to 12 months, monitored by researchers based on the patient's clinical condition.

Most patients are treated as white people (69.6%) and Asians (21.0%), 3.8% are black, 14.3% of other races.

The treatment time is at least 3 months for 3718 (91.6%) of patients using Edoxa-Ban compared to 3727 (91.4%) of the patient using Warfarin; At least 6 months for 3495 (86.1 %) of patients using Edoxaban compared to 3491 (85.6 %) patients using warfarin; and 12 months for 1643 (40.5%) of patients using Edoxaban compared to 1659 (40.4%) patients using Warfarin.

Criteria for evaluating effectiveness is the recurrence of deep venous venous boat symptoms, defined as a combination of recurrence of symptoms of deep vein embolism symptoms of non -fatal pulmonary embolism and fatal pulmonary embolism in patients in 12 months of research. The criteria for assessment of side effectiveness include the clinical results of deep veins and death due to all causes.

Edoxaban 30 mg 1 time/day is used for patients with one or more clinical factors below: Average renal failure (CRCl 30 - 50 ml/minute; body weight

In Hokusai-VTE study, Edoxaban has been shown not inferior to Warfarin on the results of the main efficiency assessment, recurrence of deep veins, appearing over 130 out of 4118 patients (3.2 %) in the group using Edoxaban compared to 146 of 4122 patients (3.5 %) in the Warfa-Rin group [HR (95 %trusted range) P

Please see more information about drugs in the instructions for the use of drugs attached.

Dynamic pharmacokinetics

absorption

Edoxaban is absorbed to reach the peak plasma concentration within 1-2 hours. The absolute bioavailability of the drug is about 62%. Food increases the peak concentration at different degrees but little affects the total concentration of the drug during the circulation. Edoxaban is used or not with food in the study of AF-Timi 48 and Hokusai-VTE research. Edoxaban is poorly dissolved at pH from 6 or more. Simultaneous use with proton pump inhibitors does not affect Edoxaban levels in the circulation.

distribution

2 -phase distribution drug. The average distribution volume is 107 (19.9) l (SD).

On vitro drugs are associated with plasma proteins about 55 %. There is no clinical manifestation related to the accumulation of Edoxaban (the cumulative rate of 1.14) at a dose 1 time/day.

The drug concentration in a stable state is achieved within 3 days.

Biological metabolism

non -sea edgaban is a major form of plasma. Edoxaban is metabolized in the hydrolysis path (via mediator of carboxy acidase 1), combined or oxidized by CYP3A4/5 (

Elimination

On a healthy volunteer, the total clearance is estimated at 22 (± 3) l/hour; 50% of kidney clearance (11 l/hour). Kidney clearance is estimated at 35% of the dose. The remaining clearance includes metabolism and excretion through bile/small intestine. The disposal time for oral drug is 10-14 hours.

linear/non -linear

Edoxaban shows that the pharmacokinetic ratio is approximately the dose ratios in the dose range from 15 mg to 60 mg on a healthy volunteer.

Special population

Elderly

After taking into account the kidney function and body weight, the age impact is not clinically significant to the pharmacokinetics of Edoxaban in the pharmacokinetics analysis of the key clinical research complex of phase 3 in the atrial fibrillation patient due to the cause of the heart valve (Engage AF-TIMI 48).

Gender

After taking into account the body weight, gender does not affect clinical significance to the pharmacokinetics of Edoxaban when analysis of pharmacokinetic pharmacokinetic complex of clinical research phase 3 in the atrial fibrillation patient without heart valve (Engage AF-TIMI 48).

Race

In the pharmacokinetic analysis of the AF-TIMI 48 study, the peak concentration and the total concentration of the drug in plasma in Asian patients and non-Asian patients are similar.

kidney failure

The area under the plasma concentration curve in patients with mild renal impairment (CrCl> 50 - 80 ml/minute), average (CrCl 30 - 50 ml/min) and severe (CrCl

There is a linear correlation between Edoxaban concentration in plasma and anti -the remote factor effects that are not related to kidney function.

ESRD -pressing diseases must separate the peritoneal with the total concentration of the drug in the circulatory higher than 93% higher than the healthy person.

Population pharmacokinetic model shows the concentration of drugs in patients with severe renal impairment (CrCl 15 - 29 ml/min) double in patients with normal kidney function.

Animal activity is far away according to the level of CrCL's clearance

Please see more information about drugs in the instructions for the use of drugs attached.

dialysis

Dialysis in 4 hours reduces 9% of the total Edoxaban concentration in the circulation.

Liver function impairment

Pharmacokinetics and pharmacokinetics of drugs in patients with mild or average liver failure with a healthy control group. Edoxaban has not been studied in patients with severe liver failure (see the dose section, usage).

Body weight

In the pharmacokinetics analysis of the study of Engage AF-TIMI 48 in patients with atrial atrial, non-heart valve, CMAX and AUC in patients with low average body weight (55 kg) increased by 40% and 13% compared to patients with high average body weight (84 kg). In phase 3 clinical studies (both for patients with atrial fibrillation without the cause of the heart valve and vein embolism), the patient has a weight of ≤ 60 kg, a 50% reduction in the dose of Edoxaban to get similar effect and less bleeding than Warfarin.

Mobile pharmacokinetic/pharmacokinetic correlation

PT, INR, APTT and resistance to remote factors have linear correlation with Edoxaban concentration.

Vaginal bleeding is commonly seen in women under 50, while rarely in women over 50 years old.

Describe the adverse reactions selected

Hemorrhage anemia

Due to the mechanism of pharmacological effects, the use of Lixiana may be associated with an increase in the risk of bleeding inexplicable or bleeding from any tissue or organs leading to anemia after hemorrhage. Signs, symptoms and severity (including death) vary depending on the location and level of bleeding and/or anemia.

In clinical studies, mucosal bleeding (such as nosebleeds, gastrointestinal bleeding, genital bleeding) and anemia that has been more often occurring when long -term treatment with Edoxaban compared to vitamin K anti -vitamin drugs, therefore, in addition to clinical monitoring, Haemoglobin/Haematocrit tests should be performed to identify unknown bleeding. The risk of bleeding may increase in some patients such as patients with uncontrolled severe arterial hypertension and/or are being treated simultaneously with drugs that affect blood clotting. Menstrual periods may be more and/or prolonged.

Hemorrhagic complications may occur such as fatigue, pale, dizziness, headache or unexplained swelling, shortness of breath and unknown shock.

Secondary complications of severe blood loss have been known as the syndrome and renal failure due to the loss of perfusion has been recorded with Lixiana. Therefore, hemorrhage should be considered when evaluating patients who are taking any anticoagulants.

Instructions on how to handle ADR:

Notify the physician the unwanted effects when using the drug.

P-GP induction drugs

Simultaneous use of Edoxaban with Rifampicin causes P-GP induction to reduce the area under the medium curve of Edoxaban and shorten the sale time, which can lead to reducing the pharmacological effect of the drug. Simultaneous use of Edoxa-Ban with other P-GP induction drugs (such as Phenytoin, Carbamazepin, Pheno-Barbital or St. Johns Wort) can lead to reduced edaxaban levels in plasma. Should be cautious when using Edoxaban and P-GP induction drugs.

The substrate of P-GP

Digoxin: Edoxaban 60 mg 1 time/day on 1 to 14 Use simultaneously with daily dose of Digoxin 0.25 mg 2 times/day (8 and 9) and 0.25 mg 1 time/day (10 to 14) increases the cmax of the Edoxaban 17%, the impact is not significant to the area under the curve or the level of kidney clearance in stable state. EDOXABAN's influence on Digoxin's pharmacokinetics has also been studied, Digoxin's CMAX increased by about 28% and AUC increased by about 7%.

This seems to have no clinical influence. There is no need to change the dose when Lixiana is used with Digoxin.

anticoagulic drugs, anti -platelets, NSAIDs and SSRIs/SSRIs/SNRRSS anticoagulants: contraindicated use of Edoxaban with other anti -blood anti -blood drugs due to increased risk of bleeding.

Acetylsalicylic acid (ASA): simultaneously use ASA (100 mg or 325 mg) and Edoxaban increases bleeding time compared to when using these drugs alone. Simultaneous use of high doses ASA (325 mg) increases the CMAX and AUC of Edoxaban in a stable state of 35% and 32% respectively. It is not recommended to simultaneously use high -dose ASA (325 mg) with Edoxaban. Only use at the same time with high doses of over 100 mg ASA under medical monitoring.

In simultaneous clinical studies (low doses ≤ 100 mg/day), other anti -plateletic drugs and thienopyridine are allowed to use, leading to an increase in the risk of massive bleeding compared to simultaneous use, although the level of encounter is similar in the group using Edoxaban and Warfarin. Simultaneously used at low doses ASA (≤ 100 mg) does not affect the peak concentration or the total concentration of the circulating of Edoxaban even when using a single dose or a stable state.

Edoxaban can be used in low doses of ASA (

Inhibition of platelet gathering: In the study of AF-Timi 48, simultaneously used the solicidin (such as clopidogrel), which is allowed to lead to clinically increased bleeding despite the risk of Edoxaban's bleeding lower than Warfarin.

Experience in the use of Edoxaban with anti -plateletic dual collection treatment or with limited fiber pepper drugs.

NSAIDS: Concomitant use of Naproxen and Edoxaban increases bleeding time compared to these drugs. Naproxen does not affect CMAX and AUC of Edoxaban. In clinical studies, simultaneously used with NSAID drugs increases clinical bleeding. Do not recommend long -term use of NSAID drugs with Edoxaban.

SSRI/SNRLS: Similar to other anticoagulants, it is likely that the patient has an increased risk of bleeding when used simultaneously with SSRIs or SNRIS due to platelets.

Effect of Edoxaban on other drugs

Edoxaban increases CMAX when used simultaneously with 28%Digoxin; However, the area under the curve is not affected. Edoxaban does not affect CMAX and AUC of Quinidin.

Edoxaban reduces CMAX and AUC when used simultaneously with Verapamil, respectively, 14% and 16%.

This is considered not clinically significant. In the study of Engage AF-Timi 48 in patients with atrial fibrillation without the cause of the heart valve, effectiveness and safety achieved similarly on patients to use or not with Amiodaron.