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Xarelto(rivaroxaban filmcoated tablets)

2015-02-06 04:57:16  作者:新特药房  来源:互联网  浏览次数:497  文字大小:【】【】【
简介: 英文药名:Xarelto(rivaroxaban film-coated tablets) 中文药名:利伐沙班膜衣片 生产厂家:拜耳公司药品介绍新型抗凝血药物Xarelto(rivaroxaban)近日在欧盟获准上市,该药每天一片,用于预防进 ...

英文药名:Xarelto(rivaroxaban film-coated tablets)

中文药名:利伐沙班膜衣片

生产厂家:拜耳公司
药品介绍
新型抗凝血药物Xarelto(rivaroxaban)近日在欧盟获准上市,该药每天一片,用于预防进行髋关节或膝关节置换手术病人的静脉血栓形成。拜耳公司将迅速启动该产品在欧盟上市。
适应证和用途
XARELTO一种因子Xa抑制剂适用于在正在膝或髋关节置换手术患者中预防深部静脉血栓形成(DVT),后者可能导致肺栓塞(PE)。
适应症和用途
XARELTO是凝血因子Xa抑制剂适用于:
● 在非瓣膜性心房颤动患者中减低卒中和全身性栓塞。
● 为治疗深部静脉血栓形成(DVT),肺栓塞(PE),和为减低DVT和PE复发的风险。
● 为预防DVT,正在进行膝或髋置换术患者中可能导致PE。
剂量和给药方法
● 有食物服用15mg和20mg片;有或无食物服用10mg片。
● 非瓣膜性心房颤动:
o 对CrCl >50 mL/min患者:口服20mg,每天1次随旁晚餐。
o 对CrCl 15-50mL/min患者:15 mg口服,每天1次随旁晚餐。
● DVT,PE治疗,和减低复发性DVT和PE的风险:对急性DVT或PE 初始治疗15mg有食物口服每天2次共头21天。初始治疗期后,20mg有食物口服每天1次对维持治疗和长期减低DVT和PE复发的风险。
● 髋或膝置换手术后预防DVT:10mg有或无食物口服,每天1次。
剂型和规格
片:10mg,15mg,和20mg。
禁忌症
● 活动性病理性出血。
● 对XARELTO严重超敏性反应。
警告和注意事项
● 出血风险:XARELTO可致严重和致命性出血。及时评价血液丢失体征和症状。
● 妊娠相关出血:由于产科出血潜能和/或紧急分娩在妊娠妇女中谨慎使用XARELTO。及时评价血液丢失体征和症状。
不良反应
最常见不良反应(>5%) 是出血。
药物相互作用
● CP-gp和强CYP3A4抑制剂和诱导剂联用:避免同时使用。
● 抗凝剂:避免同时使用。
特殊人群中使用
● 哺乳母亲:终止药物或终止哺乳。
● 肾受损:避免或根据CrCl调整剂量。
● 肝受损:在有Child-Pugh B和C肝受损或有任何程度肝病伴随凝血病患者避免使用。


Xarelto 20mg film-coated tablets
1. Name of the medicinal product
Xarelto 20 mg film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains 20 mg rivaroxaban.
Excipient with known effect:
Each film-coated tablet contains 21.76 mg lactose (as monohydrate), see section 4.4.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
Brown-red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the BAYER-cross on one side and “20” and a triangle on the other side.
4. Clinical particulars
4.1 Therapeutic indications
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients).
4.2 Posology and method of administration
Posology
Prevention of stroke and systemic embolism
The recommended dose is 20 mg once daily, which is also the recommended maximum dose.
Therapy with Xarelto should be continued long term provided the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding (see section 4.4).
If a dose is missed the patient should take Xarelto immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE, as indicated in the table below.

Dosing schedule

Maximum daily dose

Day 1-21

15 mg twice daily

30 mg

Day 22 and onwards

20 mg once daily

20 mg

The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.
If a dose is missed during the once daily treatment phase (day 22 and onwards), the patient should take Xarelto immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.
Converting from Vitamin K Antagonists (VKA) to Xarelto
For patients treated for prevention of stroke and systemic embolism, VKA treatment should be stopped and Xarelto therapy should be initiated when the International Normalized Ratio (INR) is ≤ 3.0.
For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and Xarelto therapy should be initiated once the INR is ≤ 2.5.
When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should not be used (see section 4.5).
Converting from Xarelto to Vitamin K antagonists (VKA)
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).
Converting from parenteral anticoagulants to Xarelto
For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto 0 to 2 hours before the time that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).
Converting from Xarelto to parenteral anticoagulants
Give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken.
Special populations
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2).
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15 - 29 ml/min) renal impairment the following dosage recommendations apply:
- For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2).
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients should be treated with 15 mg twice daily for the first 3 weeks.
Thereafter, the recommended dose is 20 mg once daily. A reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) (see section 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).
Elderly population
No dose adjustment (see section 5.2).
Body weight
No dose adjustment (see section 5.2).
Gender
No dose adjustment (see section 5.2).
Paediatric population
The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.
Patients undergoing cardioversion
Xarelto can be initiated or continued in patients who may require cardioversion.
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Xarelto treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought prior to cardioversion that the patient has taken Xarelto as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.
Method of administration
For oral use.
The tablets are to be taken with food (see section 5.2).
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally. After the administration of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food.
The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active clinically significant bleeding.
Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2).
Pregnancy and breast feeding (see section 4.6).
4.4 Special warnings and precautions for use
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.
Haemorrhagic risk
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8).
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see section 4.5).
Interaction with other medicinal products
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5).
Other haemorrhagic risk factors
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as:
• congenital or acquired bleeding disorders
• uncontrolled severe arterial hypertension
• other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease)
• vascular retinopathy
• bronchiectasis or history of pulmonary bleeding.
Patients with prosthetic valves
Safety and efficacy of Xarelto have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto 20 mg (15 mg in patients with moderate or severe renal impairment) provides adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for these patients.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy
Xarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Xarelto have not been established in these clinical situations.
Spinal/epidural anaesthesia or puncture
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter. Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered.
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, Xarelto 20 mg should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician (see section 5.2).
Elderly population
Increasing age may increase haemorrhagic risk (see section 5.2).
Information about excipients
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
CYP3A4 and P-gp inhibitors
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4).
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in Cmax. This increase is not considered clinically relevant. (For patients with renal impairment: see section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3 fold increase in mean rivaroxaban AUC and Cmax. This increase is not considered clinically relevant.
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This increase is not considered clinically relevant. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) an additive effect on anti-factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants (see sections 4.3 and 4.4).
NSAIDs/platelet aggregation inhibitors
No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see section 4.4).
Warfarin
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.
Other concomitant therapies
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.
Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban (see section 5.1).
4.6 Fertility, pregnancy and breast feeding
Pregnancy
Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast feeding
Safety and efficacy of Xarelto have not been established in breast feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to discontinue/abstain from therapy.
Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).
4.7 Effects on ability to drive and use machines
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.
4.8 Undesirable effects
Summary of the safety profile
The safety of rivaroxaban has been evaluated in eleven phase III studies including 32,625 patients exposed to rivaroxaban (see Table 1).
Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III studies

Indication

Number of patients*

Maximum daily dose

Maximum treatment duration

Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery

6,097

10 mg

39 days

Prevention of venous thromboembolism in medically ill patients

3,997

10 mg

39 days

Treatment of DVT, PE and prevention of recurrence

4,556

Day 1 - 21: 30 mg

Day 22 and onwards: 20 mg

21 months

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation

7,750

20 mg

41 months

Prevention of atherothrombotic events in patients after an ACS

10,225

5 mg or 10 mg respectively, co-administered with either ASA or ASA plus clopidogrel or ticlopidine

31 months

*Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see section 4.4. and 'Description of selected adverse reactions' below). The most commonly reported bleedings (≥4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).
In total about 67% of patients exposed to at least one dose of rivaroxaban were reported with treatment emergent adverse events. About 22% of the patients experienced adverse events considered related to treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip or knee replacement surgery and in hospitalised medically ill patients, bleeding events occurred in approximately 6.8% and 12.6% of patients, respectively, and anaemia occurred in approximately 5.9% and 2.1% of patients, respectively. In patients treated with either 15 mg twice daily Xarelto followed by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent DVT and PE, bleeding events occurred in approximately 27.8% of patients and anaemia occurred in approximately 2.2% of patients. In patients treated for prevention of stroke and systemic embolism, bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of cardiovascular death and myocardial infarction after an acute coronary syndrome (ACS), bleeding of any type or severity was reported with an event rate of 22 per 100 patient years. Anaemia was reported with an event rate of 1.4 per 100 patient years.
Tabulated list of adverse reactions
The frequencies of adverse reactions reported with Xarelto are summarised in table 2 below by system organ class (in MedDRA) and by frequency.
Frequencies are defined as:
very common (≥ 1/10)
common (≥ 1/100 to < 1/10)
uncommon (≥ 1/1,000 to < 1/100)
rare (≥ 1/10,000 to < 1/1,000)
very rare (< 1/10,000)
not known (cannot be estimated from the available data)
Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies

Common

Uncommon

Rare

Not known

Blood and lymphatic system disorders

Anaemia (incl. respective laboratory parameters)

Thrombocythemia (incl. platelet count increased)A

   

Immune system disorders

 

Allergic reaction, dermatitis allergic

   

Nervous system disorders

Dizziness, headache

Cerebral and intracranial haemorrhage, syncope

   

Eye disorders

Eye haemorrhage (incl. conjunctival haemorrhage)

     

Cardiac disorders

 

Tachycardia

   

Vascular disorders

Hypotension, haematoma

     

Respiratory, thoracic and mediastinal disorders

Epistaxis, haemoptysis

     

Gastrointestinal disorders

Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA

Dry mouth

   

Hepatobiliary disorders

 

Hepatic function abnormal

Jaundice

 

Skin and subcutaneous tissue disorders

Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage

Urticaria

   

Musculoskeletal and connective tissue disorders

Pain in extremityA

Haemarthrosis

Muscle haemorrhage

Compartment syndrome secondary to a bleeding

Renal and urinary disorders

Urogenital tract haemorrhage (incl. haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased)A

   

Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion

General disorders and administration site conditions

FeverA, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)

Feeling unwell (incl. malaise)

Localised oedemaA

 

Investigations

Increase in transaminases

Increased bilirubin, increased blood alkaline phosphataseA, increased LDHA, increased lipaseA, increased amylaseA, increased GGTA

Bilirubin conjugated increased (with or without concomitant increase of ALT)

 

Injury, poisoning and procedural complications

Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretionA

 

Vascular pseudoaneurysmC

A: observed in prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery
B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years
C: observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention)
Description of selected adverse reactions
Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9 Management of bleeding). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see Haemorrhagic risk in section 4.4). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.
Post-marketing observations
Angioedema and allergic oedema have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated. In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Management of bleeding
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these products in individuals receiving rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings (see section 5.1).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Direct factor Xa inhibitors, ATC code: B01AF01
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.

In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough (16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 s.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-factor Xa tests (see section 5.2).
Clinical efficacy and safety
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
The Xarelto clinical program was designed to demonstrate the efficacy of Xarelto for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to Xarelto 20 mg once daily (15 mg once daily in patients with creatinine clearance 30 - 49 ml/min) or to warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatment was 19 months and overall treatment duration was up to 41 months.
34.9% of patients were treated with acetylsalicylic acid and 11.4% were treated with class III antiarrhythmic including amiodarone.
Xarelto was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS systemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurred in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79; 95% CI, 0.66 – 0.96; P<0.001 for non-inferiority). Among all randomised patients analysed according to ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42% per year) (HR 0.88; 95% CI, 0.74 – 1.03; P<0.001 for non-inferiority; P=0.117 for superiority). Results for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in Table 3.
Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) a mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban did not differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized quartiles (P=0.74 for interaction). Within the highest quartile according to centre, the hazard ratio with rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12).
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding events) were similar for both treatment groups (see Table 4).
Table 3: Efficacy results from phase III ROCKET AF

Study population

ITT analyses of efficacy in patients with non-valvular atrial fibrillation

Treatment dosage

Xarelto 20 mg od

(15 mg od in patients with moderate renal impairment)

Event rate (100 pt-yr)

Warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0)

Event rate (100 pt-yr)

Hazard ratio (95% CI)

p-value, test for superiority

Stroke and non-CNS systemic embolism

269

(2.12)

306

(2.42)

0.88

(0.74 - 1.03)

0.117

Stroke, non-CNS systemic embolism and vascular death

572

(4.51)

609

(4.81)

0.94

(0.84 - 1.05)

0.265

Stroke, non-CNS systemic embolism, vascular death and myocardial infarction

659

(5.24)

709

(5.65)

0.93

(0.83 - 1.03)

0.158

Stroke

253

(1.99)

281

(2.22)

0.90

(0.76 - 1.07)

0.221

Non-CNS systemic embolism

20

(0.16)

27

(0.21)

0.74

(0.42 - 1.32)

0.308

Myocardial infarction

130

(1.02)

142

(1.11)

0.91

(0.72 - 1.16)

0.464

Table 4: Safety results from phase III ROCKET AF

Study population

Patients with non-valvular atrial fibrillationa)

Treatment dosage

Xarelto 20 mg once a day

(15 mg once a day in patients with moderate renal impairment)

Event rate (100 pt-yr)

Warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0)

Event rate (100 pt-yr)

Hazard ratio (95% CI)

p-value

Major and non-major clinically relevant bleeding events

1,475

(14.91)

1,449

(14.52)

1.03 (0.96 - 1.11)

0.442

Major bleeding events

395

(3.60)

386

(3.45)

1.04 (0.90 - 1.20)

0.576

Death due to bleeding*

27

(0.24)

55

(0.48)

0.50 (0.31 - 0.79)

0.003

Critical organ bleeding*

91

(0.82)

133

(1.18)

0.69 (0.53 - 0.91)

0.007

Intracranial haemorrhage*

55

(0.49)

84

(0.74)

0.67 (0.47 - 0.93)

0.019

Haemoglobin drop*

305

(2.77)

254

(2.26)

1.22 (1.03 - 1.44)

0.019

Transfusion of 2 or more units of packed red blood cells or whole blood*

183

(1.65)

149

(1.32)

1.25 (1.01 - 1.55)

0.044

Non-major clinically relevant bleeding events

1,185

(11.80)

1,151

(11.37)

1.04 (0.96 - 1.13)

0.345

All cause mortality

208

(1.87)

250

(2.21)

0.85 (0.70 - 1.02)

0.073

a) Safety population, on treatment
* Nominally significant
Patients undergoing cardioversion
A prospective, randomized, open-label, multicenter, exploratory study with blinded endpoint evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) with non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted VKA (randomized 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were employed. The primary efficacy outcome (all stroke, transient ischemic attack, non-CNS systemic embolism, MI and cardiovascular death) occurred in 5 (0.5 %) patients in the rivaroxaban group (n = 978) and 5 (1.0 %) patients in the VKA group (n = 492; RR 0.50; 95 % CI 0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6 %) and 4 (0.8 %) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 95 % CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety between rivaroxaban and VKA treatment groups in the setting of cardioversion.
Treatment of DVT, PE and prevention of recurrent DVT and PE
The Xarelto clinical program was designed to demonstrate the efficacy of Xarelto in the initial and continued treatment of acute DVT and PE and prevention of recurrence.
Over 9,400 patients were studied in three randomised controlled phase III clinical studies (Einstein DVT, Einstein PE and Einstein Extension) and additionally a predefined pooled analysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatment duration in all studies was up to 21 months.
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical judgement of the investigator.
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This was followed by 20 mg rivaroxaban once daily.
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical judgement of the investigator.
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. This was followed by 20 mg rivaroxaban once daily.
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until the PT/INR was in therapeutic range (≥ 2.0). Treatment was continued with a vitamin K antagonist dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical judgment of the investigator. Xarelto 20 mg once daily was compared with placebo.
All phase III studies used the same pre-defined primary and secondary efficacy outcomes. The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent DVT, non-fatal PE and all cause mortality.
In the Einstein DVT study (see Table 5) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); hazard ratio: 0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.67 ((95% CI: 0.47–0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the hazard ratio with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35).
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding events) as well as the secondary safety outcome (major bleeding events) were similar for both treatment groups. 

Table 5: Efficacy and safety results from phase III Einstein DVT

Study population

3,449 patients with symptomatic acute deep vein thrombosis

Treatment dosage and duration

Xareltoa)

3, 6 or 12 months

N=1,731

Enoxaparin/VKAb)

3, 6 or 12 months

N=1,718

Symptomatic recurrent VTE*

36

(2.1%)

51

(3.0%)

Symptomatic recurrent PE

20

(1.2%)

18

(1.0%)

Symptomatic recurrent DVT

14

(0.8%)

28

(1.6%)

Symptomatic PE and DVT

1

(0.1%)

0

Fatal PE/Death where PE cannot be ruled out

4

(0.2%)

6

(0.3%)

Major or clinically relevant non-major bleeding

139

(8.1%)

138

(8.1%)

Major bleeding events

14

(0.8%)

20

(1.2%)

a)Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b)Enoxaparin for at least 5 days, overlapped with and followed by VKA
*p < 0.0001 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 0.680 (0.443 - 1.042), p=0.076 (superiority)
In the Einstein PE study (see Table 6) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); hazard ratio: 1.123 (0.749 – 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to centre, the hazard ratio with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484).
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome (major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the enoxaparin/VKA group (2.2% (52/2405)) with a hazard ratio 0.493 (95% CI: 0.308 - 0.789).

Table 6: Efficacy and safety results from phase III Einstein PE

Study population

4,832 patients with an acute symptomatic PE

Treatment dosage and duration

Xareltoa)

3, 6 or 12 months

N=2,419

Enoxaparin/VKAb)

3, 6 or 12 months

N=2,413

Symptomatic recurrent VTE*

50

(2.1%)

44

(1.8%)

Symptomatic recurrent PE

23

(1.0%)

20

(0.8%)

Symptomatic recurrent DVT

18

(0.7%)

17

(0.7%)

Symptomatic PE and DVT

0

2

(<0.1%)

Fatal PE/Death where PE cannot be ruled out

11

(0.5%)

7

(0.3%)

Major or clinically relevant non-major bleeding

249

(10.3%)

274

(11.4%)

Major bleeding events

26

(1.1%)

52

(2.2%)

a)Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
*p < 0.0026 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 1.123 (0.749 – 1.684)
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see Table 7).

Table 7: Efficacy and safety results from pooled analysis of phase III Einstein DVT and Einstein PE

Study population

8,281 patients with an acute symptomatic DVT or PE

Treatment dosage and duration

Xareltoa)

3, 6 or 12 months

N=4,150

Enoxaparin/VKAb)

3, 6 or 12 months

N=4,131

Symptomatic recurrent VTE*

86

(2.1%)

95

(2.3%)

Symptomatic recurrent PE

43

(1.0%)

38

(0.9%)

Symptomatic recurrent DVT

32

(0.8%)

45

(1.1%)

Symptomatic PE and DVT

1

(<0.1%)

2

(<0.1%)

Fatal PE/Death where PE cannot be ruled out

15

(0.4%)

13

(0.3%)

Major or clinically relevant non-major bleeding

388

(9.4%)

412

(10.0%)

Major bleeding events

40

(1.0%)

72

(1.7%)

a)Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b)Enoxaparin for at least 5 days, overlapped with and followed by VKA
*p < 0.0001 (non-inferiority to a prespecified hazard ratio of 1.75); hazard ratio: 0.886 (0.661 – 1.186)
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the pooled analysis was reported with a hazard ratio of 0.771 ((95% CI: 0.614 – 0.967), nominal p value p= 0.0244).
In the Einstein Extension study (see Table 8) rivaroxaban was superior to placebo for the primary and secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared to placebo.

Table 8: Efficacy and safety results from phase III Einstein Extension

Study population

1,197 patients continued treatment and prevention of recurrent venous thromboembolism

Treatment dosage and duration

Xareltoa)

6 or 12 months

N=602

Placebo

6 or 12 months

N=594

Symptomatic recurrent VTE*

8

(1.3%)

42

(7.1%)

Symptomatic recurrent PE

2

(0.3%)

13

(2.2%)

Symptomatic recurrent DVT

5

(0.8%)

31

(5.2%)

Fatal PE/Death where PE cannot be ruled out

1

(0.2%)

1

(0.2%)

Major bleeding events

4

(0.7%)

0

(0.0%)

Clinically relevant non-major bleeding

32

(5.4%)

7

(1.2%)

a)Rivaroxaban 20 mg once daily
*p < 0.0001 (superiority), hazard ratio: 0.185 (0.087 - 0.393)
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events ( see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 2.5mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 2.5mg and 10 mg dose.
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg tablet under fasting conditions. When Xarelto 20 mg tablets are taken together with food increases in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, indicating almost complete absorption and high oral bioavailability. Xarelto 15 mg and 20 mg are to be taken with food (see section 4.2).
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state. Under fed conditions Xarelto 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided since this can result in reduced absorption and related rivaroxaban exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.
Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 litres.
Biotransformation and elimination
Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be classified as a low-clearance substance. After intravenous administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.
Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients.
Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No dose adjustment is necessary.
Different weight categories
Extremes in body weight (<50kg or> 120kg) had only a small influence on rivaroxaban plasma concentrations (less than 25 %). No dose adjustment is necessary.
Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.
Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).
Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min), moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
Pharmacokinetic data in patients
In patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the geometric mean concentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representing maximum and minimum concentrations during the dose interval) was 215 (22 - 535) and 32 (6 - 239) μg/l, respectively.
Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 µg/l). The results of the PK/PD analyses in Phase II and III were consistent with the data established in healthy subjects.
Paediatric population
Safety and efficacy have not been established for children and adolescents up to 18 years.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile toxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant exposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, hepatic multiple light coloured spots) and an increased incidence of common malformations as well as placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat:
Macrogol 3350
Hypromellose
Titanium dioxide (E171)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PP/Aluminium foil blisters in cartons of 14, 28 or 98 film-coated tablets or perforated unit dose blisters in cartons of 10 x 1, or 100 x 1 or in multipacks containing 100 (10 packs of 10 x 1) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7. Marketing authorisation holder
Bayer Pharma AG
13342 Berlin
Germany
8. Marketing authorisation number(s)
EU/1/08/472/017-021, EU/1/08/472/024.
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 30 September 2008
Date of latest renewal: 22 May 2013
10. Date of revision of the text
December 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.


包装规格(本品属德国产品)
10mgx30片
20mgx98片
20mgx28片
15mgx28片
15mgx98片
2.5mgx30片


注:各规格的详细处方资料附件:
Xarelto 10 mg film-coated tablets(http://www.medicines.org.uk/emc/medicine/21265
Xarelto 15mg film-coated tablets(http://www.medicines.org.uk/emc/medicine/25592
Xarelto 2.5 mg film-coated tablets(http://www.medicines.org.uk/emc/medicine/29371
Xarelto 20mg film-coated tablets(http://www.medicines.org.uk/emc/medicine/25586


美国FDA扩展Xarelto的使用治疗,减低血液凝固复发
2012年11月2日美国食品和药品监督管理局(FDA)扩展Xarelto(利伐沙班[rivaroxaban])的被批准使用包括治疗深部静脉血栓(DVT)或肺栓塞(PE),和减低初始治疗后DVT和PE复发的风险。
当血液粘厚和一团一团在一起发生血凝块。DVT是在身体深部静脉形成血凝块。 大多数深部静脉血凝块发生在下肢或大腿,当在深部静脉血凝块折断和移动至肺内动脉和阻断血流,造成一种潜在致死性情况成为肺动脉栓塞PE。
Xarelto早已被FDA-批准减低来自r膝或髋置换手术后发生的DVTs和PEs风险(2011年7月),和减低有典型异常心节律被称为非瓣膜性心房颤动人们卒中的风险(2011年11月)。
FDA在监管局的优先审评程序下审评了Xarelto的新适应症 ,这种程序对治疗中提供重大进展或目前没有适当治疗的药物提供加快6个月审评。
FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur,M.D.说:“Xarelto是自从接近60年前前批准华法林[warfarin]以来第一个批准的口服治疗和减低血凝块复发的抗凝药物”。
被 FDA批准治疗或减低血凝块风险的其他药物包括Lovenox (依诺肝素[enoxaparin]),依诺肝素的仿制药,Arixtra (磺达肝癸钠[fondaparinux]),Fragmin(达肝素钠[dalteparin]),Coumadin (华法林),和肝素。
在三项临床研究中评价了Xarelto对新适应症的安全性和有效性。总共9,478例DVT或PE患者被随机赋予接受Xarelto,依诺肝素和维生素 K拮抗剂(VKA)联用,或安慰剂。研究被设计测量经受复发DVT,PE症状或接受治疗后死亡患者数。
结果显示Xarelto与依诺肝素和VKA联用对治疗DVT和PE疗效一样。被Xarelto治疗患者经受复发DVT或PE约2.1 %,与之比较用依诺肝素和VKA 联用治疗患者1.8 %至3 %。此外,来自第三研究结果显示扩展Xarelto治疗患者减低DVT和PE复发的风险。用Xarelto治疗患者约3%经受复发DVT或PE 相比较接受安慰剂患者7.1 %。
用Xarelto观察到主要副作用是出血,相似于其他抗凝药物。
Xarelto由位于新泽西州Janssen Pharmaceuticals Inc.的Raritan上市。

责任编辑:admin


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