13 Feb 2012

Xarelto 20mg (Rivaroxaban) - United Kingdom

Updated: 13 Feb 2012

Xarelto 20mg film-coated tablets

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 prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults.

Xarelto 20mg Description, Presentation and Dosage

Xarelto 20mg Description

Xarelto 20mg Drug Class Description

Anti-thrombotic Agent

Xarelto 20mg Drug Description

Each film-coated tablet contains 20 mg rivaroxaban. Excipient(s): Each 20 mg film-coated tablet contains 22.9 mg lactose monohydrate.

Xarelto 20mg Generic Name

Rivaroxaban

Xarelto 20mg Presentation

Xarelto 20mg Presentation

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.

Xarelto 20mg Manufacturer

Bayer plc

Free Medical Education Resources

Xarelto 20mg Dosage

Xarelto 20mg Adult Dosage

 

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.

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 and prevention of recurrent DVT and PE

The recommended dose for the initial treatment of acute DVT 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. Short duration of therapy (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. Experience with Xarelto in this indication for more than 12 months is limited.

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 INR is  3.0.

For patients treated for DVT and prevention of recurrent DVT and PE, 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.

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 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.

Converting from parenteral anticoagulants to Xarelto

For patients currently receiving a parenteral anticoagulant, Xarelto should be started 0 to 2 hours before the time of the next scheduled administration of the parenteral medicinal product (e.g. LMWH) 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

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min).

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.

- For the treatment of DVT 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 15 mg once daily based on PK modelling.

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.

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.

Elderly population

No dose adjustment.

Body weight

No dose adjustment.

Gender

No dose adjustment.

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.

Method of administration

For oral use. The tablets are to be taken with food.

 

Xarelto 20mg Child Dosage

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.

Xarelto 20mg Precautions, Reactions and Contraindications

Xarelto 20mg Special Precautions

Xarelto 20mg Special Precautions

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.

Haemorrhagic risk

In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and anemia 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.

Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.

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.

Xarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products that are potent inhibitors of CYP3A4 (e.g. clarithromycin, telithromycin) as PK modelling shows increased rivaroxaban concentrations in these patients.

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.

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, platelet aggregation inhibitors or other antithrombotic agents. For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered.

Other haemorrhagic risk factors

Rivaroxaban, like other antithrombotic agents, is to be used with caution in patients with an increased bleeding risk such as:

• congenital or acquired bleeding disorders

• uncontrolled severe arterial hypertension

• active ulcerative gastrointestinal disease

• recent gastrointestinal ulcerations

• vascular retinopathy

• recent intracranial or intracerebral haemorrhage

• intraspinal or intracerebral vascular abnormalities

• recent brain, spinal or ophthalmological surgery

• 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.

Patients with acute pulmonary embolism

Xarelto is not recommended in the treatment of acute pulmonary embolism.

Dosing recommendations before and after invasive procedures and surgical intervention

If an invasive procedure or surgical intervention is required, Xarelto 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 after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.

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.

Xarelto 20mg Adverse Reactions

Xarelto 20mg Adverse Reactions

Summary of the safety profile

The safety of rivaroxaban has been evaluated in eight phase III studies including 16,041 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

Treatment of DVT and prevention of recurrent DVT and PE

2,194

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

*Patients exposed to at least one dose of rivaroxaban

In total about 73% of patients exposed to at least one dose of rivaroxaban were reported with treatment emergent adverse events. About 24% 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, bleeding events occurred in approximately 6.8% of patients and anaemia occurred in approximately 5.9% of patients. In patients treated with either 15 mg twice daily Xarelto followed by 20 mg once daily for treatment of DVT, or with 20 mg once daily for prevention of recurrent DVT and PE, bleeding events occurred in approximately 22.7% of patients and anaemia occurred in approximately 1.8% 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.

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:

common ( 1/100 to < 1/10)

uncommon ( 1/1,000 to < 1/100)

rare ( 1/10,000 to < 1/1,000)

Not known: cannot be estimated from the available data.

Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies (prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery (VTE-P), treatment of DVT and prevention of recurrent DVT and PE (DVT-T), and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF))

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, syncope

Cerebral and intracranial haemorrhage

   

Eye disorders

Eye haemorrhage (incl. conjunctival haemorrhage)

     

Cardiac disorders

Tachycardia

     

Vascular disorders

Hypotension, haematoma

   

Pseudoaneurysm formation following percutaneous intervention*

Respiratory, thoracic and mediastinal disorders

Epistaxis

Haemoptysis

   

Gastrointestinal disorders

Gastrointestinal tract haemorrhage (incl. gingival bleeding and 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

Urticaria, cutaneous and subcutaneous haemorrhage

   

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

   

A: observed in VTE-P; B: observed in DVT-T as very common in women < 55 years

*) These reactions ocurred in other clinical studies than the phase III studies in patients undergoing major orthopaedic surgery of the lower limbs, patients treated for DVT and prevention of recurrent DVT and PE, or patients treated for the prevention of stroke and systemic embolism

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. In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and anemia 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. 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.

Xarelto 20mg Contraindications

Xarelto 20mg Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Clinically significant active bleeding.

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C.

Pregnancy and breast feeding.

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