Xelostad 15

Rx

Indications

• Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factor, such as congestive heart failure, hypertension, age from 75 years upwards, diabetes mellitus, prior stroke and transient ischaemic attack.
• Treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults.

Dosage

Prevention of stroke and systemic embolism

• 20 mg once daily. Therapy with rivaroxaban should be continued long term provided the benefit of prevention of stroke and systemic embolisim outweights the risk of bleeding.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults

• Acute case: 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.
  Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.
• When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE): 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with rivaroxaban 10 mg once daily, a dose of rivaroxaban 20 mg once daily should be considered.

Converting from Vitamin K antagonists (VKA) to Xelostad

• For patients treated for prevention of stroke and systemic embolism, VKA treatment should be stopped and Xelostad therapy should be initiated when INR is ≤ 3.0.
• For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and Xelostad therapy should be initiated once the INR is ≤ 2.5.
• When converting patients from VKAs to Xelostad, INR values will be falsely elevated after the intake of Xelostad. The INR is not valid to measure the anticoagulant activity of Xelostad, and therefore should not be used.

Converting from Xelostad to Vitamin K antagonists (VKA)

• There is a potential for inadequate anticoagulation during the transition from Xelostad to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Xelostad can contribute to an elevated INR.
• In patients converting from Xelostad to VKA, VKA should be given concurrently until the INR is ≥ 2.0. While patients are on both Xelostad and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Xelostad. Once Xelostad is discontinued INR testing may be done reliably at least 24 hours after the last dose.

Converting from parenteral anticoagulants to Xelostad

• For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xelostad 0 to 2 hours before the time that the next scheduled administration of the parenteral medicinal product would be due or at the time of discontinuation of a continuously administered parenteral medicinal product.

Converting from Xelostad to parenteral anticoagulants

• Give the first dose of parenteral anticoagulant at the time the next Xelostad dose would be taken.

Renal impairment

• Patients with severe renal impairment (creatinine clearance 15 – 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased.
• In patients with moderate (creatinine clearance 30 – 49 ml/min) or severe (creatinine clearance 15 – 29 ml/min) renal impairment the following dose recommendations apply:
  + For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: 15 mg once daily.
  + For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: 15 mg twice daily for the first 3 weeks. Thereafter, when 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.

When the recommended dose is 10 mg once daily, no dose adjustment from the recommended dose is necessary.
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 – 80 ml/min)

Elderly population: No dose adjustment.

Body weight and gender: No dose adjustment.

Paediatric population: Xelostad is not recommended for use in children below 18 years of age.

Patients undergoing cardioversion

• Xelostad can be initiated or continued in patients who may require cardioversion.
• For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Xelostad treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation.

Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement

There is limited experience of a reduced dose of 15 mg Xelostad once daily (or 10 mg Xelostad once daily for patients with moderate renal impairment [creatinine clearance 30 – 49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement.

Usage

• Xelostad 15 is administered orally, with or without food.
• For patients who are unable to swallow whole tablets, Xelostad tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally. After the administration of crushed Xelostad, the dose should be immediately followed by food.
• The crushed Xelostad 15 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 Xelostad, the dose should then be immediately followed by enteral feeding.

• Hypersensitivity to any of the ingredients.
• 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 eoplasms 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, except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter.
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C.
• Pregnancy and breast feeding.

Common

• Anaemia (incl. respective laboratory parameters);
• Dizziness, headache;
• Eye haemorrhage (incl. conjunctival haemorrhage);
• Hypotension, haematoma;
• Epistaxis, haemoptysis;
• Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting;
• Increase in transaminases;
• Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage;
• Pain in extremity;
• Urogenital tract haemorrhage (incl. haematuria and menorrhagia), renal impairment (incl. blood creatinine increased, blood urea increased);
• Fever, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia);
• Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretion.

Haemorrhagic risk

• It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xelostad 15 administration should be discontinued if severe haemorrhage occurs.
• In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment.
• 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.
• Rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations may help to inform clinical decisions, e.g. overdose and emergency surgery.

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. Xelostad 15 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.
• Xelostad 15 should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations.

Interaction with other medicinal products

• The use of Xelostad 15 is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics. 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 nonsteroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered.

Other haemorrhagic risk factors

Rivaroxaban is not recommended in patients with an increased bleeding risk.

Patients with prosthetic valves

Treatment with Xelostad 15 is not recommended for these patients.

Patients with antiphospholipid syndrome

Rivaroxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement

Data on efficacy in this population are limited.

Haemodynamically unstable (PE) patients or patients who require thrombolysis or pulmonary embolectomy

Xelostad 15 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.

Spinal/epidural anaesthesia or puncture

Risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. 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.

Dosing recommendations before and after invasive procedures and surgical intervention

• If an invasive procedure or surgical intervention is required, Xelostad 15 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.
• Xelostad 15 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.

Elderly population

Increasing age may increase haemorrhagic risk.

Dermatological reactions

Serious skin reactions, including Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, have been reported during post-marketing surveillance in association with the use of rivaroxaban. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.

Xelostad 15 contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Xelostad 15 is contraindicated during pregnancy and lactation.

Patients should be aware of how they react to drug before driving or operating machinery.