RIVAROXABAN MILPHARM

Posology 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.

Short duration of therapy (at least 3 months) should be considered in patients with ger 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), the recommended dose is 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.

4). 5). For patients with moderate or severe renal impairment where the decision has been taken for 15 mg once daily from Day 22 onwards, other pack sizes only containing 15 mg film-coated tablets are available (see dosing instructions in section “Special populations” below).

If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take Rivaroxaban immediately to ensure intake of 30 mg rivaroxaban 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, the patient should take Rivaroxaban 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.

5. When converting patients from VKAs to Rivaroxaban, INR values will be falsely elevated after the intake of Rivaroxaban. 5). 5. When converting patients from VKAs to rivaroxaban, INR values will be falsely elevated after the intake of rivaroxaban.

5). Converting from rivaroxaban to Vitamin K antagonists (VKA) There is a potential for inadequate anticoagulation during the transition from rivaroxaban to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant.

It should be noted that rivaroxaban can contribute to an elevated INR. 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 rivaroxaban and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of rivaroxaban.

2).

Paediatric patients:

Children who convert from rivaroxaban to VKA need to continue rivaroxaban for 48 hours after the first dose of VKA. After 2 days of co-administration an INR should be obtained prior to the next scheduled dose of rivaroxaban. 0. 5). g. g.

intravenous unfractionated heparin). Converting from rivaroxaban to parenteral anticoagulants Discontinue rivaroxaban and give the first dose of parenteral anticoagulant at the time the next rivaroxaban dose would be taken.

Special populations Renal impairment Adults:

Limited clinical data for patients with severe renal impairment (creatinine clearance 15-29ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Rivaroxaban is to be used with caution in these patients.

2). 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 […]

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69,608 adult patients in nineteen phase III studies and 412 paediatric patients in two phase II and one phase III studies were exposed to rivaroxaban.

4. and ‘Description of selected adverse reactions’ below) (Table 2). 8 %). 74 per 100 patient years*** # * For all rivaroxaban studies all bleeding events are collected, reported and adjudicated. ** In the COMPASS study, there is a low anaemia incidence as a selective approach to adverse event collection was applied *** A selective approach to adverse event collection was applied # From the VOYAGER PAD study Tabulated list of adverse reactions The frequencies of adverse reactions reported with Rivaroxaban in adult and paediatric patients are summarised in table 3 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 3: All adverse reactions reported in adult patients in phase III clinical studies or through post-marketing use* and in two phase II and one phase III studies in paediatric patients Common Uncommon Rare Very rare Not known Blood and lymphatic system disorders Anaemia (incl.

respective laboratory parameters) Thrombocythemia (incl. platelet count increased) A Thrombocytopenia Immune system disorders Allergic reaction, dermatitis allergic, Angioedema and Anaphylactic reactions including allergic oedema anaphylactic shock 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 Eosinophilic pneumonia Gastrointestinal disorders Gingival bleeding, gastrointestinal tract haemorrhage (incl.

rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA Dry mouth Hepatobiliary disorders Increase in transaminases Hepatic impairment, Increased bilirubin, increased blood alkaline phosphataseA, increased GGTA Jaundice, Bilirubin conjugated increased (with or without concomitant increase of ALT), Cholestasis, Hepatitis (incl.

hepatocellular injury) Skin and subcutaneous tissue disorders Pruritus (incl. uncommon cases of generalised Urticaria Stevens- Johnson syndrome/Toxic Epidermal pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage Necrolysis, DRESS syndrome 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 Anticoagulant- related nephropathy General disorders and administration site conditions FeverA, peripheral […]

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking rivaroxaban are to be carefully observed for signs of bleeding.

It is recommended to be used with caution in conditions with increased risk of haemorrhage. 9). 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.

Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. Several subgroups of patients, as detailed below, are at increased risk of bleeding.

8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. 2). 1). The risk of bleeding should be carefully evaluated before and during therapy with rivaroxaban. 6 fold on average) which may lead to an increased bleeding risk.

Rivaroxaban is to be used with caution in patients with creatinine clearance 15-29 ml/min. 2). 5). 73 m2), as no clinical data is available. g. ritonavir). 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 or selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).

5). g. inflammatory bowel disease, oesophagitis, gastritis and gastro-esophageal reflux disease) • Vascular retinopathy • Bronchiectasis or history of pulmonary bleeding. Patients with cancer Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis.

The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in patients with active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumours located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding during rivaroxaban therapy.

3). Patients with prosthetic valves Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of rivaroxaban have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that rivaroxaban provides adequate anticoagulation in this patient population.

Treatment with rivaroxaban is not recommended for these patients. Patients with antiphospholipid syndrome Direct acting Oral Anticoagulants (DOACs) including 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), treatment with DOACs 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 Clinical data are available from an interventional study with the primary objective to […]

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 intra-spinal or intracerebral vascular abnormalities.

g. 5). 2). 6).