Rivaroxaban

Anticoagulant from the oxazolidinone group. Rivaroxaban is a synthetic so-called direct oral anticoagulant (DOAK) which, unlike the heparinoids, acts as a direct Factor Xa inhibitor. Rivaroxaban is approved for the prophylaxis and therapy of venous thromboembolism (VTE) in adult patients. Rivaroxaban is also used for the prophylaxis of venous thromboembolism (VTE) in adults after elective hip or knee replacement surgery and for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (LE) as well as the prophylaxis of recurrent DVT and LE in adults.

Rivaroxaban belongs to the pharmacotherapeutic group of anticoagulants. It acts as a highly selective dose-dependent direct Factor Xa inhibitor. This interrupts the intrinsic and extrinsic path of the blood coagulation cascade. Both the formation of thrombin (activated factor II) and the formation of thrombi is inhibited. The active substance has no direct effect on the thrombocytes. According to the expert information, regular monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine is not necessary. If it does seem clinically necessary, however, rivaroxaban levels can be determined using calibrated quantitative anti-factor Xa tests.

Pharmacokinetics: The maximum plasma concentration of the active ingredient is usually reached 2-4 hours after oral administration. The absolute bioavailability after oral administration is 80-100% and is independent of whether it was taken fasting or after a meal. The elimination of the active ingredient is renal; it takes about 4.5 hours.

The duration of therapy and dosage must be weighed against the risk of bleeding for each indication.

Prevention of stroke and peripheral embolism: In the Rocket AF study, the results of which were presented at the 2010 American Heart Association Annual Meeting, rivaroxaban was no less effective than warfarin (equivalent to the more widely known marcoumar in Germany) in preventing stroke and peripheral embolism. The rate of bleeding and other side effects was the same. Less intracranial bleeding occurred under rivaroxaban.

Prophylaxis of VTE after elective hip or knee replacement surgery: In this indication, the recommended dose is 10 mg of the active substance per day. The initial administration should be made 6-10 hours postoperatively. In the case of major hip surgery, a treatment period of 5 weeks is recommended. For major knee surgery a treatment period of 2 weeks is recommended.

Treatment of DVT, LE and prophylaxis of recurrent DVT and LE: The recommended initial dose for this indication is 15 mg twice daily for the first three weeks, then 20 mg once daily for further treatment or prophylaxis for at least 3 months. If the therapy is continued for more than 6 months, a daily dose of 10 mg rivaroxaban is recommended and in exceptional cases 20 mg daily.

Switching from vitamin K antagonists to rivaroxaban: In patients who are to be switched from rivaroxaban to vitamin K antagonists, treatment with vitamin K antagonists should be stopped and rivaroxaban therapy should be started as soon as the INR is <2.5.

Switching from parenterally administered anticoagulants to rivaroxaban: In patients who are switching from parenterally administered anticoagulants to rivaroxaban, the parenterally administered anticoagulant should be discontinued and rivaroxaban should be taken 0-2 hours before the time when administration of the parenterally administered anticoagulant would have been scheduled.

Switching from rivaroxaban to vitamin K antagonists: In patients who are to be switched from rivaroxaban to vitamin K antagonists, the vitamin K antagonist should be given concurrently until the INR is >2.0. During the first two days, the regular initial dose of vitamin K antagonist should be used, followed by a dose based on INR values. For more detailed information, please refer to the respective scientific information.

Switching from rivaroxaban to parenteral anticoagulants: In patients who are switching from rivaroxaban to parenteral anticoagulants, the first dose of the parenteral anticoagulant should be given at the time when the next dose of rivaroxaban would have been taken.

Further indications:

In livedovasculopathy, several studies have been conducted on the efficacy of rivaroxaban (Weishaupt C ET al. 2016).

The initial dosage for symptomatic venous thromboembolism is 15 mg p.o.2x/day for 3 weeks and 20 mg as maintenance dose. Compared to subcutaneously administered enoxoparin, no superiority of enoxoparin could be demonstrated (EINSTEIN study).

Rivaroxaban is administered orally. Oral administration can take place independently of meals.

Renal dysfunction: Patients with severe renal dysfunction may experience increased plasma concentrations of the active ingredient. The dose must therefore be adjusted.

Frequently

• Anemia
• Swindle
• Headaches
• Conjunctival hemorrhage
• Hypotension
• Haematomas of the skin
• Epistaxis
• Haemoptyses
• Bleeding gums
• gastrointestinal bleeding
• Gastrointestinal and abdominal pain
• Dyspepsia
• Nausea, vomiting
• Constipation, diarrhoea
• Increase in transaminases
• Bleeding in the urogenital tract (including haematuria, menorrhagia)
• renal impairment
• Fever
• Edema
• Reduced performance.

Occasionally

• thrombocytosis, thrombocytopenia
• Allergic reaction
• Allergic dermatitis
• Angioedema and allergic oedema
• Cerebral and intracranial hemorrhage
• Syncope
• Tachycardia
• Dry mouth
• Liver dysfunction, increase in bilirubin, alkaline phosphatase and GGT in the blood
• Urticaria
• Haemarthros
• Indisposition
• Increase in LDH, lipase and amylase.

Rare

• Icterus
• Cholestasis
• Hepatitis
• hemorrhage into a muscle
• Local edema
• Vascular pseudoaneurysm.

Side effects with unknown frequency

• Compartment syndrome as a result of bleeding
• Rivaroxaban-induced thrombocytopenia (Pop MK et al. 2018)
• Cutaneous necroses as observed with heparin (Vu TT et al. 2017).
• Bullous pemphigoid or pemphigoid-like bullous diseases (Ferreira C et al. 2018; Chohan SA et al. 2020)
• Stevens-Johnson syndrome
• Leucocytoclastic vasculitis (Chaaya G et al. 2016)
• False positive titres of lupus anticoagulant (Murer LM et al. 2016)

Rivaroxaban should not be used at a creatinine clearance of <15ml/min.

Liver dysfunction: in the presence of liver disease associated with coagulopathy and a clinically relevant risk of bleeding

Children and adolescents under the age of 18 (as safety and efficacy have not been proven in children and adolescents, rivaroxaban should not be used)

Xarelto®

1. Chaaya G et al (2016) Rivaroxaban-induced leukocytoclastic vasculitis: A challenging rash. Ann Allergy Asthma Immunol 116:577-578.
2. Gressenberger P (2019) Bleeding complications under DOAKs and their handling Z VESSELS 16: 5-8
3. Chohan SA et al (2020) Bullous pemphigoid-like skin rash associated with rivaroxaban use in a very elderly patient with multimorbidity and chronic kidney disease: A case report. Clin Case Rep 8:725-730.
4. Ferreira C et al (2018) Bullous pemphigoid-like skin eruption during Treatment with Rivaroxaban: A Clinical Case Study. Eur J Case Rep Internal Med 5:000724.
5. EINSTEIN Investigators (2011) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363: 2499-2510
6. Heidbuechel A et al (2013) European heart rhythm association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 15: 625-651.
7. Murer LM et al (2016) Rivaroxaban Therapy, False-Positive Lupus Anticoagulant Screening Results, and Confirmatory Assay Results. Lab Med 47:275-278.
8. Masahir I et al (2016) Profiles of direct oral anticoagulants and clinical usage -dosage and dose regimen differences. J Intensive Care 4: 19.
9. Naito T et al (2018) Pulmonary embolism and deep vein thrombosis in eosinophilic granulomatosis with polyangiitis successfully treated with rivaroxaban. Respir Med Case Rep25:33-35.
10. Pop MK et al (2018) Drug-induced thrombocytopenia after anticoagulation with rivaroxaban. On J Emerg Med 36: 531.e1-531.e2.
11. Ruff CT et al (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 383: 955-62.
12. Sherwood MW et al (2015) Gastrointestinal bleeding in patients with atrial fibrillation treated with Rivaroxaban or Warfarin: ROCKET AF Trial. J Am Coll Cardiol 66: 2271-2281.
13. Schwarb H et al (2016) New direct oral anticoagulants (DOAC) and their use today. Dent J (Basel) 4: 5.
14. Vu TT et al (2017) Adverse Drug Reactions and Cutaneous Manifestations Associated With Anticoagulation. J Cutan Med Surg 21:540-550.
15. Weishaupt C ET al (2016) Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial. Lancet Haematol 3:e72-e79.
16. Willet CK et al (2017) Use of direct oral anticoagulants for the prevention and treatment of thromboembolic disease in patients with reduced renal function: a short review of the clinical evidence. Ther Clin Risk Manag 13: 447-454.