Rivaroxaban

As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or nonmajor clinically relevant bleeding were observed in all treatment groups.

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 C_max, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of rivaroxaban 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.

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 C_max. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.

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 C_max. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.

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 C_max 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 C_max when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment.

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 C_max, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of rivaroxaban 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.

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 C_max. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.

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 C_max. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.

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 C_max 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 C_max when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment.

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 C_max. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in highrisk patients.

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.

In patients with moderate renal impairment (creatinine clearance 30-49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations, rivaroxaban is to be used with caution.

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. Rivaroxaban is to be used with caution in patients with creatinine clearance 15-29 ml/min.

Use of rivaroxaban is not recommended in patients with creatinine clearance <15 ml/min.

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 C_max, 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.

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, antifactor 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 C_trough 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.

As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as bronchiectasis or history of pulmonary bleeding.

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. There is no clinical experience with the use of rivaroxaban 2.5 mg with ASA alone or with ASA plus clopidogrel or ticlopidine in these situations.

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Platelet aggregation inhibitors should be discontinued as suggested by the manufacturer’s prescribing information.

As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease).

As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as uncontrolled severe arterial hypertension.

As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as vascular retinopathy.

As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding congenital or acquired bleeding disorders.

Safety and efficacy of rivaroxaban have not been established in pregnant women.

Studies in animals have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, rivaroxaban is contraindicated during pregnancy.

Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.

Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore rivaroxaban is contraindicated during breast-feeding. 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.

Rivaroxaban has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported. Patients experiencing these adverse reactions should not drive or use machines.

Summary of the safety profile

The safety of rivaroxaban has been evaluated in thirteen phase III studies including 53,103 patients exposed to rivaroxaban (see Table 1).

Table 1. Number of patients studied, total daily dose and maximum treatment duration in phase III studies:

* Patients exposed to at least one dose of rivaroxaban.

The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see ‘Description of selected adverse reactions’ below) (Table 2). The most commonly reported bleedings were epistaxis (4.5%) and gastrointestinal tract haemorrhage (3.8%).

Table 2. Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed phase III studies:

* 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.

List of adverse reactions

The frequencies of adverse reactions reported with rivaroxaban are summarised 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).

All adverse reactions reported in patients in phase III clinical trials or through post-marketing use*:

Blood and lymphatic system disorders

Common: Anaemia (incl. respective laboratory parameters)

Uncommon: Thrombocytosis (incl. platelet count increased)^A, Thrombocytopenia

Immune system disorders

Uncommon: Allergic reaction, dermatitis allergic, Angioedema and allergic oedema

Very rare: Anaphylactic reactions including anaphylactic shock

Nervous system disorders

Common: Dizziness, headache

Uncommon: Cerebral and intracranial haemorrhage, syncope

Eye disorders

Common: Eye haemorrhage (incl. conjunctival haemorrhage)

Cardiac disorders

Uncommon: Tachycardia

Vascular disorders

Common: Hypotension, haematoma

Respiratory, thoracic and mediastinal disorders

Common: Epistaxis, haemoptysis

Gastrointestinal disorders

Common: Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipation^A, diarrhoea, vomiting^A

Uncommon: Dry mouth

Hepatobiliary disorders

Common: Increase in transaminases

Uncommon: Hepatic impairment, Increased bilirubin, increased blood alkaline phosphatase^A, increased GGT^A

Rare: Jaundice, Bilirubin conjugated increased (with or without concomitant increase of ALT), Cholestasis, Hepatitis (incl. hepatocellular injury)

Skin and subcutaneous tissue disorders

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

Uncommon: Urticaria

Very rare: Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, DRESS syndrome

Musculoskeletal and connective tissue disorders

Common: Pain in extremity^A

Uncommon: Haemarthrosis

Rare: Muscle haemorrhage

Not known: Compartment syndrome secondary to a bleeding

Renal and urinary disorders

Common: Urogenital tract haemorrhage (incl. haematuria and menorrhagia^B), renal impairment (incl. blood creatinine increased, blood urea increased)^A

Not known: Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion

General disorders and administration site conditions

Common: Fever^A, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)

Uncommon: Feeling unwell (incl. malaise)

Rare: Localised oedema^A

Investigations

Uncommon: Increased LDH^A, increased lipase^A, increased amylase^A

Injury, poisoning and procedural complications

Common: Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretion^A

Rare: Vascular pseudoaneurysm^C

^A observed in prevention of 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)
* A pre-specified selective approach to adverse event collection was applied. As incidence of adverse reactions did not increase and no new adverse reaction was identified, COMPASS study data were not included for frequency calculation in this list.

Description of selected adverse reactions

Due to the pharmacological mode of action, the use of rivaroxaban 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 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.

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 rivaroxaban. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.