Other antithrombotic agents

Rivaroxaban

Each film-coated tablet contains 10 mg rivaroxaban

Film-coated tablet (tablet). Light red, round tablets marked with the BAYER-cross on one side and "10" and a triangle on the other side.

Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.

The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that haemostasis has been established.

The duration of treatment depends on the individual risk of the patient for venous thromboembolism which is determined by the type of orthopaedic surgery.

• For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.
• For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended.

If a dose is missed the patient should take Xarelto immediately and then continue the following day with once daily intake as before.

Xarelto can be taken with or without food.

Renal impairment

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min) .

Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased in this patient population, 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. Xarelto may be used with caution in cirrhotic patients with moderate hepatic impairment (Child Pugh B) if it is not associated with coagulopathy.

No dose adjustment is necessary in patients with other hepatic diseases.

Body weight

No dose adjustment.

Gender

No dose adjustment

Children and adolescents Xarelto is not recommended for use in children or adolescents below 18 years of age due to a lack of data on safety and efficacy.

Patients above 65 years - No dose adjustment.

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. Pregnancy and lactation (see Interactions).

Haemorrhagic risk

Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs of bleeding complications after initiation of treatment. This may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin.

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 which may lead to an increased bleeding risk. Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min.

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

Hepatic impairment

In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban plasma levels may be significantly increased which may lead to an increased bleeding risk. Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Xarelto may be used with caution in cirrhotic patients with moderate hepatic impairment (Child Pugh B) if it is not associated with coagulopathy.

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 Pgp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree which may lead to an increased bleeding risk.

Fluconazole is expected to have less effect on rivaroxaban exposure and can be co-administered with caution.

Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, platelet aggregation inhibitors or other antithrombotic agents.

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.

 Hip fracture surgery

Rivaroxaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, rivaroxaban is not recommended in these patients.

Spinal/epidural anaesthesia or puncture

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.

An epidural catheter is not to be removed earlier than 18 hours after the last administration of rivaroxaban. The next rivaroxaban dose is to be administered not earlier than 6 hours after the removal of the catheter.

If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

Interaction with CYP3A4 inducers

The concomitant use of rivaroxaban with strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to reduced rivaroxaban plasma concentrations. Strong CYP3A4 inducers should be co-administered with caution.

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.

CYP3A4 and Pgp inhibitors

Co-administration of rivaroxaban with ketoconazole (400 mg once a day [od]) or ritonavir (600 mg twice a day [bid]) 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 Pgp. Fluconazole is expected to have less effect on rivaroxaban exposure and can be co-administered with caution.

Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or Pgp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg bid), for instance, considered as strong CYP3A4 inhibitor and moderate Pgp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in C_max. This increase is not considered clinically relevant.

Erythromycin (500 mg three times a day [tid]), which inhibits CYP3A4 and Pgp moderately, led to a 1.3 fold increase in mean rivaroxaban AUC and C_max. This increase is not considered clinically relevant.

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) an additive effect on anti-Factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.

Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants.

NSAIDs/platelet aggregation inhibitors

No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.

Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction but a relevant increase in bleeding time was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.

Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk.

CYP3A4 inducers

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) may also lead to reduced rivaroxaban plasma concentrations. Strong CYP3A4 inducers should be co-administered with caution.

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of Pgp) or atorvastatin (substrate of CYP3A4 and Pgp). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.

No clinically relevant interaction with food was observed.

Laboratory parameters

Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban.

The safety of rivaroxaban 10 mg has been evaluated in three phase III studies including 4,571 patients exposed to rivaroxaban undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) treated for up to 39 days.

In total, about 14 % of the treated patients experienced adverse reactions. Bleedings or anaemia occurred in approximately 3.3 % and 1 % of patients, respectively. Other common adverse reactions were nausea, increased GGT and an increase in transaminases. The adverse reactions should be interpreted within the surgical setting.

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 posthaemorrhagic anaemia. The signs, symptoms, and severity (including possibly fatal outcome) will vary according to the location and degree or extent of the bleeding. 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 with other medicinal products affecting haemostasis.

Haemorrhagic complications may present as weakness, asthenia, paleness, dizziness, headache or unexplained swelling. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Adverse reactions in the three phase III studies are listed in table 1 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

Very rare: < 1/10,000

Not known: cannot be estimated from the available data.

Treatment-emergent adverse reactions

Investigations
Common: Increased GGT, increase in transaminases (incl. ALT increase, AST increase)
Uncommon: Increased lipase, increased amylase, blood bilirubin increased, increased LDH, increased alkaline phosphatase
Rare: Bilirubin conjugated increased (with or without concomitant increase of ALT)

Cardiac disorders
Uncommon: Tachycardia

Blood and lymphatic system disorders
Common: Anaemia (incl. respective laboratory parameter)
Uncommon: Thrombocythaemia (incl. platelet count increased)

Nervous system disorders
Uncommon: Syncope (incl. loss of consciousness), dizziness, headache

Gastrointestinal disorders
Common: Nausea
Uncommon: Constipation, diarrhoea, abdominal and gastrointestinal pain (incl. upper abdominal pain, stomach discomfort), dyspepsia (incl. epigastric discomfort), dry mouth, vomiting

Renal and urinary disorders
Uncommon: Renal impairment (incl. blood creatinine increased, blood urea increased)

Skin and subcutaneous tissue disorders
Uncommon: Pruritus (incl. rare cases of generalised pruritus), rash, urticaria (incl. rare cases of generalised urticaria), contusion

Musculoskeletal and connective tissue disorders
Uncommon: Pain in extremity

Injury, poisoning and procedural complications
Uncommon: Wound secretion

Vascular disorders
Common: Post-procedural haemorrhage (incl. post-operative anaemia, and wound haemorrhage)
Uncommon: Haemorrhage (incl. haematoma and rare cases of muscle haemorrhage), gastrointestinal tract haemorrhage (incl. gingival bleeding, rectal haemorrhage, haememesis), haematuria (incl. blood urine present), genital tract haemorrhage (incl. menorrhagia), hypotension (incl. blood pressure decreased, procedural hypotension), nose bleed
Not known: Bleeding into a critical organ (e.g. brain), adrenal haemorrhage, conjunctival haemorrhage, haemoptysis

General disorders and administration site conditions
Uncommon: Localised oedema, peripheral oedema, feeling unwell (incl. fatigue, asthenia), fever

Immune system disorders
Rare: Dermatitis allergic
Not known: Hypersensi-tivity

Hepatobiliary disorders
Rare: Hepatic function abnormal
Not known: Jaundice

*) Adverse events have been reported in other clinical studies than the three phase III studies in patients undergoing major orthopaedic surgery of the lower limbs

Bayer HealthCare

(POM)