Xarelto 10mg Tablet

Xarelto 10 film-coated tablets are indicated for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs.

The recommended dose is one Xarelto 10 tablet once daily for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. Xarelto 10 may be taken with or without food. The initial dose should be taken within 6 - 10 hours after surgery provided that haemostasis has been established. If a dose is missed the patient should take Xarelto 10 immediately and continue on the following day with the once daily intake as before. Duration of treatment: The duration of treatment depends on the type of major orthopaedic surgery. After major hip surgery patients should be treated for 5 weeks. After major knee surgery patients should be treated for 2 weeks.

Xarelto 10 is contra-indicated in patients with:

• Hypersensitivity to rivaroxaban or any excipient of the tablet.
• Clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding).
• Significant hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
• Pregnancy and lactation (see Pregnancy and Lactation).

Xarelto 10 like other antithrombotics should 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
• Shortly after brain, spinal or ophthalmological surgery

In patients with severe renal impairment (creatinine clearance < 30 mL/min) rivaroxaban plasma levels may be significantly elevated which may lead to an increased bleeding risk. Due to the underlying disease these patients are at an increased risk of both bleeding and thrombosis. Therefore due to limited clinical data Xarelto 10 should be used with caution in patients with severe renal impairment.

Xarelto 10 must be used with caution in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These drugs are strong inhibitors of both CYP 3A4 and P-gp. Therefore, these drugs may increase rivaroxaban plasma concentrations to a clinically relevant degree (see Interactions).

After treatment is initiated patients should be carefully monitored for signs of bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin. Care should be taken if patients are treated concomitantly with drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other antithrombotics (see Interactions).

Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Xarelto 10 should be used in women of childbearing potential only with effective contraception. No QTc prolonging effect was observed with Xarelto 10.

Since Xarelto 10 contains lactose, patients with rare hereditary problems of lactose or galactose intolerance (e.g., the Lapp lactase deficiency or glucose-galactose malabsorption) should not take Xarelto 10.

Neuraxial (epidural/spinal) anaesthesia: When neuraxial (epidural/spinal) anaesthesia or spinal puncture is performed patients treated with antithrombotics for prevention of thromboembolic complications are at risk for development of an epidural or spinal haematoma which may result in long-term paralysis. The risk of these events is even increased by use of indwelling epidural catheters or the concomitant use of drugs affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological deficits are noted, urgent diagnosis and treatment is necessary. The physician should consider the potential benefit versus the risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. An epidural catheter should not be withdrawn earlier than 18 hours after the last administration of Xarelto 10. Xarelto 10 should be administered at earliest 6 hours after the removal of the catheter. If traumatic puncture occurs the administration of Xarelto 10 should be delayed for 24 hours.

Rivaroxaban is cleared mainly via cytochrome P450-mediated (CYP 3A4, CYP 2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-glycoprotein (P-gp) / breast cancer resistance protein (Bcrp) transporter systems (see Pharmacokinetics).

CYP Inhibition: Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.

CYP Induction: Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.

Effects on Xarelto 10: The concomitant use of Xarelto 10 with strong CYP 3A4 and P-gp inhibitors, may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure. Co-administration of Xarelto 10 with the azole-antimycotic ketoconazole (400 mg once daily) a strong CYP 3A4 and P-gp inhibitor, led to a 2,6-fold increase in mean rivaroxaban steady state AUC and a 1,7-fold increase in mean rivaroxaban C max, with significant increases in its pharmacodynamic effects. Co-administration of Xarelto 10 with the HIV protease inhibitor ritonavir (600 mg twice daily), a strong CYP 3A4 and P-gp inhibitor, led to a 2,5-fold increase in mean rivaroxaban AUC and a 1,6-fold increase in mean rivaroxaban C max, with significant increases in its pharmacodynamic effects. Therefore Xarelto 10 must be used with caution in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors (see Warnings).

Erythromycin (500 mg three times daily), which inhibits CYP 3A4 and P-gp moderately, led to a 1,3-fold increase in mean rivaroxaban steady state AUC and C max. This increase is within the magnitude of the normal variability of AUC and C max and is considered as clinically not relevant.

Drugs strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP 3A4 or P-gp, potentially increase rivaroxaban plasma concentrations. The expected increase is considered as clinically not relevant. Co-administration of Xarelto 10 with the strong CYP 3A4 and P-gp inducer rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The concomitant use of Xarelto 10 with other strong CYP 3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbitone or St. Johnu2019s Wort) may also lead to a decreased rivaroxaban plasma concentration.

Pharmacodynamic interactions: After combined administration of enoxaparin (40 mg single dose) with Xarelto 10 (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 (see Warnings). No clinically relevant prolongation of bleeding time was observed after concomitant administration of Xarelto 10 and 500 mg naproxen. Nevertheless there may be individuals with more pronounced pharmacodynamic response (see Warnings). Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction but a relevant increase in bleeding times was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels (see Warnings).

Interactions shown not to exist: There were no mutual pharmacokinetic interactions between Xarelto 10 and midazolam (substrate of CYP 3A4), digoxin (substrate of P-glycoprotein) or atorvastatin (substrate of CYP 3A4 and P-gp). Co-administration of the H 2 receptor antagonist ranitidine and the antacid aluminum hydroxide / magnesium hydroxide did not affect rivaroxaban bioavailability and pharmacokinetics. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Xarelto 10 was co-administered with 500 mg acetylsalicylic acid.

Interactions with laboratory parameters: Clotting parameter tests (PT, aPTT, HepTestu00ae) are affected as expected by the mode of action of Xarelto 10.

Pregnancy: No human data on the use of Xarelto 10 in pregnant women are available. In rats and rabbits Xarelto 10 showed pronounced maternal toxicity with placental changes related to its pharmacological mode of action (e.g., haemorrhagic complications). No primary teratogenic potential was identified. Animal data show that rivaroxaban crosses the placental barrier. Therefore use of Xarelto 10 is contra-indicated throughout pregnancy. Xarelto 10 should be used in women of childbearing potential only with effective contraception.

Lactation: No human data on use of Xarelto 10 in nursing mothers are available. In rats rivaroxaban is secreted into breast milk. Therefore Xarelto 10 may only be administered after breastfeeding is discontinued.

No effect of Xarelto 10 on the ability to drive or operate machinery has been reported.

The safety of Xarelto 10 has been evaluated in three phase III studies including 4571 patients undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) treated up to 39 days. The adverse reactions are presented within each frequency grouping and system organ classes; the adverse reactions should be interpreted within the surgical setting. Frequencies are defined as: Common: = 1 % to 1/100 to < 1/10) Uncommon: = 0,1 % to 1/1000 to < 1/100) Rare: = 0,01 % to 1/10 000 to < 1/1 000) Very rare: < 0,01 % (< 1/10 000)

Due to the pharmacological mode of action, Xarelto 10 may be associated with an increased risk of occult or overt bleeding which may result in post haemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Haemorrhagic complications may present as weakness, asthenia, paleness, dizziness, headache or unexplained swelling. Therefore, the possibility of a haemorrhage should be considered in evaluating the condition in any anticoagulated patient. Adverse reactions as reported in the three phase III studies are listed below in Table 1, by system organ class (in MedDRA) and frequency.

Table 1: All treatment-emergent adverse drug reactions reported in patients in three phase III studies. Common = 1 % to < 10 % Uncommon = 0,1 % to < 1 % Rare = 0,01 % to < 0,1 %

BLOOD AND THE LYMPHATIC SYSTEM DISORDERS: Anaemia (incl. respective lab parameters), Thrombocythemia (incl. platelet count increased)

CARDIAC DISORDERS: Tachycardia

GASTROINTESTINAL DISORDERS: Nausea, Constipation, Diarrhoea, Abdominal and Gastrointestinal pain (incl. upper abdominal pain, stomach discomfort), Dyspepsia (incl. epigastric discomfort), Dry mouth, Vomiting

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Localised oedema, Feeling unwell (incl. fatigue, asthenia), Fever, Oedema, peripheral

HEPATOBILIARY DISORDERS: Hepatic function abnormal

IMMUNE SYSTEM DISORDERS: Dermatitis, allergic

INJURY, POISONING AND PROCEDURAL COMPLICATIONS: Wound secretion

INVESTIGATIONS: Increased GGT, Increased Lipase, Bilirubin conjugated increased (with or without concomitant increase of ALT), Increase in transaminases (incl. ALT increase, AST increase), Increased Amylase, Blood bilirubin increased, Increased LDH, Increased alkaline phosphatase

MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Pain in extremity

NERVOUS SYSTEM DISORDERS: Dizziness, Headache, Syncope (incl. loss of consciousness)

RENAL AND URINARY DISORDERS: Renal impairment (incl. blood creatinine increased, blood urea increased)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Pruritus (incl. rare cases of generalised pruritus), Rash, Urticaria (incl. rare cases of generalised urticaria), Contusion

VASCULAR DISORDERS: Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), Hypotension (incl. blood pressure decreased, procedural hypotension), Haemorrhage (incl. haematoma and rare cases of muscle haemorrhage), Gastrointestinal Tract haemorrhage (incl. gingival bleeding, rectal haemorrhage, haematemesis), Haematuria (incl. blood urine present), Genital tract haemorrhage (incl. menorrhagia), Nose bleed. In other clinical studies with Xarelto 10, single cases of adrenal haemorrhage and conjunctival haemorrhage, and fatal gastrointestinal ulcer haemorrhage were reported, jaundice and hypersensitivity were rare and haemoptysis was uncommon.

Overdose following administration of Xarelto 10 may lead to haemorrhagic complications due to its pharmacodynamic properties. The use of activated charcoal to reduce absorption in case of Xarelto 10 overdose may be considered. Administration of activated charcoal up to 8 hours after overdose may reduce the absorption of rivaroxaban. Due to the high plasma protein binding Xarelto 10 is not expected to be dialysable. Should bleeding occur, management of the haemorrhage may include the following steps:

• Delay of next Xarelto 10 administration or discontinuation of treatment as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours.
• Appropriate symptomatic treatment, e.g. mechanical compression (e.g., for severe epistaxis), surgical interventions, fluid replacement and haemodynamic support, blood product or component transfusion should be considered. If bleeding cannot be controlled by the above measures, consider administration of one of the following procoagulants:
• Activated prothrombin complex concentrate (APCC)
• Prothrombin complex concentrate (PCC)
• Recombinant Factor VIIa (rF VIIa).
• Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of Xarelto 10. There is no scientific rationale for benefit or experience with systemic haemostatics (e.g. desmopressin, aprotinin, tranexamic acid, aminocaproic acid) in individuals receiving Xarelto 10.