Rivaroxaban

Registered South African indications:

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF) 
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs

Contraindications

South African recommendations

• Hypersensitivity to rivaroxaban or any of its excipients
• Pregnancy
• Lactation
• Clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding)
• Hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C
• 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 intraspinal or intracerebral vascular abnormalities
• Known existing inherited bleeding disorders (15mg and 20mg tablets)
• Persistent triple positive antiphospholipid syndrome (APS) is contraindicated
• Coadministration with any other anticoagulants
  - Unfractionated heparin (UFH)
  - Low molecular weight heparins (enoxaparin, dalteparin, etc.)
  - Heparin derivatives (fondaparinux, etc.)
  - Oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter

Recommendations in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Pregnancy
• Breastfeeding
• 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 intraspinal or intracerebral vascular abnormalities
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C
• Coadministration with any other anticoagulants
  - Unfractionated heparin (UFH)
  - Low molecular weight heparins (enoxaparin, dalteparin, etc.)
  - Heparin derivatives (fondaparinux, etc.)
  - Oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter

Cautions

• Renal impairment (CrCl≤49ml/min)
  - Concomitant use of other medicinal products which increase rivaroxaban plasma concentrations in renal impairment
  - Children and adolescents (Recommendations in other jurisdictions)
• Elderly
• Conditions with increased risk of haemorrhage
• Children with cerebral vein and sinus thrombosis who have a central nervous system infection (Recommendations in other jurisdictions)
• Congenital or acquired bleeding disorders
• Uncontrolled severe arterial hypertension
• Gastrointestinal disease without active ulceration that can potentially lead to bleeding complications
  - Inflammatory bowel disease
  - Oesophagitis
  - Gastritis
  - Gastroesophageal reflux disease
• Risk of ulcerative gastrointestinal disease
• Vascular retinopathy
• Bronchiectasis
• History of pulmonary bleeding
• Prosthetic heart valves
• Patients having recently undergone transcatheter aortic valve replacement (TAVR) (Recommendations in other jurisdictions)
• History of thrombosis in patients who are diagnosed with antiphospholipid syndrome
• Triple positive for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies
• Non-valvular atrial fibrillation and have undergone percutaneous coronary intervention with stent placement
• Hip fracture surgery patients (South African recommendations)
• History of stroke/ transient ischaemic attack
• Haemodynamically unstable patients with pulmonary embolism
• Patients requiring thrombolysis or pulmonary embolectomy
• Post-operative use of indwelling epidural catheters
• Neuraxial (epidural/spinal) anaesthesia or spinal puncture, including traumatic or repeated epidural or spinal puncture
• Pre- or post-invasive procedure or surgical intervention
• Coadministration with medicinal products affecting haemostasis
• Coadministration with systemic azole-antimycotics or HIV protease inhibitors
• Coadministration with dronedarone
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Prevention of stroke and systemic embolism with non-valvular atrial fibrillation (SPAF)
- With one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack

• Oral (fct, tab): 20mg, dly; Max: 20mg/24hrs 

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Therapy with rivaroxaban should be continued as long as risk factors for stroke and systemic embolism persist

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If a dose is missed the patient should take rivaroxaban immediately and continue with the once daily intake as recommended on the following day. The dose should not be doubled to make up for a missed dose within the same day

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Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrence 

• Oral (fct, tab): Day 1-21: 15mg, twice daily; Max: 30mg/24hrs; Day 22 onwards: 20mg, dly; Max: 20mg/24hrs; Treatment duration: Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer 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

- Extended prevention of recurrent DVT and PE following completion of at least 6 months of therapy for DVT or PE

• Oral (fct, tab): 10mg, dly; Max: 10mg/24hrs 

- 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 10mg once daily

• Oral (fct, tab): 20mg, dly; Max: 20mg/24hrs 

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The duration of therapy and dose selection should be individualised after careful assessment of the treatment benefit against the risk for bleeding

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It is essential to adhere to the dosage schedule provided. If a dose is missed during the 15mg, 12hrly treatment phase (day 1-21), the patient should take rivaroxaban immediately to ensure intake of 30mg rivaroxaban per day. In this case, two 15mg tablets may be taken at once. The patient should continue with the regular 15mg, 12hrly intake as recommended on the following day 

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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

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Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs

• Oral (fct, tab): 10mg, dly taken 6-10hrs after surgery provided that haemostasis has been established; Treatment duration: Major hip surgery: 5 weeks, Major knee surgery: 2 weeks

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

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The 10mg film-coated tablets can be taken with or without food and the 15mg and 20mg film-coated tablets should be taken with food. The tablets may be crushed and mixed with water or apple puree for those who are unable to swallow whole tablets. The crushed tablet can also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water

Not established for use in children below 18 years in South Africa

Pregnancy

• Contraindicated
• 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

Breastfeeding

• Contraindicated
• Safety and efficacy of rivaroxaban have not been established in breastfeeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore rivaroxaban is contraindicated during breastfeeding. A decision must be made whether to discontinue breastfeeding 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

Renal Impairment

Adults

• CrCl≥50-80ml/min: No dose adjustment recommended
• CrCl≥15-49ml/min: Caution; dose adjustment recommended
  When recommended dose is 10mg, dly; no dose adjustment necessary

CrCl (ml/min)	Indication	Dose
≥15-49	Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation	Oral (tab): 15mg, dly Limited data for patients with CrCl≥15-30ml/min indicate that rivaroxaban plasma levels are significantly increased in this patient population. Use caution in these patients
	Treatment of deep vein thrombosis (DVT), treatment of pulmonary embolism (PE) and prevention of recurrent DVT and PE	Oral (tab): Day 1-21: 15mg, 12hrly; Then: 15mg*, dly should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE Limited data for patients with CrCl≥15-30ml/min indicate that rivaroxaban plasma levels are significantly increased in this patient population. Use caution in these patients

*The recommendation for the use of 15mg is based on PK modelling and has not been studied in this clinical setting 
*When the recommended dose is 20mg, dly, a reduction of dose from 20mg, dly to 15mg, dly should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE

• CrCl<15ml/min: Not recommended for use

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Due to the high plasma protein binding, rivaroxaban is not expected to be dialysable

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Hepatic Impairment

• Mild (Child-Pugh Class A): No dose adjustment recommended
  Cirrhotic adult patients with mild hepatic impairment exhibited only minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group
• Moderate to severe (Child-Pugh Classes B&C) and hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients: Contraindicated

Elderly

• Caution; no dose adjustment recommended
  Elderly patients exhibited higher plasma concentrations than younger patients with mean AUC values being approximately 1,5-fold higher, mainly due to reduced (apparent) total and renal clearance
  Increasing age may increase haemorrhagic risk

Body Weight

South African recommendations

• No dose adjustment recommended

Recommendations in other jurisdictions

• Adults: No dose adjustment recommended
• Paediatrics: Caution; dose adjustment recommended
  The dose is determined based on body weight

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Potentially porphyrinogenic side effects that can also be confused with an acute porphyria attack through reduction in carbohydrate intake are gastrointestinal and abdominal pain, dyspepsia, nausea, obstipation, diarrhoea and vomiting. Side effects that commonly also occur include tachycardia and fever

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Cerebral and intracranial haemorrhage
• Syncope
• Decreased general strength and energy
  - Including fatigue
• Feeling unwell
  - Including malaise

Cardiovascular Disorders

• Tachycardia
• Hypotension
• Haematoma
• Vascular pseudoaneurysm
• Cardiac ischaemia as a consequence of anemia
  - Chest pain
  - Angina pectoris

Respiratory Disorders

• Haemoptysis
• Epitaxis
• Dyspnoea

Gastrointestinal Disorders

• Gingival bleeding
• Gastrointestinal tract haemorrhage
  - Rectal haemorrhage
• Gastrointestinal and abdominal pains
• Dyspepsia
• Nausea and vomiting
• Constipation
• Diarrhoea
• Dry mouth

Hepatobiliary Disorders

• Hepatic impairment
• Increased transaminases
• Increased bilirubin
  - Increased conjugated bilirubin (with or without a concomitant increase of alanine aminotransferase (ALT))
• Increased blood alkaline phosphatase (ALP)
• Jaundice
• Cholestasis
• Hepatitis
  - Hepatocellular injury
• Increased lactate dehydrogenase (LDH)
• Increased gamma-glutamyl transferase (GGT)

Genitourinary Disorders

• Urogenital tract haemorrhage
  - Haematuria
  - Menorrhagia
• Renal impairment
• Increased blood creatinine
• Increased blood urea
• Renal failure/ acute renal failure secondary to bleeding sufficient to cause hypoperfusion

Endocrine and Metabolic Disorders

• Increased lipase
• Increased amylase

Musculoskeletal Disorders

• Pain in extremity
• Haemarthrosis
• Muscle haemorrhage
• Compartment syndrome secondary to bleeding

Skin and Subcutaneous Tissue Disorders

• Pruritus
  - Including generalised pruritus
• Rash
• Ecchymosis
• Cutaneous and subcutaneous haemorrhage
• Urticaria
• Allergic dermatitis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome
• Contusion

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytosis
• Increased platelet count
• Thrombocytopenia
• Allergic reaction
• Angioedema
• Allergic oedema
• Anaphylactic reactions
• Anaphylactic shock
• Fever
• Peripheral oedema
• Localised oedema
• Haemorrhagic complications
  - Weakness
  - Paleness
  - Unexplained swelling
  - Unexplained shock

Sensory Disorders

• Eye haemorrhage
  - Conjunctival haemorrhage

Others

• Postprocedural haemorrhage
  - Postoperative anaemia
  - Wound haemorrhage)
• Wound secretion

• Strong CYP3A4 inhibitors
• Strong P-glycoprotein inhibitors
• Systemic azole-antimycotics
• Ketoconazole
• Itraconazole
• Voriconazole
• Posaconazole
• HIV protease inhibitors
• Ritonavir
• Clarithromycin (See additional prescribing points)
• Erythromycin (See additional prescribing points)
• Fluconazole (See additional prescribing points)
• Anticoagulants
• Vitamin K antagonists
• Warfarin
• Enoxaparin
• Non-steroidal anti-inflammatory drugs (See additional prescribing points)
• Naproxen
• Acetylsalicylic acid
• Platelet aggregation inhibitors
• Clopidogrel
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Strong CYP3A4 inducers
• Rifampicin
• Phenytoin
• Carbamazepine
• Phenobarbital
• Unfractionated heparin (UFH)
• Low molecular weight heparins
• Dalteparin
• Heparin derivatives
• Fondaparinux
• Dabigatran etexilate
• Apixaban
  (See additional prescribing points)

Other interactions

• St. John's Wort
• Clotting parameters (See additional prescribing points)

• Full blood count
• Renal function

Specific cases may require

• Anti-Factor Xa assay
• Creatinine clearance
• Hepatic function
• Weight (in children)
• International Normalised Ratio (INR)

Additional observations

• Signs and symptoms of bleeding, such as weakness, dizziness, unexplained oedema, especially in patients with renal impairment
• Unexplained decrease in haemoglobin or blood pressure
• Signs and symptoms of neurologic impairment, such as midline back pain, numbness/weakness of legs, bowel/ bladder dysfunction (in patients receiving rivaroxaban therapy during neuraxial anaesthesia (epidural or spinal anaesthesia) or spinal puncture)
• Fetal monitoring
  - Evaluation for fetal bleeding
  - Assessments for risk of preterm delivery if the direct-acting oral anticoagulant is continued

Important safety information on the treatment of patients with antiphospholipid syndrome (APS) and the use of rivaroxaban: Possible increased risk of recurrent thrombotic events In patients with a history of thrombosis diagnosed with APS, use of rivaroxaban has been associated with an increased risk of recurrent thrombotic events, compared with warfarin Rivaroxaban is not recommended in patients with APS, especially high risk patients (those who test positive for all three antiphospholipid tests - lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), where the use of rivaroxaban is contraindicated Where appropriate, consideration should be made on switching to a vitamin K antagonist

Converting from vitamin K antagonists (VKA) to rivaroxaban

- Treatment of DVT, PE and prevention of recurrence:

• VKA treatment should be stopped and rivaroxaban therapy should be initiated once the INR is ≤2.5

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When converting patients from VKAs to rivaroxaban, INR values will be falsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity of rivaroxaban, and therefore should not be used

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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
• In patients converting from rivaroxaban to VKA, VKA should be given concurrently until the INR is ≥2.0
• 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 24hrs after the previous dose but prior to the next dose of rivaroxaban. Once rivaroxaban is discontinued INR testing may be done reliably at least 24hrs after the last dose

Converting from parenteral anticoagulants to rivaroxaban

• For adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start rivaroxaban 0-2hrs before the time that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.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

Interactions with CYP3A4 inhibitors

• 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 (500mg, 12hrly), 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 (500mg, 8hrly), 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
• Fluconazole (400mg, 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 high-risk patients

Interactions with non-steroidal anti-inflammatory drugs and platelet aggregation inhibitors

• No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (10mg or 15mg) and 500mg 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 500mg acetylsalicylic acid
• Clopidogrel (300mg loading dose followed by 75mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban (15mg) 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

Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.

Tablet 10mg 

• Ixarola 10 (Bayer)
• Rezalto 10mg (Austell Laboratories)
• Rivaxored 10 (Dr Reddy's Laboratories)
• Xarelto  (Bayer) originator

Tablet 15mg 

• Ixarola 15 (Bayer)
• Rezalto 15mg (Austell Laboratories)
• Rivaxored 15 (Dr Reddy's Laboratories)
• Xarelto  (Bayer) originator

Tablet 20mg 

• Ixarola 20 (Bayer)
• Rezalto 20mg (Austell Laboratories)
• Rivaxored 20 (Dr Reddy's Laboratories)
• Xarelto  (Bayer) originator