Consumer medicine information

ARX-Rivaroxaban Tablets

Rivaroxaban

BRAND INFORMATION

Brand name

ARX-Rivaroxaban

Active ingredient

Rivaroxaban

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using ARX-Rivaroxaban Tablets.

SUMMARY CMI

ARX-RIVAROXABAN TABLETS

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ARX-RIVAROXABAN?

ARX-RIVAROXABAN contains the active ingredient rivaroxaban. ARX-RIVAROXABAN reduces the tendency of blood to form clots and is used to treat a number of conditions.

For more information, see Section 1. Why am I using ARX-RIVAROXABAN? in the full CMI.

2. What should I know before I use ARX-RIVAROXABAN?

Do not use if you have ever had an allergic reaction to ARX-RIVAROXABAN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ARX-RIVAROXABAN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ARX-RIVAROXABAN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ARX-RIVAROXABAN?

Follow all directions given to you by your doctor and other health professionals carefully including:

  • How much ARX-RIVAROXABAN to take each day
  • If you need to take ARX-RIVAROXABAN with food

More instructions can be found in Section 4. How do I use ARX-RIVAROXABAN? in the full CMI.

5. What should I know while using ARX-RIVAROXABAN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ARX-RIVAROXABAN.
Things you should not do
  • Do not take ARX-RIVAROXABAN to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor first because
    ARX-RIVAROXABAN treats and prevents serious conditions.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ARX-RIVAROXABAN affects you.
  • If this medicine makes you feel faint or dizzy, do not drive or use machinery.
Looking after your medicine
  • Keep your tablets in their blister pack until it is time to take them.
  • Store the tablets in a cool dry place where the temperature stays below 25°C

For more information, see Section 5. What should I know while using ARX-RIVAROXABAN? in the full CMI.

6. Are there any side effects?

Call your doctor immediately or go to the nearest emergency department if you feel dizzy or faint, or if you have any form of excessive bleeding, from the nose, the gums, lips, mouth, and genitals. Vomiting or coughing blood or heavy prolonged menstrual bleeding.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ARX-RIVAROXABAN TABLETS

Active ingredient(s): rivaroxaban

Consumer Medicine Information (CMI)

This leaflet provides important information about using ARX-RIVAROXABAN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ARX-RIVAROXABAN.

Where to find information in this leaflet:

1. Why am I using ARX-RIVAROXABAN?
2. What should I know before I use ARX-RIVAROXABAN?
3. What if I am taking other medicines?
4. How do I use ARX-RIVAROXABAN?
5. What should I know while using ARX-RIVAROXABAN?
6. Are there any side effects?
7. Product details

1. Why am I using ARX-RIVAROXABAN?

ARX-RIVAROXABAN contains the active ingredient rivaroxaban. ARX-RIVAROXABAN is It belongs to a group of medicines called anticoagulants. It works by inhibiting the blood clotting protein called Factor Xa, thus reducing the tendency of blood to form clots.

ARX-RIVAROXABAN is used for

  • Prevention of blood clots in your veins after a hip or knee replacement operation because after an operation you are at an increased risk of getting blood clots.
  • Prevention of blood clots in your brain (stroke) and/or other blood vessels in your body if you have a form of irregular heart rhythm called non-valvular atrial fibrillation.
  • Treatment of blood clots in the veins of your legs (deep vein thrombosis, DVT) and clots in your lung (pulmonary embolism, PE) and to prevent blood clots from re-occurring in your legs and/or lungs.

2. What should I know before I use ARX-RIVAROXABAN?

Warnings

Do not use ARX-RIVAROXABAN if:

  • you are allergic to rivaroxaban, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take ARX-RIVAROXABAN

  • if you are bleeding excessively or at an increased risk of bleeding
  • if you have liver disease which leads to an increased risk of bleeding
  • if you have end stage kidney disease or if you are undergoing dialysis (a procedure used to remove waste products from the blood). Your doctor will know how to determine your kidney function.
  • If you are taking medicines for fungal infections e.g. ketoconazole, or itraconazole, voriconazole, or posaconazole, unless they are only applied to the skin
  • if you are taking anti-viral medicines for HIV/AIDS e.g. ritonavir
  • if you had bleeding in the brain within the last 6 months.

Check with your doctor if you:

  • have any other medical conditions
  • if you have kidney disease. Your doctor will need to take special care in patients with moderate or severe kidney disease. Your doctor will do tests to determine how severe your kidney disease is.
  • if you have kidney disease and undergoing dialysis (a procedure used to remove waste products from the blood)
  • if you have prosthetic heart valves
  • if you have liver disease
  • if a doctor has told you that you have a severe form of antiphospholipid syndrome (a disease which can cause blood clots)
  • if you have an increased risk of bleeding such as:
    - bleeding disorders
    - very high blood pressure, not controlled by medical treatment
    - an active ulcer or a recent ulcer of your stomach or bowel
    - a problem with the blood vessels in the back of your eyes
    - recent bleeding in your brain
    - a recent operation on your brain, spinal column or eye
    - abnormalities in blood vessels of your spine or brain
    - a lung disease where your bronchi are widened (bronchiectasis), or history of bleeding in the lungs. Your doctor may decide to keep you under closer observation.
  • take any medicines for any other condition

In the event of a surgery

Tell your doctor, dentist or pharmacist if you need to have an operation (including dental work) while you are taking ARX-RIVAROXABAN. It is very important to take ARX-RIVAROXABAN and any other medications you might be on, before and after the operation exactly at the times you have been told by your doctor.

During any invasive procedure or operation, if it involves a catheter or injection into your spinal column (e.g. for epidural or spinal anaesthesia or pain reduction):

  • it is very important to take ARX-RIVAROXABAN before and after the injection or removal of the catheter exactly at the times you have been told by your doctor
  • tell your doctor immediately if you get numbness or weakness of your legs or problems with your bowel or bladder after the end of anaesthesia, because urgent care is necessary

ARX-RIVAROXABAN contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking it.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not use this medicine if you are pregnant or intend to become pregnant. Women should use a reliable contraceptive while taking ARX-RIVAROXABAN.

Do not use ARX-RIVAROXABAN if you are breastfeeding. It is not known whether rivaroxaban passes into human breast milk.

Mechanical heart valve

Tell your doctor if you have a mechanical heart valve.
ARX-RIVAROXABAN may not be suitable for you because it has not been studied in patients with mechanical heart valve.

Child under the age of 18 years

  • This medicine should not be used in a child under the age of 18 years.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with ARX-RIVAROXABAN and affect how it works.

These include:

  • other medicines to reduce blood clotting e.g. enoxaparin, clopidogrel or warfarin
  • some medicines to treat depression (selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs))
  • anti-inflammatory and pain-relieving medicines e.g. naproxen or medicines used for the protection of heart disease e.g. acetylsalicylic acid (aspirin)
  • medicines for treatment of epilepsy (phenytoin, carbamazepine) St John's Wort, a herbal product used for depression
  • Rifampicin, an antibiotic

These medicines may be affected by ARX-RIVAROXABAN, may increase the effect of ARX-RIVAROXABAN or may affect how well ARX-RIVAROXABAN works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ARX-RIVAROXABAN.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ARX-RIVAROXABAN.

4. How do I use ARX-RIVAROXABAN?

How much to take

  • To prevent clots in your veins after a hip or knee replacement operation, the dose is one ARX-RIVAROXABAN 10 mg tablet once a day with or without food.
  • To prevent blood clots in brain (stroke) and other blood vessels, the usual dose is one ARX-RIVAROXABAN 20 mg tablet once daily. If your kidneys are not working properly, your doctor may reduce your dose to one ARX-RIVAROXABAN 15 mg tablet once daily. The tablet packs are marked with days of the week to help you remember if you have taken your daily dose. ARX-RIVAROXABAN 15 mg and 20 mg tablets are to be taken with food.
  • To treat blood clots in your legs and clots in your lungs and for preventing blood clots from reoccurring, the usual dose is one ARX-RIVAROXABAN 15 mg tablet TWICE daily for the first three weeks, followed by one ARX-RIVAROXABAN 20 mg tablet ONCE daily. The initial treatment pack (42 tablet pack) is marked with days of the week and “am” for the morning dose and “pm” for the evening dose. This will help you remember if you have taken the required dose. After 6 to 12 months treatment your doctor may decide to continue treatment with either one ARX-RIVAROXABAN 20 mg tablet ONCE a day or one ARX-RIVAROXABAN 10 mg tablet ONCE a day. ARX-RIVAROXABAN 15 mg and 20 mg tablets are to be taken with food.
  • If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take ARX-RIVAROXABAN. The tablet may be crushed and mixed with water or apple puree immediately before you take it. This drink should be immediately followed by food.
  • If necessary, the crushed ARX-RIVAROXABAN tablet may be given to you through a stomach tube.
  • After giving the crushed ARX-RIVAROXABAN tablet via the stomach tube, you or your carer should flush the tube with water.
  • If you are taking the 15 or 20 mg ARX-RIVAROXABAN tablet, you should be fed via the stomach tube straight after your dose of ARX-RIVAROXABAN.
  • Follow the instructions provided and use ARX-RIVAROXABAN until your doctor tells you to stop.

When to take ARX-RIVAROXABAN

ARX-RIVAROXABAN should be used following hip or knee replacement operation: Take the first tablet 6 to10 hours after your operation or as advised by your doctor. Then take a tablet every day for the duration prescribed, unless your doctor tells you to stop. If you have had a hip replacement, you will usually take the tablets for 5 weeks. If you have had a knee replacement, you will usually take the tablets for 2 weeks. Your doctor will advise you about the exact duration.

For prevention of stroke or treatment or prevention of blood clots in your legs and/or lungs, take the tablet(s) every day until your doctor tells you to stop. Your doctor will decide how long you must continue your treatment.

If your heartbeat needs to be restored to normal by a procedure called cardioversion, take ARX-RIVAROXABAN according to your doctor's instructions. If you need a procedure to treat blocked blood vessels in your heart (called a percutaneous coronary intervention – PCI with an insertion of a stent), the dose may be changed by your doctor. Your doctor will advise you about any changes to the amount of ARX-RIVAROXABAN you should take.

If you forget to use ARX-RIVAROXABAN

ARX-RIVAROXABAN should be used regularly at the same time each day.

If you are taking one ARX-RIVAROXABAN 10 mg, or one 15 mg, or one 20 mg tablet ONCE a day: If you have missed a dose, take it as soon as you remember. Do not take more than one tablet in a single day to make up for a forgotten dose. Take the next tablet on the following day and then carry on taking a tablet once a day as normal. Do not take a double dose to make up for a forgotten tablet.

If you are taking one ARX-RIVAROXABAN 15 mg tablet TWICE a day and have missed a dose, take it as soon as you remember. If you forget to take a dose; you can take two ARX-RIVAROXABAN 15 mg tablets at the same time to get a total dose of 30 mg in one day. The following day onwards, you should take one ARX-RIVAROXABAN 15 mg tablet twice a day as normal, until required.

If you use too much ARX-RIVAROXABAN

If you think that you have used too much ARX-RIVAROXABAN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ARX-RIVAROXABAN?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor, dentist and pharmacist that you are taking ARX-RIVAROXABAN.
  • Take ARX-RIVAROXABAN exactly as your doctor has prescribed.

Call your doctor straight away if:

  • You need to have a surgical or dental procedure.
  • Your doctor is planning for you to have an anaesthetic injection in your back (spinal or epidural injection).
  • Are prescribed other medications during the course of therapy with ARX-RIVAROXABAN
  • You become pregnant while you are taking ARX-RIVAROXABAN

Remind any doctor, dentist or pharmacist you visit that you are using ARX-RIVAROXABAN.

Things you should not do

  • Do not take ARX-RIVAROXABAN to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor first because ARX-RIVAROXABAN treats and prevents serious conditions.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ARX-RIVAROXABAN affects you.

If this medicine makes you feel faint or dizzy, do not drive or use machinery.

Looking after your medicine

  • Keep your tablets in their blister pack until it is time to take them.
  • Store the tablets in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal:
  • diarrhoea, indigestion, or stomach pain
  • constipation
  • feeling sick (nausea)
Heart:
  • fast heart beat
General disorders/Other:
  • tiredness, pale skin and breathlessness
  • fever
  • headache
Musculoskeletal:
  • pain in the arms or legs
Immune system:
  • frequent infections such as severe chills, sore throat and mouth ulcers
Skin-related:
  • mild rash, itchy skin
  • bruising
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Bleeding:
  • prolonged or excessive bleeding from gums, nose, etc
  • heavy menstrual bleeding
Severe allergy:
  • signs such as rash, itching or hives on skin, swelling of the face, lips, tongue, or other parts of the body, shortness of breath, wheezing or trouble breathing
Gastrointestinal-related:
  • signs of liver problems such as yellowing of the skin and/or eyes (jaundice)
  • blood in the urine or stool
  • vomiting or coughing up blood
Respiratory-related:
  • breathlessness, chest pain
Nervous system-related:
  • dizziness, fainting
  • exceptional weakness
Musculoskeletal-related:
  • numbness in the arms and legs
  • unexplained swelling
Skin-related:
  • skin condition with severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
Injury/wound-related:
  • oozing from a surgical wound
Anticoagulant-related nephropathy
  • blood in urine
  • reduced urine output
  • swelling of the ankles, feet and legs
  • increased time for blood to clot
  • heavy bleeding
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Your doctor may need to monitor and conduct blood tests, as ARX-RIVAROXABAN can affect your liver or pancreatic enzymes. You may not experience any specific symptoms.

Like other similar medicines (anticoagulants), ARX-RIVAROXABAN may cause bleeding, which may potentially be life threatening. In some cases this bleeding may not be obvious. There is no antidote available to reverse the effects of ARX-RIVAROXABAN, however there are measures your health professional can take to control /stop the bleeding.

Please see your doctor if you experience any symptoms of bleeding.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ARX-RIVAROXABAN contains

Active ingredient
(main ingredient)		rivaroxaban
Other ingredients
(inactive ingredients)		microcrystalline cellulose,
croscarmellose sodium,
lactose monohydrate,
hypromellose,
sodium lauryl sulfate,
magnesium stearate,
Opadry Pink 03F540112 (10 mg ARTG: 140394),
Opadry Brown 03F565079 (15 mg ARTG: 140395),
Opadry II Brown 85F565098 IH (20 mg ARTG: 140396)

Do not take this medicine if you are allergic to any of these ingredients.

What ARX-RIVAROXABAN looks like

ARX-RIVAROXABAN 10 mg – Round, light red, biconvex film-coated tablets having “A1” debossed on one side and plain on other side (Aust R 357805).

It is packed in blister packs in cartons of 3, 10, 14, 15, 28, 30 and 100 tablets.

ARX-RIVAROXABAN 15 mg – Round, red, biconvex film-coated tablets having “A2” debossed on one side and plain on other side (Aust R 357809).

It is packed in blister packs in cartons of 7, 14, 28, 30, 42, 84, 98 and 100 tablets.

ARX-RIVAROXABAN 20 mg – Dark red coloured, oval shaped, biconvex film coated tablet with “A3” debossed on one side and plain on other side (Aust R 357803).

It is packed in blister packs in cartons of 7, 14, 28, 30, 84, 98 and 100 tablets.

Not all pack sizes may be marketed.

Who distributes ARX-RIVAROXABAN

Arrotex Pharmaceuticals Pty Ltd
15 - 17 Chapel Street
Cremorne VIC 3121

www.arrotex.com.au

This leaflet was prepared in October 2023.

Published by MIMS November 2024

BRAND INFORMATION

Brand name

ARX-Rivaroxaban

Active ingredient

Rivaroxaban

Schedule

S4

 

1 Name of Medicine

Rivaroxaban.

2 Qualitative and Quantitative Composition

Each film-coated tablet of ARX-Rivaroxaban:
10 mg contains 10 mg of rivaroxaban.
15 mg contains 15 mg of rivaroxaban.
20 mg contains 20 mg of rivaroxaban.

Excipient with known effect.

Each film-coated tablet of ARX-Rivaroxaban:
10 mg contains 24.70 mg lactose (as monohydrate).
15 mg contains 13.88 mg lactose (as monohydrate).
20 mg contains 18.52 mg lactose (as monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated (immediate release) tablet.

ARX-Rivaroxaban 10 mg.

Round, light red, biconvex film-coated tablets having "A1" debossed on one side and plain on other side.

ARX-Rivaroxaban 15 mg.

Round, red, biconvex film-coated tablets having "A2" debossed on one side and plain on other side.

ARX-Rivaroxaban 20 mg.

Dark red coloured, oval shaped, biconvex film coated tablet with "A3" debossed on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

ARX-Rivaroxaban is indicated for:
Prevention of venous thromboembolism (VTE) in adult patients who have undergone major orthopaedic surgery of the lower limbs (elective total hip replacement, treatment for up to 5 weeks; elective total knee replacement, treatment for up to 2 weeks).
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for the prevention of recurrent DVT and PE.

4.2 Dose and Method of Administration

Dosage.

VTE prevention in total hip and knee replacement.

The recommended dose of ARX-Rivaroxaban for VTE prevention in major orthopaedic surgery of the lower limbs (elective total hip or knee replacement) is a 10 mg tablet taken once daily.
The initial dose should be taken 6 - 10 hours after surgery provided that haemostasis has been established.
The duration of treatment depends on the type of major orthopaedic surgery.
For patients undergoing hip replacement surgery, a treatment duration of 5 weeks is recommended.
For patients undergoing knee replacement surgery, a treatment duration of 2 weeks is recommended.
Dose of 10 mg once daily and duration specified for each type of surgery is not to be exceeded.

Stroke prevention in atrial fibrillation.

The recommended dose is 20 mg once daily.
For patients with severe and moderate renal impairment (Creatinine clearance: 15 - 49 mL/min), one 15 mg tablet of ARX-Rivaroxaban should be taken once daily. Due to limited clinical data caution should be taken in patients with severe renal impairment (Creatinine clearance 15 - 29 mL/min).
Therapy with ARX-Rivaroxaban should be continued long term provided the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding.

Cardioversion.

ARX-Rivaroxaban can be initiated or continued in patients who may require cardioversion.
For TOE-guided cardioversion in patients not previously treated with anticoagulants, ARX-Rivaroxaban treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).

Treatment of DVT and PE and prevention of recurrent DVT and PE.

The recommended dose for the initial treatment of acute DVT and PE is 15 mg ARX-Rivaroxaban twice daily for the first three weeks followed by 20 mg ARX-Rivaroxaban once daily for the continued treatment and the prevention of recurrent DVT and PE.
During the initial 3 weeks of acute treatment 15 mg of ARX-Rivaroxaban should be taken twice daily.
After the initial 3 weeks treatment ARX-Rivaroxaban should be continued at 20 mg once daily. Therapy should be continued as long as the VTE risk persists. The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding.
Following completion of six to twelve months therapy, based on an individual assessment of the risk of recurrent DVT or PE against the risk for bleeding, dose reduction to 10 mg ARX-Rivaroxaban once daily may be considered.

Method of administration.

ARX-Rivaroxaban 10 mg tablets may be taken with or without food (see Section 5.2 Pharmacokinetic Properties). ARX-Rivaroxaban 15 mg tablets and ARX-Rivaroxaban 20 mg tablets should be taken with food (see Section 5.2 Pharmacokinetic Properties).
For patients who are unable to swallow whole tablets; ARX-Rivaroxaban 10 mg, 15 mg, or 20 mg tablets may be crushed and mixed with water or apple sauce immediately prior to use and administered orally. After the administration of crushed ARX-Rivaroxaban 15 mg or 20 mg tablets, the dose should be immediately followed by food.
The crushed ARX-Rivaroxaban 10 mg, 15 mg, or 20 mg tablet may be given through gastric tubes. Gastric placement of the tube should be confirmed before administering ARX-Rivaroxaban. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed ARX-Rivaroxaban 15 mg or 20 mg tablets, the dose should be immediately followed by enteral feeding (see Section 5.2 Pharmacokinetic Properties).
An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed ARX-Rivaroxaban tablet to PVC or silicone nasogastric (NG) tubing.

Special populations.

Elderly (patients above 65 years).

Based on clinical data, no dose adjustment is required for these patient populations (see Section 5.2 Pharmacokinetic Properties).
Increasing age is associated with declining renal function.
The risk of bleeding increases with increasing age (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

Prior to commencing treatment with ARX-Rivaroxaban, an accurate assessment of renal function should be undertaken, especially if there is any suspicion that the person may have a degree of renal impairment (see Section 5.2 Pharmacokinetic Properties).
No clinical data are available for patients with (CrCl < 15 mL/min) or patients on dialysis. Therefore, use of ARX-Rivaroxaban is contraindicated in this patient population (see Section 4.3 Contraindications). ARX-Rivaroxaban should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
See Table 1 for dosing instructions for patients with renal impairment by indications.

Hepatic impairment.

ARX-Rivaroxaban is contraindicated in patients with significant hepatic disease (including moderate to severe hepatic impairment, i.e. Child-Pugh B and C) which is associated with coagulopathy leading to a clinically relevant bleeding risk (see Section 4.3 Contraindications). No dose adjustment is necessary in patients with other hepatic diseases (see Section 5.2 Pharmacokinetic Properties).
Limited clinical data in patients with moderate hepatic impairment (Child-Pugh B) indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment (Child-Pugh C) (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).

Paediatric population.

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

Body weight.

No dose adjustment is required for these patient populations (see Section 5.2 Pharmacokinetic Properties).

Gender.

No dose adjustment is required for these patient populations (see Section 5.2 Pharmacokinetic Properties).

Ethnic differences.

No dose adjustment is required based on ethnic differences (see Section 5.2 Pharmacokinetic Properties).
See Table 2.

Missed dose.

It is essential to adhere to the dosage schedule provided.

ARX-Rivaroxaban 10 mg, 15 mg or 20 mg tablets taken once a day.

If a dose is missed, the patient should take ARX-Rivaroxaban immediately on the same day and continue on the following day with the once daily intake as before. A double dose should not be taken to make up for a missed tablet.

ARX-Rivaroxaban 15 mg tablets taken twice a day.

If a dose is missed during the 15 mg twice daily treatment phase the patient should take the next dose immediately to ensure the intake of 30 mg total dose per day. In this case two 15 mg tablets may be taken at once. The following day the patient should continue with the regular 15 mg twice daily intake schedule as recommended.

4.3 Contraindications

ARX-Rivaroxaban is contraindicated in patients:
who are hypersensitive to the active substance or to any of the excipients listed in Section 6.1 List of Excipients;
with clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding);
with lesions at increased risk of clinically significant bleeding and patients with spontaneous impairment of haemostasis;
with significant hepatic disease (including moderate to severe hepatic impairment, i.e. Child-Pugh B and C) which is associated with coagulopathy leading to a clinically relevant bleeding risk (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties);
undergoing dialysis or patients with severe renal impairment with a creatinine clearance < 15 mL/min for ARX-Rivaroxaban 10 mg, 15 mg and 20 mg tablets, due to increased plasma levels which may lead to an increased risk of bleeding (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties);
concomitantly treated with strong inhibitors of both CYP 3A4 and P-glycoprotein such as HIV protease inhibitors (e.g. ritonavir) or systemically administered azole anti-mycotics (e.g. ketoconazole) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
who are pregnant or breast-feeding (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Use in hepatic impairment.

ARX-Rivaroxaban is contraindicated in patients with significant hepatic disease (including moderate to severe hepatic impairment, i.e. Child-Pugh B and C) which is associated with coagulopathy leading to a clinically relevant bleeding risk. Limited clinical data in patients with moderate hepatic impairment (Child-Pugh B) indicate a significant increase in the pharmacological activity. ARX-Rivaroxaban may be used in cirrhotic patients with moderate hepatic (Child-Pugh B) impairment if it is not associated with coagulopathy (see Section 5 Pharmacological Properties; Section 4.3 Contraindications).

Use in renal impairment.

Due to limited clinical data rivaroxaban 10 mg, 15 mg and 20 mg should be used with caution in patients with CrCl 15 - 29 mL/min. ARX-Rivaroxaban should not be used in patients with CrCl < 15 mL/min. Patients on dialysis have not been studied. ARX-Rivaroxaban should not be used in this population (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration; Section 5 Pharmacological Properties).
ARX-Rivaroxaban is to be used with caution in patients with moderate renal impairment (creatinine clearance 30 - 49 mL/min) receiving co-medications (including moderate inhibitors of CYP3A4 or P-gp) leading to increased rivaroxaban plasma concentrations (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Physicians should consider the benefit/risk of anticoagulant therapy before administering ARX-Rivaroxaban to patients with moderate renal impairment having a creatinine clearance close to the severe renal impairment category (CrCl < 30 mL/min), or in those with a potential to have deterioration of renal function to severe impairment during therapy. Renal function should be followed carefully in these patients. In patients with severe renal impairment (CrCl 15 - 29 mL/min), rivaroxaban plasma levels may be significantly elevated compared to healthy volunteers (1.6-fold on average) which may lead to an increased bleeding risk.
No clinical data are available for patients with creatinine clearance less than 15 mL/min. Therefore, use of ARX-Rivaroxaban is contraindicated in these patients (see Section 4.3 Contraindications).

Anticoagulant-related nephropathy.

There have been post-marketing reports of anticoagulant-related nephropathy (ARN) following anticoagulant use, presenting as acute kidney injury.
In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur, possibly in relation to episodes of excessive anticoagulation and haematuria. A few cases have been reported in patients with no pre-existing kidney disease. Close monitoring including renal function evaluation is advised in patients with excessive anticoagulation, compromised renal function and haematuria (including microscopic).

Use in the elderly.

No dose adjustment is required for the elderly (> 65 years of age). It should be taken into consideration that increasing age may be associated with declining renal and hepatic function (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

ARX-Rivaroxaban is not recommended for use in children or adolescents below 18 years of age due to a lack of data on safety and efficacy (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

Rivaroxaban at recommended doses prolongs the global clotting tests prothrombin time (PT), activated partial thromboplastin time (aPTT), HepTest, as well as the specific clotting test, anti-Factor Xa activity. PT is influenced by rivaroxaban in a dose-dependent manner if Neoplastin is used for the assay. The 5/95 percentiles of PT (Neoplastin) 2 to 4 hours after tablet intake (i.e. at the time of maximum effect) is described in Table 9 (see Section 5.1 Pharmacodynamic Properties). In case of excessive doses, the PT is expected to be outside of this range. Although aPTT, anti-Factor Xa activity and HepTest are also prolonged dose-dependently, none of these reliably assesses the pharmacodynamic effects of rivaroxaban.
During any conversion period when warfarin and rivaroxaban are overlapped, the pharmacodynamic effects of rivaroxaban can be tested with the anti-Factor Xa activity, PiCT (Prothrombinase-induced Clotting Time) and HepTest assays, as these tests were not affected by warfarin. Four days after cessation of warfarin and onwards, all tests (including PT, aPTT, anti-Factor Xa activity and ETP) only reflected the effect of rivaroxaban (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
INR is not a valid measure for the anticoagulant activity of rivaroxaban, and therefore should not be used. If measurement of rivaroxaban exposure is required in special clinical situations (such as suspected overdose, or emergency settings), both prothrombin time and chromogenic anti-Factor Xa assays using validated rivaroxaban calibrators and controls have the potential to assess rivaroxaban plasma concentrations gravimetrically (nanogram/mL or microgram/L). The pharmacokinetic profile of rivaroxaban has to be taken into account when interpreting results of these tests.

Haemorrhagic risk.

Like other anticoagulants, ARX-Rivaroxaban increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe ARX-Rivaroxaban to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Due to the pharmacological mode of action, the use of ARX-Rivaroxaban may be associated with an increased risk of occult or overt bleeding which may result in post-haemorrhagic anaemia (see Section 4.8 Adverse Effects (Undesirable Effects)). 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. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock.
Patients at high risk of bleeding should not be prescribed ARX-Rivaroxaban (see Section 4.3 Contraindications).
Close clinical surveillance is recommended in presence of multiple risk factors for bleeding including pharmacokinetic factors (renal impairment, hepatic impairment, drug interactions), pharmacodynamic interactions (NSAIDs, platelet aggregation inhibitors) and general haemorrhagic risk factors (see below).

General haemorrhagic risk factors.

ARX-Rivaroxaban 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; intraspinal or intracerebral vascular abnormalities; shortly after brain, spinal or ophthalmological surgery; bronchiectasis or history of pulmonary bleeding.
Care should be taken if patients are treated concomitantly with drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, other antithrombotics, or selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs), (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Bleeding during antithrombotic treatment may unmask underlying yet unknown malignancy in particular in the gastrointestinal or genitourinary tract. Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis.

Different gender and different weight categories.

No dose adjustment is required for these patient populations (see Section 5.2 Pharmacokinetic Properties).

Strong CYP 3A4 and P-gp inhibitors.

ARX-Rivaroxaban is contraindicated in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP 3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree which may lead to an increased bleeding risk (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
However, fluconazole, a less potent CYP3A4 and P-gp inhibitor has less effect on rivaroxaban and may be co-administered (Table 2 and Table 3).

Concomitant medications.

Non-steroidal anti-inflammatory drugs.

Care should be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs) as these drugs may impact haemostasis (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Anticoagulants.

Co-administration of rivaroxaban with other anticoagulants has not been studied in clinical trials and is not recommended, as it may lead to an increased bleeding risk (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Platelet aggregation inhibitors.

Care should be taken if patients are treated concomitantly with platelet aggregation inhibitors (e.g. clopidogrel and acetylsalicylic acid) as it may lead to an increased bleeding risk (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). For patients on antiplatelet therapy, a careful individual risk benefit assessment should be performed regarding the additional bleeding risk versus the thrombotic risk associated with the underlying diseases.

Management of bleeding.

Should bleeding occur, management of the haemorrhage may include the following steps:
Identify and treat the underlying cause of the bleeding.
Where no source of bleeding can be identified, delay of next rivaroxaban administration or discontinuation of treatment as appropriate. Rivaroxaban has a terminal half-life between 5 and 13 hours (see Section 5.2 Pharmacokinetic Properties). Management should be individualised according to the severity and location of the haemorrhage. A specific agent to reverse the anti-coagulant effect of rivaroxaban is not yet available. Because of high plasma protein binding, rivaroxaban is not expected to be dialysable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
Appropriate symptomatic treatment, e.g. mechanical compression, surgical interventions, fluid replacement and haemodynamic support, blood product (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.
If life threatening bleeding cannot be controlled by the above measures, administration of one of the following procoagulants may be considered:
activated prothrombin complex concentrate (APCC);
prothrombin complex concentrate (PCC);
recombinant factor VIIa.
While there is currently no experience with the use of these products in individuals receiving rivaroxaban, all three procoagulants have demonstrated significant reductions in rivaroxaban-induced bleeding time prolongation in nonclinical studies.
There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the systemic haemostatics desmopressin and aprotinin in individuals receiving rivaroxaban.

Surgery and interventions.

If an invasive procedure or surgical intervention is required, based on clinical judgement of the physician, ARX-Rivaroxaban 10 mg, 15 mg and 20 mg should be stopped at least 24 hours before the intervention if possible. Individual patient factors will need to be taken into account in the decision as to how long ARX-Rivaroxaban should be stopped prior to surgery. Consider longer duration of treatment cessation based on benefit/risk with patients at higher risk of bleeding or in cases of major surgery where complete haemostasis may be required.
A specific agent to reverse the anti-coagulant effect of rivaroxaban is not yet available. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
ARX-Rivaroxaban should be restarted as soon as possible after the invasive procedure or surgical intervention, provided the clinical situation allows and adequate haemostasis has been established (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

Patients with prosthetic heart valves.

ARX-Rivaroxaban is not recommended for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). In the GALILEO study, patients randomised to rivaroxaban experienced higher rates of all-cause mortality, thromboembolic and bleeding events compared to those randomised to an anti-platelet regimen.
The safety and efficacy of rivaroxaban have not been studied in patients with other prosthetic heart valves or other valve procedures; therefore, there are no data to support that rivaroxaban provides adequate anti-coagulation in those patient populations. Treatment with ARX-Rivaroxaban is not recommended for these patients.

Patients with antiphospholipid syndrome.

Direct acting oral anticoagulants (DOACs) including rivaroxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome, particularly high-risk patients (patients who are triple positive for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). Treatment with rivaroxaban is associated with an increased rate of recurrent thrombotic events compared with vitamin K antagonists (VKA) in patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome and are persistently triple positive (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Spinal/ epidural anaesthesia or puncture.

When neuraxial anaesthesia (spinal / epidural anaesthesia) or spinal /epidural puncture is performed, 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 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 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 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.
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. The exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An epidural catheter is not to be removed before at least 2 half-lives have elapsed (i.e. at least 18 hours in young patients and 26 hours in elderly patients) after the last administration of ARX-Rivaroxaban (see Section 5.2 Pharmacokinetic Properties).
The next ARX-Rivaroxaban dose is to be administered not earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs the administration of ARX-Rivaroxaban is to be delayed for 24 hours. There is no clinical experience with the use of 15 mg and 20 mg rivaroxaban, therefore the use of indwelling epidural catheters is not recommended in these situations.

Hip fracture surgery.

Rivaroxaban has not been studied in interventional clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients.

DVT and PE treatment: haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy.

ARX-Rivaroxaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of rivaroxaban have not been established in these clinical situations.

Dermatological reactions.

Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients appear to be at highest risk for these reactions early in the course of therapy; the onset of the reaction occurring in the majority of cases within the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading intense and/or blistering) or any other sign of hypersensitivity in conjunction with mucosal lesions.

Information about excipients.

Lactose intolerance.

ARX-Rivaroxaban contains lactose. Patients with rare hereditary problems of lactose or galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take ARX-Rivaroxaban.

Information for the patient.

A consumer medicine information leaflet is available. Please advise your patient to read this information carefully.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

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.
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 rivaroxaban.

Strong inhibitors of both CYP3A4 and P-gp.

The concomitant use of ARX-Rivaroxaban with substances that strongly inhibit both CYP 3A4 and P-gp may lead to reduced hepatic and renal clearance and thus significantly increased systemic exposure of rivaroxaban.
Co-administration of ARX-Rivaroxaban with the azole-antimycotic ketoconazole (400 mg od), 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 Cmax, with significant increases in its pharmacodynamic effects.
Co-administration of ARX-Rivaroxaban with the HIV protease inhibitor ritonavir (600 mg bid), 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 Cmax, with significant increases in its pharmacodynamic effects.
Therefore, ARX-Rivaroxaban is contraindicated in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors (see Section 4.3 Contraindications). However, fluconazole (400 mg once daily) considered a less potent CYP3A4 and P-gp inhibitor led to an increase in rivaroxaban AUC and Cmax within the magnitude of normal variability (see Section 4.4 Special Warnings and Precautions for Use; see Table 3, Table 4).

Strong inhibitors of CYP3A4 or P-gp.

Drugs strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, increase rivaroxaban plasma concentrations to a level which is considered not clinically relevant (see Table 4).
Patients with renal impairment taking P-gp and weak to moderate CYP 3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.
ARX-Rivaroxaban is to be used with caution in patients with moderate renal impairment (creatinine clearance 30 - 49 mL/min) receiving co-medications (including moderate inhibitors of CYP3A4 or P-gp) leading to increased rivaroxaban plasma concentrations (see Section 4.4 Special Warnings and Precautions for Use). Physicians should consider the benefit/risk of anticoagulant therapy before administering ARX-Rivaroxaban to patients with moderate renal impairment having a creatinine clearance close to the severe renal impairment category (CrCl < 30 mL/min), or in those with a potential to have deterioration of renal function to severe impairment during therapy. Renal function should be followed carefully in these patients. In patients with severe renal impairment (CrCl 15 - 29 mL/min), rivaroxaban plasma levels may be significantly elevated compared to healthy volunteers (1.6-fold on average) which may lead to an increased bleeding risk.

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. Caution should be taken when ARX-Rivaroxaban 15 and 20 mg tablets are co-administered with strong CYP3A4 inducers (see Table 4).

Pharmacodynamic interactions.

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. Co administration of rivaroxaban with other anticoagulant therapy has not been studied in clinical trials and is not recommended, as it may lead to an increased bleeding risk (see Section 4.4 Special Warnings and Precautions for Use).
Converting patients from warfarin (INR 2.0 to 3.0) to ARX-Rivaroxaban 20 mg or from ARX-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. It should be noted that the anticoagulant effect of rivaroxaban does not correlate to INR values and therefore INR should not be used.
If it is desired to test the pharmacodynamic effects of ARX-Rivaroxaban during the conversion period, anti-Factor Xa activity, PiCT, and HepTest can be used as these tests were not affected by warfarin. From day 4 after stopping warfarin onwards, all tests (including PT, aPTT, inhibition of Factor Xa activity and ETP) reflected only the effect of ARX-Rivaroxaban (see Section 4.2 Dose and Method of Administration).
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the Ctrough 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.

Non-steroidal anti-inflammatory drugs.

Bleeding time was prolonged after co-administration of naproxen (500 mg) and rivaroxaban (mean 11.3 minutes) as compared to naproxen (500 mg) alone (7.9 minutes) and rivaroxaban alone (6.1 minutes, normal range of bleeding time: 2 to 8 minutes). In the three Phase III trials (RECORD 1, 2, and 3) more than 70% of subjects received concomitant NSAIDs with a similar risk of bleeding as compared to comparator treatment. However, due to the general impact on haemostasis, care should be taken if anticoagulated patients are treated concomitantly with NSAIDs (see Section 4.4 Special Warnings and Precautions for Use).
No clinically relevant prolongation of bleeding time was observed after concomitant administration of ARX-Rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with more pronounced pharmacodynamic response (see Section 4.4 Special Warnings and Precautions for Use).

Platelet aggregation inhibitors.

Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction (with rivaroxaban 15 mg). Bleeding time was prolonged after co-administration of clopidogrel and rivaroxaban (mean 21.7 minutes) as compared to clopidogrel alone (12.7 minutes) and rivaroxaban alone (7.7 minutes, normal range of bleeding time: 2 to 8 minutes). This increase in the combined treatment group was driven by a subset of patients in whom pronounced prolongations of bleeding times were observed. These prolongations of bleeding time did not correlate to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels. For patients on antiplatelet therapy, a careful individual risk benefit assessment should be performed regarding the additional bleeding risk versus the thrombotic risk associated with the underlying diseases (see Section 4.4 Special Warnings and Precautions for Use).

Selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors.

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 program, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.

Food and dairy products.

ARX-Rivaroxaban 10 mg tablets can be taken with or without food (see Section 5.2 Pharmacokinetic Properties).
ARX-Rivaroxaban 15 mg and 20 mg tablets should be taken with food (see Section 5.2 Pharmacokinetic Properties).

Interactions shown not to exist.

There were no mutual pharmacokinetic interactions between rivaroxaban and midazolam (substrate of CYP 3A4), digoxin (substrate of P-gp) or atorvastatin (substrate of CYP 3A4 and P-gp).
Co-administration of the H2 receptor antagonist ranitidine, the antacid aluminium hydroxide / magnesium hydroxide, naproxen, clopidogrel or enoxaparin did not affect rivaroxaban bio-availability and pharmacokinetics.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Rivaroxaban did not affect male or female fertility at oral doses up to 200 mg/kg/day in Wistar rats, which corresponds to 33-fold (males) and 49-fold (females) the unbound rivaroxaban AUC in humans at the maximum recommended dose.
(Category C)
There are no data from the use of rivaroxaban in pregnant women. Thrombolytic agents can produce placental haemorrhage and subsequent prematurity and foetal loss.
Studies in rats and rabbits were affected by the anticoagulant effects of rivaroxaban on the mother. In rats, altered placental appearance and necrosis were observed at doses ≥ 10 mg/kg/day (4 times human exposure based on unbound plasma AUC). A NOAEL in rats for embryofoetal development was established at 35 mg/kg/day (17 times human exposure based on unbound plasma AUC).
In rabbits, abortions occurred at doses ≥ 10 mg/kg/day (11 times human exposure based on unbound plasma AUC), while deaths occurred at doses ≥ 40 mg/kg/day (52 times human exposure based on unbound plasma AUC). Changes in placental appearance (course, grained and/or necrotic) were also noted at doses ≥ 10 mg/kg/day. A NOAEL in rabbits for embryofoetal development was established at 2.5 mg/kg/day (3 times human exposure based on unbound plasma AUC). In rats and rabbits rivaroxaban showed pronounced maternal toxicity with placental changes related to its pharmacological mode of action (e.g. haemorrhagic complications) leading to reproductive toxicity. No primary teratogenic potential was identified. Due to the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, ARX-Rivaroxaban is contraindicated in pregnancy (see Section 4.3 Contraindications). ARX-Rivaroxaban should be used in women of childbearing potential only with effective contraception.
 No data on the use of rivaroxaban in nursing mothers are available. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, ARX-Rivaroxaban is contraindicated during breast-feeding (see Section 4.3 Contraindications).
[14C] rivaroxaban was administered orally to lactating Wistar rats (day 8 to 10 post-partum) as a single oral dose of 3 mg/kg body weight. [14C] rivaroxaban-related radioactivity was secreted into the milk of lactating rats only to a low extent in relation to the administered dose. The estimated amount of radioactivity excreted into milk was 2.12% of the maternal dose within 32 hours after administration.

4.7 Effects on Ability to Drive and Use Machines

Syncope and dizziness have been reported and may affect the ability to drive and use machines (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients experiencing these adverse reactions should not drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
The safety of rivaroxaban has been evaluated in ten Phase III studies including 36,647 patients exposed to rivaroxaban (see Table 5).
In total about 69% of patients exposed to at least one dose of rivaroxaban were reported with treatment emergent adverse events (regardless of causality). About 24% of patients experienced adverse events considered related to treatment as assessed by investigators.
See Table 6.
Due to the pharmacological mode of action, the use of ARX-Rivaroxaban may be associated with an increased risk of occult or overt bleeding from any tissue and organ which may result in post-haemorrhagic anaemia. The signs, symptoms, and severity (including possible fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension and/or taking concomitant medications affecting haemostasis (see Section 4.4 Special Warnings and Precautions for Use).
Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, asthenia, 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 a haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.
Results from the COMPASS clinical trial showed bleeding incidence rates of 6.7 per 100 patient years and anaemia incidence rates of 0.15 per 100 patient years1.
1 A pre-specified selective approach to adverse event collection was applied.

VTE prevention in total hip and knee replacement.

The safety of rivaroxaban has been evaluated in three Phase III studies including 4,571 patients undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) treated up to 39 days. In the population of subjects who have taken at least one dose of rivaroxaban 10 mg od, a total of 1,191 subjects were included in the knee replacement trial with a scheduled treatment period of about 2 weeks and 3,380 subjects included in the total hip replacement trials with a scheduled treatment period of about 5 weeks. The two treatment groups, rivaroxaban and enoxaparin/placebo showed very similar demographic and baseline characteristics.
The incidence of common treatment-emergent adverse reactions reported in the safety population was similar in both treatment groups for the three Phase III studies irrespective of treatment duration and for treatment period until Day 12 ± 2. The most frequently reported treatment-emergent adverse reactions in both treatment groups during both treatment periods were gastrointestinal disorders, in particular nausea; procedural complications such as post-operative anaemia; and investigations, in particular related to liver function tests. The adverse events and adverse reactions are presented within each system organ class; and should be interpreted within the surgical setting.
Adverse events and adverse reactions as reported by the investigators in the three Phase III studies are listed in Table 7 below by system organ class (in MedDRA). RECORD 1-3 trials were similar in study design and patient population, the dose regimen tested was rivaroxaban 10 mg od compare to enoxaparin 40 mg od.

Less frequent clinical trial adverse drug reactions < 1% in the phase III studies; 11354, 11357, 11356 (RECORD 1 to 3).

Blood and the lymphatic system disorders.

Thrombocytosis (incl. platelet count increased).

Cardiac disorders.

Tachycardia.

Gastrointestinal disorders.

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, decreased general strength and energy (incl. fatigue, asthenia), feeling unwell (incl. malaise).

Hepatobiliary disorders.

Hepatic impairment.

Immune system disorders.

Dermatitis allergic.

Injury, poisoning and procedural complications.

Wound secretion.

Investigations.

Increased lipase, increased amylase, blood bilirubin increased, increased LDH, increased alkaline phosphatase, bilirubin conjugated increased (with or without concomitant increase of ALT).

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.

Hypotension (incl. blood pressure decrease, procedural hypotension), haematoma (incl. rare cases of muscle haemorrhage), gastrointestinal tract haemorrhage (incl. gingival bleeding, rectal haemorrhage, haematemesis), urogenital tract, haemorrhage, nose bleed.

Treatment of DVT, PE and prevention of recurrent VTE.

The safety of rivaroxaban has been evaluated in three Phase III trials with 4,556 patients treated up to 21 months and exposed to either 15 mg rivaroxaban twice daily for 3 weeks followed by 20 mg once daily (EINSTEIN DVT and EINSTEIN PE) or 20 mg once daily (EINSTEIN Extension).
Treatment-emergent drug-related adverse events were reported by 28.5% of rivaroxaban treated subjects and by 28.6% of enoxaparin/VKA treated subjects (pooled studies 11702 DVT and 11702 PE). The respective incidence rates for the study 11899 were 16% rivaroxaban vs. 11% placebo.
The most common treatment-emergent adverse reactions reported in patients valid for safety analysis in the three Phase III studies for DVT or PE treatment and prevention of recurrent VTE are presented in Table 8.

Less frequent ADRs ≥ 0.1% to < 1% unless otherwise specified (pooled EINSTEIN-DVT, EINSTEIN-PE and EINSTEIN-Extension).

Eye disorders.

Eye haemorrhage.

Gastrointestinal disorder.

Anal haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, lower gastrointestinal haemorrhage, melaena, lip haemorrhage, mouth haemorrhage, tongue haemorrhage, abdominal discomfort, abdominal pain lower, dry mouth.

General disorders and administration site conditions.

Feeling abnormal (≥ 0.01% to < 0.1%), malaise.

Hepatobiliary disorders.

Hepatic impairment, jaundice (≥ 0.01% to < 0.1%).

Immune system disorders.

Hypersensitivity.

Injury, poisoning and post procedural complications.

Operative haemorrhage, post procedural haemorrhage, traumatic haematoma, traumatic haemorrhage, subdural haematoma (≥ 0.01% to < 0.1%).

Investigations.

Haemoglobin decreased, liver function test abnormal, hepatic enzyme increased, transaminases increased, blood bilirubin increased, bilirubin conjugated increased (with or without concomitant increase of ALT), gamma-glutamyltransferase increased, blood alkaline phosphatase increased, blood amylase increased, occult blood positive.

Nervous system disorders.

Syncope, cerebellar haemorrhage (≥ 0.01% to < 0.1%), cerebral haemorrhage (≥ 0.01% to < 0.1%), haemorrhage intracranial (≥ 0.01% to < 0.1%), haemorrhagic transformation stroke (≥ 0.01% to < 0.1%).

Reproductive system and breast disorders.

Menometrorrhagia (≥ 0.01% to < 0.1%), metrorrhagia.

Skin and subcutaneous tissue disorders.

Urticaria, ecchymosis, skin haemorrhage, drug eruption, dermatitis allergic, pruritus generalised.

Vascular disorders.

Hypotension.

Prevention of stroke and systemic embolism in patients with atrial fibrillation.

In the pivotal double-blind ROCKET AF study, a total of 14,264 unique subjects with non-valvular atrial fibrillation who were at risk for stroke and non-CNS systemic embolism were randomly assigned to treatment with either rivaroxaban (7,131 subjects) or warfarin (7,133 subjects) in 45 countries. Patients received rivaroxaban 20 mg orally once daily (15 mg orally once daily in patients with moderate (CrCl: 30-49 mL/min) renal impairment) or warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The safety population included subjects who were uniquely randomised and took at least 1 dose of study medication.
In total, 14,236 subjects were included in the safety population (used for the safety analyses), with 7,111 and 7,125 subjects in rivaroxaban and warfarin groups, respectively. The median time on treatment was 19 months and overall treatment duration was up to 41 months. The mean duration of rivaroxaban treatment exposure was 572 days. The treatment-emergent adverse reactions reported in patients valid for safety analysis in ROCKET AF are presented in Table 9.

Less frequent ADRs ≥ 0.1% to < 1% unless otherwise specified - ROCKET AF.

Cardiac disorders.

Tachycardia.

Eye disorders.

Eye haemorrhage, vitreous haemorrhage.

Gastrointestinal disorders.

Melaena, upper gastrointestinal haemorrhage, haemorrhoidal haemorrhage, haematochezia, mouth haemorrhage, lower gastrointestinal haemorrhage, anal haemorrhage, gastric ulcer haemorrhage, gastritis haemorrhagic, gastric haemorrhage, haematemesis, abdominal discomfort, abdominal pain lower, dry mouth.

General disorders and administration site conditions.

Malaise.

Hepatobiliary disorders.

Hepatic impairment, hyperbilirubinaemia, jaundice (≥ 0.01% to < 0.1%).

Immune system disorders.

Hypersensitivity.

Injury, poisoning, and procedural complications.

Post procedural haemorrhage, wound haemorrhage, traumatic haematoma, incision site haemorrhage, subdural haematoma, subcutaneous haematoma, periorbital haematoma.

Investigations.

Haemoglobin decreased, haematocrit decreased, blood bilirubin increased, liver function test abnormal, aspartate aminotransferase increased, hepatic enzyme increased, blood urine present, creatinine renal clearance decreased, blood creatinine increased, blood urea increased, blood alkaline phosphatase increased, lipase increased, bilirubin conjugated increased (with or without concomitant increase of ALT) (≥ 0.01% to < 0.1%).

Renal and urinary disorders.

Renal impairment.

Reproductive system disorders.

Vaginal haemorrhage, metrorrhagia.

Musculoskeletal, connective tissue, and bone disorders.

Haemarthrosis, muscle haemorrhage (≥ 0.01% to < 0.1%).

Nervous system disorder.

Loss of consciousness, haemorrhagic stroke, haemorrhage intracranial.

Skin and subcutaneous tissue disorders.

Dermatitis allergic, rash pruritic, rash erythemateous, rash generalized, pruritus generalized, urticaria, skin haemorrhage.

Vascular disorders.

Haemorrhage, bleeding varicose vein.
In other clinical studies, vascular pseudoaneurysm formation following percutaneous intervention has been reported.
See Section 5.1 Pharmacodynamic Properties, Clinical trials for safety study in patients with non-valvular atrial fibrillation undergoing PCI.

Post-marketing observations.

The following adverse reactions have been reported post-marketing in temporal association with the use of rivaroxaban. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated.

Immune system disorders.

Angioedema and allergic oedema.

Hepatobiliary disorders.

Cholestasis, hepatitis (including hepatocellular injury).

Blood and lymphatic system disorders.

Thrombocytopaenia, agranulocytosis.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndrome.

Respiratory, thoracic and mediastinal disorders.

Eosinophilic pneumonia.

Renal and urinary disorders.

Frequency: Not known, Anticoagulant-related nephropathy (see Section 4.4 Special Warnings and Precautions for Use).

4.9 Overdose

Overdose following administration of rivaroxaban may lead to haemorrhagic complications due to its pharmacodynamic properties.
Rare cases of overdose up to 1960 mg have been reported. In case of overdose, observe your patient carefully for bleeding complications or other adverse reactions (see Section 4.4 Special Warnings and Precautions for Use, Management of bleeding). Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg or above.
A specific antidote antagonising the pharmacological effect of rivaroxaban is not available.
For all overdoses, the mainstay of treatment is supportive and symptomatic care.
Activated charcoal may reduce absorption of the drug if given within 8 hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antithrombotic agent.

Mechanism of action.

Rivaroxaban is a highly selective direct Factor Xa inhibitor with oral bioavailability.
Activation of Factor X to Factor Xa (FXa) via the intrinsic and extrinsic pathway plays a central role in the cascade of blood coagulation. FXa directly converts prothrombin to thrombin through the prothrombinase complex, and ultimately, this reaction leads to fibrin clot formation and activation of platelets by thrombin. One molecule of FXa is able to generate more than 1,000 molecules of thrombin due to the amplification nature of the coagulation cascade. In addition, the reaction rate of prothrombinase-bound FXa increases 300,000-fold compared to that of free FXa and causes an explosive burst of thrombin generation. Selective inhibitors of FXa can terminate the amplified burst of thrombin generation. Consequently, several specific and global clotting tests are affected by rivaroxaban. Dose dependent inhibition of Factor Xa activity was observed in humans.

Pharmacodynamic effects.

Dose dependent inhibition of Factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only calibrated and validated for coumarins and cannot be used for any other anticoagulant. See Table 10.
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. Anti-Factor Xa activity is influenced by rivaroxaban (see Section 4.4 Special Warnings and Precautions for Use).
There is no need for monitoring of coagulation parameters while using rivaroxaban. No QTc prolonging effect was observed with rivaroxaban.

Clinical trials.

Prevention of venous thromboembolic events (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. The RECORD clinical program was designed to demonstrate the efficacy of rivaroxaban for the prevention of venous thromboembolic events (VTE), i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopaedic surgery of the lower limbs. Over 9,500 patients (7,050 in total hip replacement surgery and 2,531 in total knee replacement surgery) were studied in controlled randomised double-blind Phase III clinical studies, known as the RECORD-program.
RECORD 1 and 2 were conducted in patients undergoing elective total hip replacement surgery (THR) and RECORD 3 was performed in patients undergoing elective total knee replacement (TKR) surgery. Rivaroxaban has not been studied in interventional clinical trials in patients undergoing hip fracture surgery. See Table 11.
The respective studies were heterogeneous with respect to their composition of participating countries (centres from Europe, North and South America, Asia and Australia). Men and women of 18 years or older scheduled for hip or knee replacement surgery could be enrolled provided that they had no active or high risk of bleeding or other conditions contraindicating treatment with low-molecular weight heparin, no significant liver disease, were not pregnant or breastfeeding, or were not using HIV protease inhibitors.
In all three pivotal studies, rivaroxaban 10 mg once daily started not earlier than 6 hours postoperatively was compared with enoxaparin 40 mg once daily started 12 hours preoperatively.
The primary efficacy analysis in all studies was based on stratified (by geographical region) risk difference between rivaroxaban and enoxaparin and corresponding 2-sided 95% confidence intervals. Efficacy was assessed in two steps; first a non-inferiority test was performed based on the per protocol population. Since non-inferiority was shown, a pre-specified superiority analysis was performed subsequently based on the modified ITT population.
In all three phase III studies (see Table 12) rivaroxaban significantly reduced the rate of total VTE (any venographically detected or symptomatic DVT, non-fatal PE or death) and major VTE (proximal DVT, non-fatal PE or VTE-related death), the pre-specified primary and major secondary efficacy endpoints. The results were clinically meaningful and statistically significant. Relative risk reductions in total VTE were 49% (RECORD 3) and 70% (RECORD 1) in comparison to enoxaparin and 79% (RECORD 2) in comparison to enoxaparin/placebo. Furthermore, in all three studies the rate of symptomatic VTE (symptomatic DVT, non-fatal PE, VTE-related death) was lower in rivaroxaban treated patients compared to patients treated with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treated with rivaroxaban 10 mg compared to enoxaparin 40 mg.
The analysis of the pooled results of the Phase III trials corroborated the data obtained in the individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with rivaroxaban 10 mg once daily compared to enoxaparin 40 mg once daily.
In addition to the phase III RECORD program, a post-authorisation, non-interventional, open- label cohort study (XAMOS) has been conducted in 17,413 patients undergoing major orthopaedic surgery of the hip or knee, to compare rivaroxaban 10 mg with other standard-of-care (82% received LMWH) pharmacological thromboprophylaxis in a real-life setting. Symptomatic VTE occurred in 57 (0.6%) patients in the rivaroxaban group (n=8,778) and 88 (1.0%) of patients in the standard-of-care group (n=8,635; HR 0.63; 95% CI 0.43-0.91); safety population). Major bleeding occurred in 35 (0.4%) and 29 (0.3%) of patients in the rivaroxaban and standard-of-care groups (HR 1.10; 95% CI 0.67-1.80). This non-interventional study confirmed the efficacy and safety results seen in the RECORD program.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. The ROCKET-AF clinical program was designed to demonstrate the efficacy of rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF).
In the pivotal randomised, double-blind, double-dummy, parallel-group, event-driven, non-inferiority ROCKET-AF study comparing once daily oral rivaroxaban with adjusted-dose oral warfarin, 14,264 patients were assigned either to rivaroxaban 20 mg orally once daily (15 mg orally once daily in patients with CrCl 30 - 49 mL/min) or to warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatment was 19 months and overall treatment duration was up to 41 months.
Patients included in the trial had non-valvular atrial fibrillation and a history of prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or two or more of the following risk factors without prior stroke:
age ≥ 75 years;
hypertension;
heart failure or left ventricular ejection fraction ≤ 35%, or;
diabetes mellitus.
The mean age of patients was 71 years with 44% > 75 years. The population was 60% male, 83% Caucasian, 13% Asian and 4% other. There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less). A few patients were on clopidogrel and 11.4% on class III antiarrhythmics including amiodarone. The study included patients with co morbidities e.g. 55% secondary prevention population (prior stroke/ TIA/ Systemic embolism), hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. Patients with various degrees of renal impairment were included in the study, see Table 13 for details.
Exclusion criteria included:
cardiac related conditions (haemodynamically significant mitral valve stenosis, prosthetic heart valve, planned cardioversion, transient atrial fibrillation caused by reversible disease, known presence of atrial myxoma or left ventricular thrombus and active endocarditis);
haemorrhage risk related conditions (active internal bleeding, major surgical procedure or trauma within 30 days before randomisation, clinically significant gastrointestinal (GI) bleeding within 6 months of randomisation, history of intracranial, intraocular, spinal or atraumatic intra-articular bleeding, chronic haemorrhagic disorder, known intracranial neoplasm, arteriovenous malformation, or aneurysm);
planned invasive procedure with potential for uncontrolled bleeding;
sustained uncontrolled hypertension (> 180/100 mmHg) and;
concomitant conditions and therapies listed under Section 4.3 Contraindications as well as severe disabling stroke (modified Rankin score 4-5) or any stroke within 14 days, TIA within 3 days, > 100 mg acetylsalicylic acid (aspirin), anticipated need for chronic NSAIDs treatment, known HIV infection at the time of screening, significant hepatic impairment or (ALT > 3 x ULN).
The principal investigators were instructed to dose their patients with warfarin orally once daily, dose-adjusted to a target International Normalised Ratio [INR] of 2.5 [range 2.0 to 3.0, inclusive]. During the study, INR monitoring (using a Hemosense point of-care INR device [INRatio]) was to occur as clinically indicated but at least every 4 weeks. Unblinded INR measurements were not performed while subjects were on study drug, except in case of a medical emergency.
In order to maintain the integrity of the blind, local unblinded INR measurements (i.e. not using the study Hemosense INRatio device) were discouraged for at least 3 days after subjects stopped receiving study drug (after the start of open-label VKA therapy), including when the subject discontinued study medication, or completed the study. After 3 days, VKA dosing was managed using local unblinded INR measurements.
Comparative efficacy with standard of care (warfarin) in the double-blind clinical trial setting provides evidence that rivaroxaban is as effective as warfarin. There is insufficient experience to determine how rivaroxaban and warfarin compare when warfarin therapy is well controlled.
Unlike some other contemporary trials, these committees did not provide detailed and focused direction to the sites about their handling of individual patient INRs, since one goal of the trial was to run the study as close to usual care as possible, to maximize generalisability of the final results to standard practice.
The primary objective of the study was met, as rivaroxaban was shown to be non-inferior to warfarin in the primary efficacy endpoint, composite of stroke and systemic embolism (HR 0.79, 95% CI 0.66 - 0.96, p < 0.001). As non-inferiority was met, rivaroxaban was tested, as per the pre-specified analysis, for superiority in primary and secondary endpoints. rivaroxaban demonstrated superiority over warfarin for stroke and systemic embolism in the on treatment, safety population (HR 0.79, 95% CI 0.65 - 0.95, p = 0.015). Major secondary endpoints; composite of stroke, systemic embolism and vascular death and composite of stroke, systemic embolism, myocardial infarction (MI) and vascular death were also reduced significantly (see Table 14).
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding events) were similar for both treatment groups (see Table 15).
In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorisation, non-interventional, open-label cohort study (XANTUS) with central outcome adjudication including thromboembolic events and major bleeding has been conducted, wherein 6,785 patients with non-valvular atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS) systemic embolism under real-world conditions (safety analysis set n= 6,784). The mean CHADS2 score was 2.0 compared to a mean CHADS2 score of 3.5 in ROCKET AF. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in 0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNS systemic embolism was recorded in 0.8 per 100 patient years. These observations from routine clinical practice are consistent with the results observed in the ROCKET AF study.
Cardioversion. A prospective, randomised, open-label, multicentre, exploratory study with blinded endpoint evaluation (X-VERT) was conducted in 1,504 patients (oral anticoagulant naïve and pre- treated) with non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted VKA (randomised 2:1), for the prevention of cardiovascular events. Transoesophageal echocardiogram-guided (TOE-guided) (1-5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were employed. The primary efficacy outcome (all stroke, transient ischaemic attack, non-CNS systemic embolism, MI and cardiovascular death) occurred in 5 (0.5%) patients in the rivaroxaban group (n=978) and 5 (1.0%) patients in the VKA group (n=492; RR 0.50; 95% CI 0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6%) and 4 (0.8%) patients in the rivaroxaban (n=988) and VKA (n=499) groups, respectively (RR 0.76; 95% CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety between rivaroxaban and the VKAs treatment groups in the setting of cardioversion.
Safety study in patients who undergo PCI (percutaneous coronary intervention) with stent placement. A randomised, open-label, multicentre study (PIONEER AF-PCI) was conducted in 2124 patients with non-valvular atrial fibrillation who underwent PCI with stent placement for primary atherosclerotic disease to compare safety of two rivaroxaban regimens and a VKA regimen.
PIONEER AF-PCI was designed and powered to assess safety but was not powered to compare efficacy between the rivaroxaban regimens and a VKA regimen. Data on efficacy (including thromboembolic events) in this population are limited.
In this 12-month safety study, Group 1 of 696 patients received rivaroxaban 15 mg once daily (10 mg once daily in patients with creatinine clearance 30 - 49 mL/min) plus single antiplatelet (P2Y12 inhibitor). Group 2 of 706 patients received rivaroxaban 2.5 mg twice daily plus DAPT (dual antiplatelet therapy i.e. clopidogrel 75 mg or alternate P2Y12 inhibitor plus low dose acetylsalicylic acid (ASA) for 1, 6 or 12 months followed by rivaroxaban 15 mg (or 10 mg for subjects with creatinine clearance 30 - 49 mL/min) once daily plus low dose ASA. Group 3 of 697 patients received dose-adjusted VKA plus DAPT for 1, 6 or 12 months followed by dose-adjusted VKA plus low-dose ASA. Patients with a history of stroke or TIA were excluded from the trial.
The primary safety endpoint, clinically significant bleeding events [a composite of TIMI major bleeding, TIMI minor bleeding and Bleeding Requiring Medical Attention (BRMA)], occurred in 109 (15.7%) and in 117 (16.6%), and 167 (24.0%) subjects in Group 1, Group 2, and Group 3, respectively (HR 0.59; 95% CI 0.47-0.76; p < 0.001, and HR 0.63; 95% CI 0.50-0.80; p < 0.001, respectively) The reduction in the risk of clinically significant bleeding events was primarily a result of significantly fewer BRMA events in patients on the rivaroxaban regimen.
The secondary efficacy endpoints composite of cardiovascular events (CV death, MI, or stroke) occurred in 41 (5.9%) and in 36 (5.1%) and 36 (5.2%) subjects in the Group 1, Group 2 and Group 3, respectively.
Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE) and prevention of recurrent DVT and PE. The EINSTEIN clinical program was designed to demonstrate the efficacy of rivaroxaban in the initial and continued treatment of acute DVT and PE and prevention of recurrent DVT and PE. Over 12,800 patients were studied in four randomised controlled Phase III clinical studies (EINSTEIN DVT, EINSTEIN PE and EINSTEIN Extension) and additionally a predefined analysis of the pooled EINSTEIN DVT and EINSTEIN PE studies was conducted (see Table 19). The overall combined treatment duration in all studies was up to 21 months.
EINSTEIN DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent DVT, non-fatal PE and all-cause mortality.
In EINSTEIN CHOICE, the primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT or fatal or non-fatal PE. The secondary efficacy outcome was the composite of the primary efficacy outcome, MI, ischemic stroke, or non-CNS systemic embolism.

EINSTEIN DVT and EINSTEIN PE studies.

In the EINSTEIN DVT and EINSTEIN PE, open label, randomised, event driven non-inferiority studies, 3,449 patients with acute DVT were studied for the treatment of DVT and the prevention of recurrent DVT and PE; 4,832 patients with acute PE were studied for the treatment of PE and the prevention of recurrent DVT and PE. Concomitant conditions listed under Section 4.3 Contraindications as well as subjects who had significant liver disease or ALT > 3 x ULN, bacterial endocarditis, VKA treatment indicated other than DVT and/or PE were excluded from these studies.
Based on the clinical judgement of the investigator, the treatment duration was up to 12 months in both studies, assigned prior to randomisation. For the initial 3 week treatment of acute DVT and acute PE, 15 mg of rivaroxaban was administered twice daily. This was followed by 20 mg of rivaroxaban once daily. Patients with moderate renal impairment (creatinine clearance 30 - 49 mL/min) were treated with the same dose as patients with creatinine clearance above 50 mL/min (i.e. 15 mg twice daily for the first three weeks and 20 mg once daily from day 22 onwards). The comparator treatment regimen consisted of enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until the prothrombin time/international normalised ratio (PT/INR) was in therapeutic range (≥ 2.0). Treatment was continued with a vitamin K antagonist dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.
After randomisation, subjects allocated to the comparator arm received enoxaparin twice daily for at least 5 days in combination with VKA (overlap 4 to 5 days) and continued with VKA only after the INR had been ≥ 2 for two consecutive measurements at least 24 hours apart. Warfarin and acenocoumarol were allowed as VKAs. Warfarin and acenocoumarol were to be started not later than 48 hours after randomisation. VKA dosages were individually titrated and adjusted to achieve a target INR of 2.5 and maintain the INR within the therapeutic range (range 2.0-3.0) for either 3, 6 or 12 months. The INR had to be measured initially every 2 to 3 days, and at least once monthly once stable. Each centre had to specify before study start which VKA compound (warfarin or acenocoumarol) would be used during the study.
In the ITT analysis of EINSTEIN DVT, subjects were comparable between treatment groups. About 57% of subjects were male. The race of about 77% of subjects was described as white, about 13% as Asian, and about 2% as black. Age ranged from 18-95 years in the rivaroxaban and from 18-97 years in the enoxaparin/VKA group, with a mean of approximately 56 years in both groups. Mean body weight was about 82 kg, with ranges from 33 to 193 kg.
In the ITT analysis of EINSTEIN PE, subjects were comparable between treatment groups. 54.1% and 51.7% were men in the rivaroxaban and enoxaparin / VKA groups respectively. The race of about 66% of subjects was described as white. Age ranged from 18 to 97 years, with a mean of approximately 58 years in both treatment groups. Mean body weight was about 83 kg, ranging from 35 to 220 kg. See Table 16.
EINSTEIN-DVT (see Table 17) met its principal objective, demonstrating that rivaroxaban was non-inferior to enoxaparin/VKA for the primary outcome of symptomatic recurrent VTE (HR of 0.68 [95% CI = 0.44 - 1.04], p < 0.001). The pre-specified test for superiority was not statistically significant (p = 0.0764). The incidence rates for the principal safety outcome (major or clinically relevant non-major bleeding events), as well as the secondary safety outcome (major bleeding events), were similar for both groups (HR of 0.97 [95% CI = 0.76 - 1.22], p = 0.77 and HR of 0.65 [95% CI = 0.33 - 1.30), p = 0.21, respectively). The pre-defined secondary outcome of net clinical benefit, (the composite of the primary efficacy outcome and major bleeding events), was reported with a HR of 0.67 ([95% CI = 0.47 - 0.95], p = 0.03) in favour of rivaroxaban.
The relative efficacy and safety findings were consistent regardless of pre-treatment (none, LMWH, unfractionated heparin or fondaparinux) as well as among the 3, 6 and 12-month durations. In terms of other secondary outcomes, vascular events occurred in 12 patients (0.7%) in the rivaroxaban arm and 14 patients (0.8%) in the enoxaparin/VKA group (HR of 0.79 [95% CI = 0.36 - 1.71], p = 0.55), and total mortality accounted for 38 (2.2%) vs. 49 (2.9%) patients in the rivaroxaban vs. enoxaparin/VKA arms, respectively (p = 0.06).
In the EINSTEIN PE study (see Table 18) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); hazard ratio: 1.12 (0.75 - 1.68)). The pre-specified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.85 ((95% CI: 0.63 - 1.14), nominal p value p=0.275)).
The incidence rate for the primary safety outcome (major or clinically relevant non-major bleeding events) was slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome (major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the enoxaparin/VKA group (2.2% (52/2405)) with a hazard ratio 0.49 (95% CI: 0.31 - 0.79; p-value for superiority 0.0032).
A prespecified pooled analysis of the outcome of the EINSTEIN DVT and PE studies was conducted (see Table 19).

EINSTEIN extension study.

EINSTEIN Extension, a double-blind, randomised, event driven superiority study included 1,197 patients with confirmed symptomatic DVT or PE. rivaroxaban 20 mg once daily was compared with placebo for an additional 6 to 12 months in patients who had completed initial treatment for DVT or PE for 6 to 14 months; where clinical uncertainty with respect to the need for continued anticoagulation existed. Patients with moderate renal impairment (creatinine clearance 30 - 49 mL/min) were treated with the same dose as patients with creatinine clearance above 50 mL/min (i.e. 20 mg once daily). The treatment duration, assigned prior to randomisation, was based on the clinical judgement of the investigator.
In the EINSTEIN-Extension study (see Table 20), rivaroxaban was superior to placebo for the primary efficacy outcome with a HR of 0.18 [95% CI = 0.09 - 0.39], p < 0.001 (i.e. a relative risk reduction of 82%). For the principal safety outcome (major bleeding events) there was no significant difference between patients treated with rivaroxaban compared to placebo (p=0.11). Therefore, the pre-defined secondary outcome of net clinical benefit, defined as the composite of the primary efficacy outcome and major bleeding events, was reported with a HR of 0.28 ([95% CI = 0.15 - 0.53], p < 0.001) in favour of rivaroxaban.
In terms of other secondary outcomes, vascular events occurred in 3 patients in the rivaroxaban arm and 4 patients in the placebo group (HR of 0.74 [95% CI = 0.17 - 3.3], p=0.69) and total mortality accounted for 1 (0.2%) vs. 2 (0.3%) of patients in the rivaroxaban vs. placebo arms, respectively.

EINSTEIN CHOICE study.

In EINSTEIN CHOICE, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-12 months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatal symptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosed anticoagulation were excluded from the study. The treatment duration was up to 12 months depending on the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily and rivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.
In the EINSTEIN CHOICE study rivaroxaban 20 mg and 10 mg were both superior to 100 mg acetylsalicylic acid for the primary efficacy outcome. The secondary efficacy outcome was reduced when comparing rivaroxaban 20 mg or 10 mg vs. 100 mg acetylsalicylic acid. The principal safety outcome (major bleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to 100 mg acetylsalicylic acid. The secondary safety outcome (non-major bleeding associated with treatment cessation of more than 14 days) was similar when comparing rivaroxaban 20 mg or 10 mg vs. 100 mg acetylsalicylic acid. Outcomes were consistent across the patients with provoked and unprovoked VTE (see Table 21).
In addition to the phase III EINSTEIN program, a prospective, non-interventional, open-label cohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and death has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term safety of rivaroxaban compared with standard-of-care anticoagulation therapy under real-world conditions. In the safety analysis set (n=4,768), rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%, respectively. There were differences in patient baseline characteristics including age, cancer and renal impairment. A pre-specified propensity score stratified analysis was used to adjust for measured baseline differences but residual confounding may, in spite of this, influence the results. Adjusted hazard ratios comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all- cause mortality were 0.77 (95% CI 0.40-1.50, p=0.44), 0.91 (95% CI 0.54-1.54, p=0.72) and 0.51 (95% CI 0.24-1.07, p=0.074), respectively.
Rivaroxaban showed similar safety and efficacy compared to standard anticoagulation.
These results in patients who were observed in routine clinical practice are consistent with those observed in the EINSTEIN DVT study.
Patients with high risk triple positive antiphospholipid syndrome. In an investigator sponsored randomised open-label multicentre study with blinded endpoint adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). The trial was terminated prematurely after the enrolment of 120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. Fifty-nine patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine clearance between 30 up to 49 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomised to rivaroxaban (4 ischaemic stroke and 3 myocardial infarction). No events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) of the rivaroxaban group and 2 patients (3%) of the warfarin group.

5.2 Pharmacokinetic Properties

Absorption.

Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after tablet intake. The absolute bioavailability of rivaroxaban is high (80-100%) for the 10 mg dose irrespective of fasting/fed conditions. Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. Oral bioavailability of rivaroxaban 20 mg tablet is reduced to 66% under fasting conditions. When rivaroxaban 20 mg tablet is taken with food mean AUC is increased by 39% compared to tablet taken under fasting conditions. This indicates almost complete absorption and high oral bioavailability.
Rivaroxaban 10 mg tablets can be taken with or without food. Intake with food does not affect rivaroxaban AUC or Cmax at the 10 mg dose (see Section 4.2 Dose and Method of Administration).
Rivaroxaban 15 mg and 20 mg tablets should be taken with food (see Section 4.2 Dose and Method of Administration). The data regarding food effect is limited.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%, apart from the day of surgery and the following day when variability in exposure is high (70%) in patients who underwent hip or knee replacement.
Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. In case of administration of ARX-Rivaroxaban through nasogastric/enteral tube, avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple sauce, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given, the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.

Distribution.

Plasma protein binding in human is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 L.

Metabolism.

Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation.
Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma with no major or active circulating metabolites being present.

Excretion.

Of the approximately 2/3 that undergoes metabolic degradation, half is then eliminated renally and the other half eliminated by the faecal route. The other 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active secretion.
With a systemic clearance of about 10 L/h rivaroxaban can be classified as a low-clearance drug. Elimination of rivaroxaban from plasma occurred with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

Gender / elderly (above 65 years).

Whilst 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, no dose adjustment is necessary (see Section 4.2 Dose and Method of Administration).
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients (see Section 4.2 Dose and Method of Administration).

Different weight categories.

Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%). No dose adjustment is necessary (see Section 4.2 Dose and Method of Administration).

Children and adolescents (from birth to 18 years).

No data are available for this patient population (see Section 4.2 Dose and Method of Administration). ARX-Rivaroxaban is not recommended for use in children or adolescents below 18 years of age due to a lack of data on safety and efficacy.

Interethnic differences.

No clinically relevant interethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics (see Section 4.2 Dose and Method of Administration).

Hepatic impairment.

The critical aspect of liver impairment is the reduced synthesis of normal coagulation factors in the liver, which is captured by only one of the five clinical/biochemical measurements composing the Child-Pugh classification system. The bleeding risk in patients may not clearly correlate with this classification scheme. Therefore, the decision to treat patients with an anticoagulant should be made independently of the Child-Pugh classification.
Cirrhotic patients with mild hepatic impairment (classified as Child-Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2-fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. No relevant difference in pharmacodynamics properties was observed between these groups. In cirrhotic patients with moderate hepatic impairment (classified as Child-Pugh B), rivaroxaban mean AUC was significantly increased by 2.3-fold compared to healthy volunteers, due to significantly impaired drug clearance which indicates significant liver disease. Unbound AUC was increased 2.6-fold. There are no data in patients with severe hepatic impairment. The inhibition of FXa activity was increased by a factor of 2.6 as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1.
The global clotting test PT assesses the extrinsic pathway that comprises of coagulation Factors VII, X, V, II, and I, which are synthesised in the liver. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT. The elevated PT at baseline and a significantly altered sensitivity in anti-coagulant activity towards rivaroxaban plasma exposure (increase in slope for PT/rivaroxaban plasma concentration relationship by more than 2-fold) in cirrhotic patients with moderate hepatic impairment indicate the decreased ability of the liver to synthesize coagulation factors. The PK/PD changes in these patients are markers for the severity of the underlying hepatic disease which is expected to lead to a subsequent increased bleeding risk in this patient group.
Therefore, ARX-Rivaroxaban is contraindicated in patients with significant hepatic disease (including moderate and severe hepatic impairment, i.e. Child-Pugh B and C) which is associated with coagulopathy leading to a clinically relevant bleeding risk. No data are available for severe hepatic impairment (Child-Pugh C patients) (see Section 4.2 Dose and Method of Administration). ARX-Rivaroxaban may be used with caution in cirrhotic patients with moderate hepatic impairment if it is not associated with coagulopathy.

Renal impairment.

Rivaroxaban exposure was inversely correlated to the decrease in renal function, as assessed via creatinine clearance (CrCl) measurements. In individuals with mild (creatinine clearance 50 - 80 mL/min), moderate (creatinine clearance 30 - 49 mL/min) and severe (creatinine clearance 15 - 29 mL/min) renal impairment, rivaroxaban plasma concentrations (AUC) were 1.4, 1.5 and 1.6-fold increased respectively as compared to healthy volunteers (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
Corresponding increases in pharmacodynamic effects were more pronounced (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use) in individuals with mild, moderate or severe renal impairment; the overall inhibition of FXa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers. Prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively.
There are no data in patients with CrCl < 15 mL/min. Use is contraindicated in patients with creatinine clearance < 15 mL/min (see Section 4.3 Contraindications). ARX-Rivaroxaban 10 mg, 15 mg and 20 mg are to be used with caution in patients with severe renal impairment creatinine clearance 15 - 29 mL/min (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Due to the underlying disease, patients with severe renal impairment are at an increased risk of both bleeding and thrombosis. The increased exposure to rivaroxaban further increases the risk of bleeding in these patients. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
If there is a suspicion of renal impairment, the degree of renal impairment must be determined accurately. Caution must be exercised when renal function estimates are based on eGFR. In clinical trials, renal function was determined using the calculated creatinine clearance, using the Cockcroft-Gault formula as follows:

5.3 Preclinical Safety Data

Genotoxicity.

Rivaroxaban showed no genotoxicity potential in bacterial mutagenicity tests, chromosomal aberration assays in Chinese hamster cells or in an in vivo mouse micronucleus assay.

Carcinogenicity.

Testing was performed by oral dosing for 2 years at up to 60 mg/kg/day reaching unbound plasma rivaroxaban exposure levels similar to humans (mice) or up to 3.6-fold higher (rats) than in humans.
Rivaroxaban showed no carcinogenic potential in either species.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, hypromellose, sodium lauryl sulfate, magnesium stearate, Opadry Pink 03F540112 (10 mg ARTG: 140394), Opadry Brown 03F565079 (15 mg ARTG: 140395), Opadry II Brown 85F565098 IH (20 mg ARTG: 140394).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

The tablets are packed in Alu-Alu blisters or Aluminium-PVC/PVDC blisters:
The 10 mg tablets are supplied in packs of 3, 10, 14, 15, 28, 30, 100 tablets.
The 15 mg tablets are supplied in packs of 7, 14, 28, 30, 42, 84, 98, 100 tablets.
The 20 mg tablets are supplied in packs of 7, 14, 28, 30, 84, 98, 100 tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements by taking to your local pharmacy.

6.7 Physicochemical Properties

Rivaroxaban is an odourless, non-hygroscopic white to yellowish powder. Rivaroxaban is practically insoluble in water and aqueous media in the pH range 1 to 9. An amount of approximately 5 - 7 mg/L rivaroxaban is pH-independently soluble in aqueous media at 25°C. Rivaroxaban is only slightly soluble in organic solvents (e.g. acetone, polyethylene glycol 400).

Chemical structure.

Rivaroxaban is 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5- yl}methyl)-2-thiophene-carboxamide. The empirical formula is C19H18ClN3O5S and molecular weight is 435.89 g/mole.
Rivaroxaban has the following structural formula:

CAS number.

366789-02-8.

7 Medicine Schedule (Poisons Standard)

S4-Prescription Only Medicine.

Summary Table of Changes