Patient leaflet - Rivaroxaban Milpharm 20 mg film-coated tablets

1. What Rivaroxaban is and what it is used for

This medicine contains the active substance rivaroxaban and is used in adults to:

Prevent blood clots in brain (stroke)
and other blood vessels in your body if you have a form of irregular heart rhythm called non-valvular atrial fibrillation.
Treat blood clots in the veins of your
legs (deep vein thrombosis) and in the blood vessels of your lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood vessels of your legs and/or lungs.

Rivaroxaban is used in children and adolescents below 18 years and with a body weight of 30 kg or more to:

treat blood clots and prevent re-
occurrence of blood clots in the veins or in the blood vessels of the lungs, following initial treatment of at least 5 days with injectable medicines used to treat blood clots.

Rivaroxaban belongs to a group of medicines called antithrombotic agents. It works by blocking a blood clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.

2. What you need to know before you take Rivaroxaban

Do not take Rivaroxaban:

If you are allergic to rivaroxaban or
any of the other ingredients of this medicine (listed in section 6).
If you are bleeding excessively
If you have a disease or condition in an
organ of the body that increases the risk of serious bleeding (e.g., stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes)
If you are taking medicines to
prevent blood clotting (e.g. warfarin, dabigatran, apixaban or heparin), except when changing anticoagulant treatment or while getting heparin through a venous or arterial line to keep it open.
If you have a liver disease which leads
to an increased risk of bleeding
If you are pregnant or are breast
feeding
Do not take Rivaroxaban and tell your doctor if any of these apply to you.
Warnings and precautions
Talk to your doctor or pharmacist before taking Rivaroxaban
Take special care with Rivaroxaban
- If you have an increased risk of
  bleeding, as could be the case in situations such as:
Severe kidney disease for adults, and
moderate or severe kidney disease for children and adolescents, since your kidney function may affect the amount of medicine that works in your body
If you are taking other medicines to
prevent blood clotting (e.g. warfarin, dabigatran, apixaban or heparin), when changing anticoagulant treatment or while getting heparin through a venous or arterial line to keep it open (see section “Other medicines and Rivaroxaban”)
Bleeding disorders
Very high blood pressure, not
controlled by medical treatment
Diseases of your stomach or bowel
that might result in bleeding, e.g. inflammation of the bowels or stomach, or inflammation of the oesophagus (gullet) e.g. due to gastroesophageal reflux disease (disease where stomach acid goes upwards into the oesophagus) or tumours located in the stomach or bowels or genital tract or urinary tract
A problem with the blood vessels in the
back of your eyes (retinopathy)
A lung disease where your bronchi
are widened and filled with pus (bronchiectasis), or previous bleeding from your lung
If you have a prosthetic heart valve
If you know that you have a disease
called antiphospholipid syndrome (a disorder of the immune system that causes an increased risk of blood clots), tell your doctor who will decide if the treatment may need to be changed.
If your doctor determines that your
blood pressure is unstable or another treatment or surgical procedure to remove the blood clot from your lungs is planned

If any of the above apply to you, tell your doctor before you take Rivaroxaban. Your doctor will decide, if you should be treated with this medicine and if you should be kept under closer observation.

If you need to have an operation:

It is very important to take Rivaroxaban
before and after the operation exactly at the times you have been told by your doctor.
If your operation 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
  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.

Children and adolescents

Rivaroxaban is not recommended for children with a body weight below 30 kg. There is not enough information on the use of Rivaroxaban in children and adolescents in the adult indications.

Other medicines and Rivaroxaban

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

If you are taking:
- Some medicines for fungal
  infections (e.g. fluconazole, itraconazole, voriconazole, posaconazole), unless they are only applied to the skin
- Ketoconazole tablets (used to treat Cushing’s syndrome - when the body produces an excess of cortisol)
- Some medicines for bacterial infections (e.g. clarithromycin, erythromycin)
- Some anti-viral medicines for HIV /
  AIDS (e.g. ritonavir)
- Other medicines to reduce
  blood clotting (e.g. enoxaparin, clopidogrel or vitamin K
  antagonists such as warfarin and acenocoumarol)
- Anti-inflammatory and pain
  relieving medicines (e.g. naproxen or acetylsalicylic acid)
- Dronedarone, a medicine to treat abnormal heart beat
- Some medicines to treat
  depression (selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs))

If any of the above apply to you, tell your doctor before taking Rivaroxaban, because the effect of Rivaroxaban may be increased. Your doctor will decide, if you should be treated with this medicine and if you should be kept under closer observation.

If your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he may also use a preventative ulcer treatment.

If you are taking:
- Some medicines for treatment of epilepsy (phenytoin,
  carbamazepine, phenobarbital)
- St John’s Wort (Hypericum
  perforatum), a herbal product used for depression
- Rifampicin, an antibiotic

If any of the above apply to you, tell your doctor before taking Rivaroxaban, because the effect of Rivaroxaban may be reduced. Your doctor will decide, if you should be treated with Rivaroxaban and if you should be kept under closer observation.

Pregnancy, breast-feeding and fertility

Do not take Rivaroxaban if you are pregnant or breast feeding. If there is a chance that you could become pregnant, use a reliable contraceptive while you are taking Rivaroxaban. If you become pregnant while you are taking this medicine, tell your doctor immediately, who will decide how you should be treated.

Driving and using machines

Rivaroxaban may cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4. ‘Possible side effects’). You should not drive, ride a bicycle or use any tools or machines if you are affected by these symptoms.

Rivaroxaban contains lactose and sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per each film-coated tablet, that is to say essentially ‘sodium-free’.

3. How to take Rivaroxaban

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

You must take Rivaroxaban together with a meal.

Swallow the tablet(s) preferably with water.

If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take Rivaroxaban. The tablet may be crushed and mixed with water or apple puree immediately before you take it. This mixture should be immediately followed by food. If necessary, your doctor may also give you the crushed Rivaroxaban tablet through a stomach tube.

How much to take

Adults
To prevent blood clots in brain (stroke)
and other blood vessels in your body The recommended dose is one
Rivaroxaban 20 mg tablet once a day. If you have kidney problems, the dose may be reduced to one Rivaroxaban 15 mg tablet once a day.
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), there is limited evidence to reduce the dose to one Rivaroxaban 15 mg tablet once a day (or to one Rivaroxaban 10 mg tablet once a day in case your kidneys are not working properly) in addition to an antiplatelet medicine such as clopidogrel.
To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs, and for preventing blood clots from re-occurring
The recommended dose is one
Rivaroxaban 15 mg tablet twice a day for the first 3 weeks. For treatment after 3 weeks, the recommended dose is one Rivaroxaban 20 mg tablet once a day.
After at least 6 months blood clot treatment your doctor may decide to continue treatment with either one 10 mg tablet once a day or one 20 mg tablet once a day.
If you have kidney problems, and take one 20 mg tablet once a day, your doctor may decide to reduce the dose for the treatment after 3 weeks to one 15 mg tablet once a day if the risk for bleeding is greater than the risk for having another blood clot.
Children and adolescents
The dose of Rivaroxaban depends on the body weight, and will be calculated by the doctor.
The recommended dose for children and adolescents with a body weight between 30 kg and less than 50 kg is one Rivaroxaban 15 mg tablet once a day.
The recommended dose for children and adolescents with a body weight of 50 kg or more is one Rivaroxaban 20 mg tablet once a day.

Take each Rivaroxaban dose with a drink (e.g. water or juice) during a meal. Take the tablets every day at approximately the same time. Consider setting an alarm to remind you.

For parents or caregivers: please observe the child to ensure the full dose is taken.

As the Rivaroxaban dose is based on body weight it is important to keep scheduled doctor’s visits because the dose may need to be adjusted as the weight changes.

Never adjust the dose of

Rivaroxaban by yourself. The doctor will adjust the dose if necessary. Do not split the tablet in an attempt to provide a fraction of a tablet dose. If a lower dose is required please use the alternative presentation of Rivaroxaban granules for oral suspension.

For children and adolescents who are unable to swallow tablets whole, please use Rivaroxaban granules for oral suspension.

If the oral suspension is not available, you may crush the Rivaroxaban tablet and mix with water or apple puree immediately before taking. Take some food after taking this mixture. If necessary, your doctor may also give the crushed Rivaroxaban tablet through a stomach tube.

If you spit up the dose or vomit

less than 30 minutes after you have
taken Rivaroxaban, take a new dose.
more than 30 minutes after you have
taken Rivaroxaban, do not take a new dose. In this case, take the next Rivaroxaban dose at the usual time.

Contact the doctor if you repeatedly spit up the dose or vomit after taking Rivaroxaban.

When to take Rivaroxaban

Take the tablet(s) every day until your doctor tells you to stop.

Try to take the tablet(s) at the same time every day to help you to remember it. Your doctor will decide how long you must continue treatment.

To prevent blood clots in the brain (stroke) and other blood vessels in your body: If your heart beat needs to be restored to normal by a procedure called cardioversion, take Rivaroxaban at the times your doctor tells you.

If you take more Rivaroxaban than you should

Contact your doctor immediately if you have taken too many Rivaroxaban tablets. Taking too much Rivaroxaban increases the risk of bleeding.

If you forget to take Rivaroxaban

Adults, children and adolescents: If you are taking one 20 mg tablet or
one 15 mg tablet once a day and 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 one tablet once a day.
Adults:
If you are taking one 15 mg tablet
twice a day and have missed a dose, take it as soon as you remember. Do not take more than two 15 mg tablets in a single day. If you forget to take a dose you can take two 15 mg tablets at the same time to get a total of two tablets (30 mg) on one day. On the following day you should carry on taking one 15 mg tablet twice a day.

If you stop taking Rivaroxaban

Do not stop taking Rivaroxaban without talking to your doctor first, because Rivaroxaban treats and prevents serious conditions.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Like other similar medicines to reduce the formation of blood clots, Rivaroxaban may cause bleeding which may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure (shock). In some cases the bleeding may not be obvious.

Tell your doctor immediately if you or the child experience any of the following side effects:

Signs of bleeding
bleeding into the brain or
inside the skull (symptoms can include headache, one-sided weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness. A serious medical emergency. Seek medical attention immediately!)
Long or excessive bleeding
Exceptional weakness, tiredness,
paleness, dizziness, headache, unexplained swelling, breathlessness, chest pain or angina pectoris. Your doctor may decide to keep you under closer observation or change the treatment.
Signs of severe skin reactions
Spreading intense skin rash, blisters
or mucosal lesions, e.g. in the mouth or eyes (Stevens-Johnson syndrome/ toxic epidermal necrolysis).
A drug reaction that causes rash, fever,
inflammation of internal organs, blood abnormalities and systemic illness (DRESS syndrome).

The frequency of these side effects is very rare (up to 1 in 10,000 people).

Signs of severe allergic reactions
Swelling of the face, lips, mouth,
tongue or throat; difficulty swallowing; hives and breathing difficulties; sudden drop in blood pressure.

The frequencies of severe allergic reactions are very rare (anaphylactic reactions, including anaphylactic shock; may affect up to 1 in 10,000 people) and uncommon (angioedema and allergic oedema; may affect up to 1 in 100 people.

Overall list of possible side effects found in adults, children and adolescents:

Common (may affect up to 1 in 10 people):

Reduction in red blood cells which
can make the skin pale and cause weakness or breathlessness
Bleeding in the stomach or bowel,
urogenital bleeding (including blood in the urine and heavy menstrual bleeding), nose bleed, bleeding in the gum
Bleeding into the eye (including
bleeding from the whites of the eyes)
Bleeding into tissue or a cavity of the
body (haematoma, bruising)
Coughing up blood
Bleeding from the skin or under the
skin
Bleeding following an operation
Oozing of blood or fluid from surgical
wound
Swelling in the limbs
Pain in the limbs
Impaired function of the kidneys (may
be seen in tests performed by your doctor)
Fever
Stomach ache, indigestion, feeling or
being sick, constipation, diarrhoea
Low blood pressure (symptoms may
be feeling dizzy or fainting when standing up)
Decreased general strength and
energy (weakness, tiredness), headache, dizziness
Rash, itchy skin
Blood tests may show an increase in
some liver enzymes

Uncommon (may affect up to 1 in 100 people):

Bleeding into the brain or inside the
skull (see above, signs of bleeding)
Bleeding into a joint causing pain and
swelling
- Thrombocytopenia (low number of platelets, which are cells that help blood to clot)
- Allergic reactions, including allergic skin reactions
- Impaired function of the liver (may be seen in tests performed by your doctor)
- Blood tests may show an increase in bilirubin, some pancreatic or liver enzymes or in the number of platelets
- Fainting
- Feeling unwell
- Faster heartbeat
- Dry mouth
- Hives

Rare (may affect up to 1 in 1,000 people):

Bleeding into a muscle
Cholestasis (decreased bile flow), hepatitis incl. hepatocellular injury (inflamed liver incl. liver injury)
Yellowing of the skin and eye
(jaundice)
Localised swelling
Collection of blood (haematoma) in the groin as a complication of the cardiac procedure where a catheter is inserted in your leg artery (pseudoaneurysm)

Very rare (may affect up to 1 in 10,000 people)

accumulation of eosinophils, a type of white granulocytic blood cells that cause inflammation in the lung (eosinophilic pneumonia)

Not known (frequency cannot be estimated from the available data):

Kidney failure after a severe bleeding
Bleeding in the kidney sometimes with presence of blood in urine leading to inability of the kidneys to work properly (anticoagulant-related nephropathy)
Increased pressure within muscles of the legs or arms after a bleeding, which leads to pain, swelling, altered sensation, numbness or paralysis (compartment syndrome after a bleeding)

Side effects in children and adolescents

In general, the side effects observed in children and adolescents treated with Rivaroxaban were similar in type to those observed in adults and were primarily mild to moderate in severity.

Side effects that were observed more often in children and adolescents: Very common (may affect more than 1 in 10 people)

headache
fever
nose bleeding
vomiting

Common (may affect up to 1 in 10 people)

raised heartbeat
blood tests may show an increase in bilirubin (bile pigment)
thrombocytopenia (low number of platelets which are cells that help blood to clot)
heavy menstrual bleeding

Uncommon (may affect up to 1 in 100 people)

blood tests may show an increase in a subcategory of bilirubin (direct bilirubin, bile pigment)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Rivaroxaban

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label, blister, carton, bottle after “EXP”.The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Crushed tablets

Crushed tablets are stable in water or apple puree for up to 4 hours.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Rivaroxaban contains

The active substance is rivaroxaban.
Each tablet contains 15 mg and 20 mg of rivaroxaban.
The other ingredients are:
Tablet core: Cellulose, Microcrystalline
(Grade-101 and Grade-102), lactose monohydrate, croscarmellose sodium, hypromellose type 2910 (3 cPs), sodium laurilsulfate, magnesium stearate Tablet coating: Polyvinyl alcohol, macrogol 3350, talc, titanium dioxide (E171), iron oxide red (E172)

What Rivaroxaban looks like and contents of the pack

Film-coated tablet.

Rivaroxaban 15 mg:

Red, round, biconvex film-coated tablet with ‘M’ on one side and ‘15’on the other side.

Rivaroxaban 20 mg:

Dark red to brown red, oval, biconvex film-coated tablet with ‘M’ on one side and ‘20’on the other side.

Rivaroxaban film-coated tablets are available in blister packs and HDPE bottle packs.

Pack sizes:

Blister packs: 5, 10, 14, 15, 28, 30, 42, 90, 98 and 100 film-coated tablets HDPE Packs: 30, 100, 250 and 500 film-coated tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Milpharm Limited

Ares Block, Odyssey Business Park West End Road

Ruislip HA4 6QD

United Kingdom

Manufacturer

APL Swift Services (Malta) Limited HF26, Hal Far Industrial Estate, Hal Far, Birzebbugia, BBG 3000

Malta