How does it work?

Marevan tablets contain the active ingredient warfarin, which is a type of medicine called an oral anticoagulant. It is used to stop blood clots forming within the blood vessels. (NB. Warfarin is also available without a brand name, ie as the generic medicine.)

Blood clots normally only form to stop bleeding that has occurred as a result of injury to the tissues. The clotting process is complicated and begins when blood cells called platelets clump together at the site of damage and produce chemicals that activate clotting factors in the blood. Clotting factors are proteins that are produced by the liver. Vitamin K is essential for their production. The activated clotting factors cause a protein called fibrinogen to be converted into another called fibrin. Fibrin binds the platelets together, forming a blood clot. This is the body'’s natural way of repairing itself.

Sometimes, however, a blood clot can form abnormally within the blood vessels. This is known as a thrombus and can be dangerous because the clot may detach and travel in the bloodstream, where it becomes known as an embolus. The clot may eventually get lodged in a blood vessel, thereby blocking the blood supply to a vital organ such as the heart, brain or lungs. This is known as a thromboembolism.

Some people have an increased tendency for blood clots to form within the blood vessels. This is usually due to a disturbance in the blood flow within the blood vessels. For example, fatty deposits on the walls of the blood vessels (atherosclerosis) can disrupt the blood flow, giving a tendency for platelets to clump together and start off the clotting process. Slow blood flow in the leg and pelvic veins can also result in clots forming (deep vein thrombosis). These clots can break off and travel to the lungs (pulmonary embolism). A type of fast irregular heartbeat called atrial fibrillation can also disrupt blood flow and may lead to blood clots forming in the heart. Heart valve disease can have the same effect, particularly if artificial heart valves have been fitted. Clots in the heart can detach and travel to the brain, causing a stroke. Warfarin is used to reduce the risk of blood clots forming inside the blood vessels in conditions such as these.

Warfarin works by preventing the vitamin K dependent production of the clotting factors described above. Warfarin prevents the production of these clotting factors by inhibiting the action of vitamin K. Without these clotting factors fibrinogen cannot be converted into fibrin and blood clots are therefore less likely to occur.

Warfarin takes about three days to produce its full anticoagulant effect because, while it prevents the production of new clotting factors, it takes about this long for clotting factors that have already been produced to be used up. For this reason, when treating blood clots such as deep vein thrombosis (DVT) or pulmonary embolism, a faster acting injectable anticoagulant, such as a heparin, is often used as well to begin with.

The anticoagulant effect of warfarin is measured in terms of the prothombin time, which is the time taken for blood clotting to occur in a sample of blood to which calcium and a substance known as thromboplastin have been added. This time is expressed as the International Normalised Ratio (INR). Your doctor will take regular blood samples and adjust your dose of warfarin as necessary to make your INR fall into the range that has been shown to be effective at preventing blood clots in your particular condition.

What is it used for?

• Preventing abnormal blood clots in conditions with increased risk, eg rheumatic heart disease, atrial fibrillation and after insertion of artificial (prosthetic) heart valves.
• Preventing blood clots that could cause a stroke in people who have had a mini-stroke (transient ischaemic attack).
• Treatment and prevention of blood clots in the veins of the leg (deep vein thrombosis).
• Treatment and prevention of blood clots in the lungs (pulmonary embolism).

Warning!

• You should take extra care when participating in physical activities while taking this medicine, as even minor injury may result in bleeding/bruising.
• Because this medicine prevents blood clotting, too much can increase your risk of bleeding. On the other hand, too little will not be effective at preventing clotting. It is therefore important that you have regular blood tests to monitor your blood clotting ability (INR) so that your dose can be altered if necessary. When first starting treatment this test should be daily or on alternate days, and as your INR becomes more stable the tests can be at longer intervals. You will probably need your INR checking after any changes to your warfarin dose, if you become ill suddenly, if you have vomiting or diarrhoea, or if you start taking certain other medicines (see end of this factsheet for examples of medicines that can affect warfarin). Talk to your doctor about when your INR will need checking.
• As warfarin works by inhibiting the action of vitamin K, changes to your dietary intake of vitamin K can alter the effect of your warfarin. For this reason, avoid making sudden major changes to your diet, particularly your consumption of green tea, salad and green vegetables (eg broccoli, brussel sprouts, or spinach), which contain large amounts of vitamin K. Large amounts of green vegetables (more than 500g daily) can reduce the effect of warfarin and should be avoided. Changes to your consumption of fats and oils can also alter the effect of warfarin, as vitamin K is a fat soluble vitamin.
• Drinking large amounts of alcohol in one go should be avoided while taking warfarin, as this may increase its effect. In contrast, chronic heavy drinking can decrease the effect of warfarin. However, it is fine to drink alcohol now and then in moderation.
• The effects of warfarin can also be altered by other foods, for example soya bean products can reduce the effect of warfarin, and avocados and large amounts of ice cream (over a litre a day) have also been reported to have this effect. There have been reports of cases where it seemed that drinking cranberry juice increased the effect of warfarin and some health professionals recommend avoiding cranberry juice, or increased monitoring of INR in people who regularly drink it. However, recent controlled studies have since shown that moderate consumption of cranberry juice is unlikely to have a significant affect on warfarin in otherwise healthy people.
• Warfarin's effect can also be altered by sudden increases or decreases in your body weight. For these reasons you should avoid making sudden major changes to your diet during treatment with warfarin. For more information talk to your pharmacist.
• Consult your doctor immediately if you experience any unexplained bruising, bleeding, dark stools, blood in the urine, vomiting, diarrhoea, fever or acute illness while taking this medicine, so that your INR can be checked.
• You should be given an anticoagulant treatment booklet when you start treatment with this medicine. This will contain details of your warfarin dose and INR and will also give advice on your anticoagulant treatment.
• It is important that you tell any health professional treating you, including your dentist, that you are taking this medicine. If you are due to have any surgery it is also important to talk to your doctor in advance about your warfarin. For some surgery it is safe to keep taking warfarin, whereas if you are going to have major surgery with a higher risk of bleeding your doctor may want you to stop taking your warfarin three days before the surgery. Follow the instructions given by your doctor.

Use with caution in

• Elderly people.
• Decreased kidney function.
• Decreased liver function.
• People with a peptic ulcer or history of bleeding in the gut.
• Bacterial infection of the heart valves and the lining surrounding the heart (bacterial endocarditis).
• People who have recently had a stroke caused by a blood clot (ischaemic stroke).
• Uncontrolled high blood pressure (hypertension).
• People who have had recent surgery, bleeding or major injury.
• People who are at increased risk of bleeding for any other reason.

Not to be used in

• Active bleeding.
• People who have had a stroke caused by bleeding in the brain.
• First and third trimesters of pregnancy.
• The first 48 hours after giving birth.
• The first 72 hours after major surgery with a risk of severe bleeding.

This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy. If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.

Pregnancy and breastfeeding

Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.

• This medicine should not be used during pregnancy, especially during the first and third trimesters, because warfarin is known to be harmful to a developing baby. It increases the chances of malformations, as well as increasing the risk of bleeding in the baby and placenta. It is important to use an effective method of contraception to avoid pregnancy while you are taking this medicine and to seek medical advice from your doctor immediately if you think you could be pregnant.
• Warfarin passes into breast milk in very low amounts, but is not known to have any harmful effects on a nursing infant. It can be used safely during breastfeeding. Seek further medical advice from your doctor.

Label warnings

• Follow the printed instructions you have been given with this medication.

Side effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.

• Bleeding.
• Increased time taken to stop bleeding.
• Bruising.
• Diarrhoea.
• Nausea and vomiting.
• Fever.
• Rash.
• Purple toes.
• Hair loss (alopecia).
• Liver disorders.
• Yellowing of the skin and eyes (jaundice).
• Inflammation of the pancreas (pancreatitis).

The side effects listed above may not include all of the side effects reported by the medicine's manufacturer. For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.

How can this medicine affect other medicines?

The anticoagulant effect of warfarin can be affected by many medicines. It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while taking this one, to make sure that the combination is safe.

The following medicines may enhance the effect of warfarin. This may increase your INR and increase the risk of bleeding. Your INR should be checked more frequently if you take any of these with warfarin, particularly when starting or stopping any of these medicines. Your warfarin dose may need reducing while you are taking any of these:

• allopurinol
• amiodarone
• anabolic steroids (oxymetholone, stanozolol)
• antibiotic medicines (eg ampicillin, cefaclor, ciprofloxacin, co-trimoxazole, erythromycin, metronidazole)
• aspirin (may also irritate the stomach lining, which can result in bleeding from the stomach or intestine in people taking warfarin)
• azole antifungal medicines (eg fluconazole, ketoconazole, itraconazole, miconazole, voriconazole)
• capecitabine
• the herbal remedy Chinese angelica
• cimetidine
• danazol
• the Chinese herbal remedy danshen
• dextropropoxyphene (found in co-proxamol/Distalgesic)
• disulfiram
• erlotinib
• etoposide
• exenatide
• fibrate medicines for lowering cholesterol (eg bezafibrate, ciprofibrate, clofibrate)
• fluorouracil
• flutamide
• glucagon (large doses)
• glucosamine supplements
• ifosfamide
• leflunomide
• methylphenidate
• non-steroidal anti-inflammatory drugs (NSAIDs, eg ibuprofen and particularly azapropazone, diclofenac, flurbiprofen, indometacin, phenylbutazone, piroxicam. NSAIDs may also irritate the stomach and intestinal lining, which can result in bleeding from the gut in people taking warfarin. The interaction does not generally apply to NSAIDs applied to the skin.)
• paracetamol (long-term regular use, occasional painkilling doses should not affect warfarin significantly)
• proguanil
• propafenone
• proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole
• quinine
• sitaxentan
• sorafenib
• statins for lowering cholesterol such as rosuvastatin, fluvastatin
• sulfinpyrazone
• tamoxifen
• testosterone
• thyroxine (levothyroxine)
• toremifene
• tramadol
• zafirlukast.

The following medicines affect blood clotting and so may also increase the risk of bleeding if taken with warfarin:

• antiplatelet or 'blood thinning' medicines such as low-dose aspirin, clopidogrel, dipyridamole
• bivalirudin
• dabigatran
• duloxetine
• fondaparinux
• the herbal remedy ginko
• glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab
• heparin
• low molecular weight heparins, eg dalteparin
• prasugrel
• rivaroxaban
• SSRI antidepressants such as paroxetine or fluoxetine
• venlafaxine.

The following medicines may reduce the effect of warfarin. This could decrease your INR and make the warfarin less effective at preventing blood clots. Your INR should be checked more frequently if you take any of these with warfarin, particularly when starting or stopping any of these medicines. Your warfarin dose may need increasing while you are taking any of these:

• azathioprine
• barbiturates, including phenobarbital and primidone
• bosentan
• carbamazepine
• colestyramine
• eslicarbazepine
• griseofulvin
• mercaptopurine
• raloxifene
• rifampicin
• sucralfate
• the herbal remedy St John's wort (Hypericum perforatum)
• vitamin K.

The following medicines may also alter the effect of warfarin and your dose of warfarin may need to be adjusted up or down (as INR may be increased or reduced by the following medicines):

• corticosteroids
• the herbal remedy ginseng
• nevirapine
• oestrogens
• phenytoin
• progestogens
• protease inhibitors for HIV such as ritonavir
• trazodone.

The weight loss medicine orlistat (Xenical or Alli) may reduce the absorption of vitamin K from food and may therefore affect the action of warfarin. Your INR should be monitored if you start or stop taking orlistat while you are taking warfarin.

Other medicines containing the same active ingredient

Warfarin tablets are also available without a brand name, ie as the generic medicine.