Warfarin

Despite warfarin's use in clinical practice for over 50 years, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK still receives a substantial number of case reports on adverse reactions with warfarin. As such, the the Summaries of Product Characteristics (SPCs) for all warfarin products are to be amended to give clearer and up-to-date advice to healthcare professionals.

A quick overview of warfarin before we look at the update in the MHRA Public Assessment Report of Dec 2009:

Indication & Duration
Warfarin is an anticoagulant used to treat stroke patients, patients who develop deep vein thrombosis/ are at risk of embolism, and to prevent stroke in patients with atrial fibrillation.

Patients who suffer from atrial fibrillation or have undergone surgery for insertion of mechanical prosthetic heart valves need lifelong therapy with warfarin, while patients with a single episode of deep vein thrombosis require treatment for only 6 months.

Patients are told to take warfarin at 6 p.m. every day to enable blood test to be done the following morning.


Moving on to the updates in the MHRA Public Assessment Report of Dec 2009:
Contraindications
• Known hypersensitivity to warfarin or to any of the excipients
• Haemorrhagic stroke
• Clinically significant bleeding
• Within 72 hours of major surgery with risk of severe bleeding
• Within 48 hours postpartum
• Pregnancy (first and third trimesters)
• Patients on fibrinolytic drugs such as streptokinase and alteplase


Special Warnings & Precautions of Use
1) Commencement of Therapy
INR should be monitored more frequently in patients at an increased risk of over coagulation e.g. patients with severe hypertension, liver or renal disease.

Patients with protein C deficiency are at risk of developing skin necrosis when starting warfarin treatment. In patients with protein C deficiency, therapy should be introduced without a loading dose of warfarin even if heparin is given.


2) Risk of Haemorrhage
Warfarin should be given with caution to patients where there is a risk of serious haemorrhage (e.g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal bleeding).

Risk Factors for Bleeding:

• high intensity of anticoagulation (INR >4.0)
• age ≥65,
• highly variable INRs
• history of gastrointestinal bleeding
• uncontrolled hypertension
• cerebrovascular disease
• serious heart disease
• risk of falling
• anaemia
• malignancy
• trauma
• renal insufficiency
• concomitant drugs (refer to 'drug interactions' below)
  

Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed on measures to minimise risk of bleeding and to report signs and symptoms of bleeding to doctors/pharmacists.


3) Ischaemic Stroke
Anticoagulation following an ischaemic stroke increases the risk of secondary haemorrhage into the infarcted brain.

Warfarin treatment should be re-started 2–14 days following ischaemic stroke, depending on the size of the infarct and blood pressure. In patients with large embolic strokes, or uncontrolled hypertension, warfarin treatment should be stopped for 14 days.


4) Surgery
Surgery with no risk of severe bleeding: surgery can be performed with an INR of <2.5

Sugery with risk of severe bleeding: warfarin should be stopped 3 days prior to surgery

Where it is necessary to continue anticoagulation e.g. risk of life-threatening thromboembolism, the INR should be reduced to <2.5> re-instating warfarin therapy depends on the risk of post-operative haemorrhage. In most instances warfarin treatment can be re-started as soon as the patient has an oral intake.


Dental Surgery: Warfarin need not be stopped before routine dental surgery, eg, tooth extraction.


5) Active Peptic Ulceration
Due to a high risk of bleeding, patients with active peptic ulcers should be treated with caution. Such patients should be reviewed regularly and informed of how to recognise bleeding and what to do in the event of bleeding occurring.


6) Thyroid Disorders
The rate of warfarin metabolism depends on thyroid status. Therefore patients with hyper- or hypo-thyroidism should be closely monitored on starting warfarin therapy.


7) Additional Circumstances where Changes in Dose may be required
The following also may exaggerate the effect of warfarin tablets, and necessitate a reduction of dosage:
• Loss of weight
• Acute illness
• Cessation of smoking


The following may reduce the effect of warfarin tablets, and require the dosage to be increased:
• Weight gain
• Diarrhoea
• Vomiting


Drug Interactions
Drugs which should be avoided if possible:
(or administered with caution with increased clinical and laboratory monitoring)
• Clopidogrel
• NSAIDs (including aspirin and cox-2 specific NSAIDS)
• Sulfinpyrazone
• Thrombin inhibitors such as bivalirudin, dabigatran
• Dipyridamole
• Unfractionated heparins and heparin derivatives, low molecular weight heparins
• Fondaparinux, rivaroxaban
• Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab
• Prostacyclin
• SSRI and SNRI antidepressants
• Other drugs which inhibit haemostasis, clotting or platelet action

Warfarin is a mixture of enantiomers which are metabolised by different CYPP450 cytochromes. R-warfarin is metabolised primarily by CYP1A2 and CYP3A4. S-warfarin is metabolised primarily by CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.


Drugs which Potentiate the Effects of Warfarin

• allopurinol
• amiodarone
• azole antifungals (ketoconazole, fluconazole etc)
• capecitabine
• disulfiram
• erlotinib
• erythromycin
• fibrates
• methylphenidate
• metronidazole
• omeprazole
• paracetamol (prolonged regular use)
• propafenone
• statins (not pravastatin; predominantly associated with fluvastatin)
• sulfamethoxazole
• tamoxifen
• zafirlukast

Drugs which Antagonise the Effect of Warfarin

• azathioprine
• barbiturates
• carbamazepine
• griseofulvin
• oral contraceptives
• phenytoin
• primidone
• rifampicin

Drugs with Variable Effect

• corticosteroids
• nevirapine
• ritonavir

Other Drug Interactions
Broad spectrum antibiotics may potentiate the effect of warfarin by reducing the gut flora which produce vitamin K. Similarly, orlistat may reduce absorption of vitamin K. Cholestyramine and sucralfate potentially decrease absorption of warfarin.



Interactions with Herbal Products
These products are best avoided when patient is on warfarin (according to “Stockley’s herbal medicines interactions”):

Coenzyme Q10(ubidecarenone)
(A controlled study found no interaction. Reduced warfarin effects have been reported in four cases and increased effects have been reported in others.)

Danshen (Salvia miltiorrhiza)
(There have been three cases of markedly increased INRs and bleeding, and one animal study suggests increased warfarin bioavailability. Danshen may have some antiplatelet effects.)

Dong quai (Chinese angelica; Angelica sinensis)
(There have been two cases of markedly increased INRs and two experimental studies suggesting a modest increase in prothrombin times with dong quai.)

Feverfew (Tanacetum parthenium)
Fenugreek together with boldo (Peumus boldus)

Fish oil supplements containing eicosapentaenoic acid and docosahexaenoic acid
(Two studies in patients found no interaction (increase in INR or bleeding time), but one study found an increased bleeding time. There is an isolated and unexplained case of raised INR but no bleeding

High doses of these products increase the risk of bleeding, so some caution is appropriate.)

Ginkgo biloba
(Studies in patients and healthy subjects found no interaction, but there is an isolated and unexplained case of bleeding, and a few cases of bleeding with ginkgo alone.)

Ginseng
(A controlled study using P ginseng found no interaction, whereas two case reports describe reduced anticoagulation. Another controlled study using P quinquefolius found a small reduction in warfarin effects.)

Glucosamine with or without chondroitin
(increased INR has been reported in patients taking glucosamine and warfarin)

St John’s wort (Hypericum perforatum)
(controlled studies and case reports describe a small reduction in warfarin effects)

Vitamin K
(Vitamin K is an antidote to warfarin. Small doses (10 to 50µg) in multivitamin supplements are probably unimportant in those with normal vitamin K status, but good monitoring is advisable when starting or stopping the supplement.)

Wintergreen (topical methyl salicylate)
(Some reports of increased warfarin effects (raised INRs, bleeding) with topical methylsalicylate. )


Alcohol
Acute ingestion of a large amount of alcohol may inhibit the metabolism of warfarin and increase INR. Conversely, chronic heavy alcohol intake may induce the metabolism of warfarin. Moderate alcohol intake can be permitted.


Interactions with food
Patients should be advised to avoid cranberry products as individual case reports suggest a possible interaction between warfarin and cranberry juice, in most cases leading to an increase in INR or bleeding event.

Certain foods such as liver, broccoli, Brussels sprouts and green leafy vegetables contain large amounts of vitamin K. Sudden changes in diet can potentially affect control of anticoagulation. Patients should be informed of the need to seek medical advice before undertaking any major changes in diet.


Pregnancy & Lactation
Warfarin is contraindicated in pregnancy in the 1st and 3rd trimester. (Warfarin causes congenital malformations and foetal death when administered during pregnancy.)

Women of child-bearing age who are taking warfarin tablets should use effective contraception during treatment.

Warfarin can be used during breast-feeding.
Although warfarin is excreted in breast milk in small amounts, at therapeutic does of warfarin no effects on the breast-feeding child are anticipated.


Management of Warfarin Overdose

Condition	Management
Pt presents within 1 hour of ingestion of > 0.25 mg/kg or > pt’s therapeutic dose	activated charcoal (50 g for adults; 1 g/kg for children)
Life-threatening haemorrhage	Stop warfarin treatment Give prothrombin complex concentrate (factors II, VII, IX, and X) 30–50 units/kg or (if no concentrate available) fresh frozen plasma 15 mL/kg, or both.
Non-life threatening haemorrhage where anticoagulation can be suspended where rapid re-anticoagulation is desirable	Give slow intravenous injection of phytomenadione (vitamin K1) 10–20 mg for adults (250 micrograms/kg for a child) Give prothrombin complex concentrate (factors II, VII, IX, and X) 30–50 units/kg or (if no concentrate available) fresh frozen plasma 15 mL/kg. [Monitor INR to determine when to restart normal therapy. Monitor INR for at least 48 hours post overdose.]
Pt on long-term warfarin therapy without major haemorrhage INR >8·0, no bleeding or minor bleeding INR 6·0–8·0, no bleeding or minor bleeding INR <6·0 but > 0·5 units above target value	Stop warfarin. Give phytomenadione (vitamin K1) 0·5–1 mg for adults, 0·015–0·030 mg/kg for children by slow intravenous injection or 5 mg by mouth. (for partial reversal of anticoagulation give smaller oral doses of phytomenadione eg, 0·5–2·5 mg using the intravenous preparation orally) Repeat dose of phytomenadione if INR still too high after 24 hours. [Large doses of phytomenadione may completely reverse the effects of warfarin and make re-establishment of anticoagulation difficult.] Stop warfarin, restart when INR <5·0 Reduce dose or stop warfarin, restart when INR <5·0
Pt NOT on long-term anticoagulants without major haemorrhage	Measure the INR (prothrombin time) at presentation and sequentially every 24–48 hours after ingestion depending on the initial dose and initial INR. If the INR remains normal for 24–48 hours and there is no evidence of bleeding, there should be no further monitoring necessary. Give vitamin K1 (phytomenadione) if: a) there is no active bleeding and the patient has ingested more than 0·25 mg/kg; OR b) the prothrombin time is already significantly prolonged (INR >4·0).

The adult dose of vitamin K1 is 10–20 mg orally (250 micrograms/kg body weight for a child). Delay oral vitamin K1 at least 4 hours after any activated charcoal has been given. Repeat INR at 24 hours and consider further vitamin K1.

References:
The Medicines and Healthcare products Regulatory Agency public assessment report. Dec 2009.
http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywar
ningsandmessagesformedicines/index.htm

Youssef S. Patients taking warfarin: problems revealed by medicines use reviews. http://www.pjonline.com/news/patients_taking_warfarin_problems_revealed_by_medicines_use_reviews

Stockley IV and Lee CR. Can I take herbal products or dietary supplements with my warfarin?
http://www.pjonline.com/cpd/can_i_take_herbal_products_or_dietary_supplements_with_my_warfarin