Warfarin Sodium
Drug Nomenclature
Note. The use of the term warfarin sodium in site should generally be taken to include the sodium clathrate. Until 1991 the BP, like the USP, allowed the use of either warfarin sodium or warfarin sodium clathrate in the definition of warfarin sodium.
Pharmacopoeias. In China, Europe, and US. China, International, and US permit either warfarin sodium or warfarin sodium clathrate. Europe has a separate monograph for warfarin sodium clathrate (see below). Japan includes Warfarin Potassium.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Warfarin Sodium). A white or almost white, hygroscopic, amorphous powder. Very soluble in water and in alcohol; soluble in acetone; very slightly soluble in dichloromethane. A 1% solution in water has a pH of 7.6 to 8.6. Store in airtight containers. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Warfarin Sodium). A white, odourless, amorphous solid or a crystalline clathrate which is discoloured by light. Very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether. A 1 % solution in water has a pH of 7.2 to 8.3. Protect from light.
Adsorption. Studies carried out for periods of 24 hours to 3 months found some adsorption of warfarin sodium by PVC when dissolved in 0.9% sodium chloride solution or in 5% glucose solution. In one of these studies, adsorption was decreased by buffering the solution from its initial pH of 6.7 to a pH of 7.4. The second study could demonstrate no adsorption onto polyethylene-lined or glass infusion containers.
Incompatibility. Solutions of warfarin sodium have been reported to be incompatible with adrenaline hydrochloride, amikacin sulfate, metaraminol tartrate, oxytocin, promazine hydrochloride, and tetracycline hydrochloride. Visual incompatibility has been reported with solutions of warfarin sodium mixed with solutions of aminophylline, bretylium tosilate, ceftazidime, cimetidine hydrochloride, ciprofloxacin lactate, dobutamine hydrochloride, esmolol hydrochloride, gentamicin sulfate, labetalol hydrochloride, metronidazole hydrochloride, orvancomycin hydrochloride. Haze was also reported after 24 hours with sodium chloride 0.9%.
Warfarin Sodium Clathrate
Drug Nomenclature
Note. The use of the term warfarin sodium in site should generally be taken to include the sodium clathrate. Until 1991 the BP, like the USP, allowed the use of either warfarin sodium or warfarin sodium clathrate in the definition of warfarin sodium.
Pharmacopoeias. In Europe.
China, International, and US permit either warfarin sodium or warfarin sodium clathrate.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Warfarin Sodium Clathrate). A white or almost white, crystalline powder. Very soluble in water; freely soluble in alcohol; soluble in acetone; very slightly soluble in dichloromethane. A 1% solution in water has a pH of 7.6 to 8.6. Store in airtight containers. Protect from light. Warfarin sodium clathrate contains about 92% of warfarin sodium.
Adverse Effects
The major risk from warfarin therapy is of haemorrhage from almost any organ of the body with the consequent effects of haematomas as well as anaemia. Although good control of warfarin anticoagulation is essential in preventing haemorrhage, bleeding has occurred at therapeutic international normalised ratio (INR) values. In such cases the possibility of an underlying cause such as renal or alimentary tract disease should be investigated. Skin necrosis, and purple discoloration of the toes (due to cholesterol embolisation) have occasionally occurred. Hypersensitivity reactions are extremely rare. Other effects not necessarily associated with haemorrhage include alopecia, fever, nausea, vomiting, diarrhoea, skin reactions, jaundice, hepatic dysfunction, and pancreatitis.
Warfarin is a recognised teratogen. Given in the first trimester of pregnancy it can cause a fetal warfarin syndrome or warfarin embryopathy characterised by bone stippling (chondrodysplasia punctata) and nasal hypoplasia. CNS abnormalities may develop after use in any trimester but appear most likely when used in the second or third trimester. Use of warfarin during pregnancy has been associated with an increased rate of abortion and still-birth, although this may, in part, be the consequence of an underlying maternal condition. Use in the late stages of pregnancy is associated with fetal haemorrhage. Reported incidences of the above complications have varied; one estimate is that if a coumarin anticoagulant is taken during pregnancy, one-sixth of pregnancies will result in an abnormal liveborn infant, and one-sixth will result in abortion or stillbirth.
Effects on the blood. The incidence and risk of haemorrhage during long-term oral anticoagulation has been studied in patients in clinical trials and in population-based studies. The risk of bleeding was generally higher with more intense anticoagulation and in the presence of other risk factors, but the relationship with age was less clear. Some studies have shown higher rates of bleeding in elderly patients, but others have not; the risk of intracranial bleeding, however, does seem to be higher in the elderly. Although cumulative risk of bleeding was related to duration of anticoagulation therapy, risk may be highest early in the course.
Withdrawal of warfarin therapy may lead to rebound hypercoagulability and it has been suggested that warfarin should be withdrawn gradually, although there is no clinical evidence to support this.
Effects on the bones. Vitamin K is involved in bone metabolism and vitamin K deficiency is associated with an increased risk of osteoporotic fractures. It has been suggested, therefore, that patients on long-term treatment with those oral anticoagulants that are vitamin K antagonists may be at increased risk of osteoporosis and fractures. However, two large observational studies in older women have produced conflicting results. A prospective study of both users and nonusers of warfarin found that warfarin was not associated with decrease in bone density or increase in fracture rates. A retrospective study reported an association between long-term anticoagulant use and increased risk of vertebral and rib fractures, compared with the general population. Overall, however, the risk of any fracture was not significantly increased.
Effects on the fetus. Fetal complications of coumarin anticoagulants during pregnancy have been reviewed.
Effects on the liver. There have been a few isolated reports of cholestatic liver damage in patients taking warfarin sodium, which resolved on withdrawal.
Effects on sexual function. There have been reports of pri-apism in patients taking oral anticoagulants such as warfarin.
Effects on the skin and hair. Skin and soft-tissue necrosis is a rare but well-established adverse effect of coumarin anticoagulants. It is characterised by a localised, painful skin lesion, initially erythematous or haemorrhagic in appearance, that becomes bullous and eventually culminates in gangrenous necrosis. Fatalities have occurred. Areas of increased subcutaneous fat such as breast, thigh, and buttocks have most often been involved. The aetiology appears to be thrombotic but the exact pathophysiology is not known. Patients with protein C deficiency appear to be at highest risk. Treatment with coumarin anticoagulants should be stopped if skin lesions appear and vitamin K should be given to reverse their effect. Heparin should be given to provide anticoagulation. Fresh frozen plasma or protein C concentrates may also have a role in reversing the condition. Surgical intervention is usually required if necrosis does develop.
Other skin reactions have also been reported with coumarins. Vasculitis affecting both legs developed in a 74-year-old woman a few weeks after starting treatment with acenocoumarol for deep-vein thrombosis and pulmonary embolism. Acenocoumarol treatment was stopped and the skin lesions steadily improved over 15 days. However, the skin lesions reappeared a few hours after re-exposure to a single dose of acenocoumarol. The patient had also been taking amiodarone which may have contributed to the reaction. Henoch-Schonlein purpura was reported in a 76-year-old woman 2 months after she started treatment with acenocoumarol; it resolved rapidly after the drug was withdrawn.
Increased shedding of telogen hair has been stated to occur in patients given coumarin anticoagulants.
Treatment of Adverse Effects
The methods used to manage bleeding and/or excessive anticoagulation during warfarin therapy, or after warfarin overdosage, depend upon the degree of bleeding, the value of the international normalised ratio (INR), and the degree of thromboembolic risk. For patients over-anticoagulated on warfarin, the British Society for Haematology recommends the following:
• in cases where the INR is 0.5 above the target value but less than 6.0, warfarin should be reduced in dose or withdrawn until the INR falls to below 5.0
• if the INR is greater than 6.0 but less than 8.0 and there is no bleeding or only minor bleeding, warfarin should be temporarily withheld until the INR falls to below 5.0
• for an INR greater than 8.0 use of phytomenadione (vitamin K1) should also be considered if there are other risk factors for bleeding; typical doses of phytomenadione are 0.5 mg intravenously or up to 2.5 mg orally using the intravenous preparation. (The BNF allows 5 mg orally for more complete reversal of anticoagulation.)
• if there is any major bleeding warfarin should be stopped and phytomenadione given in a dose of 5 or 10 mg, preferably by slow intravenous injection. A concentrate of factors II, VII, IX, and X should also be given. The dose of concentrate should be calculated based on 50 units of factor IX/kg. If no concentrate is available fresh frozen plasma should be infused (about one litre for an adult), but may not be as effective. Higher doses of phytomenadione have been used (see Over-anticoagulation); however phytomenadione takes several hours to act and large doses may reduce the response to resumed therapy with anticoagulants for a week or more.
US guidelines from the American College of Chest Physicians are as follows:
• if the INR is above therapeutic range but below 5.0, without significant bleeding, warfarin should be reduced in dose or stopped until the INR falls to therapeutic range
• for an INR of 5.0 or over but less than 9.0, warfarin should be stopped. If the patient is at increased risk of bleeding, phytomenadione 1 to 2.5 mg should be given orally, or up to 5 mg orally for more complete reversal of anticoagulation
• if the INR is 9.0 or above with no significant bleeding, warfarin should be stopped and phytomenadione 2.5 to 5 mg may be given orally
• if there is any major bleeding, warfarin should be stopped and phytomenadione 10 mg given by slow intravenous injection, with fresh plasma, concentrates of factors II, VII, IX, and X, or recombinant factor Vila.
If bleeding occurs unexpectedly at therapeutic INR values, the possibility of an underlying cause such as renal or alimentary tract disease should be investigated.
See under Effects on the Skin and Hair, above, for the management of skin and soft tissue necrosis. For poisoning in individuals not taking anticoagulant therapy, the UK National Poisons Information Service recommends that those who have ingested more than 250 micrograms/kg of warfarin or who have an INR greater than 6.0, should be given phytomenadione 10 to 20 mg orally or intravenously. If there is active bleeding, factor concentrate or fresh frozen plasma should also be given.
Precautions
Warfarin should not be given to patients who are haemorrhaging. In general it should not be given to patients at serious risk of haemorrhage, although it has been used with very careful control; patients at risk include those with haemorrhagic blood disorders, peptic ulcer disease, severe wounds (including surgical wounds), cerebrovascular disorders, and bacterial endocarditis. Consideration should be given to stopping warfarin a few days before an invasive procedure and using an alternative form of antithrombotic therapy. Severe hepatic and renal impairment as well as severe hypertension are considered by some to be contra-indications. Pregnancy is also generally considered to be a contra-indication, especially in the first trimester and during the late stages of pregnancy (see Adverse Effects, above).
Many factors may affect anticoagulant control with warfarin. These include vitamin K status, thyroid status, renal function, bioavailability differences between warfarin preparations, factors affecting absorption of warfarin, genetic variation in warfarin metabolism (see below), and drug interactions. Such factors may be responsible for apparent resistance to warfarin and a few patients have displayed hereditary resistance. Dosage alterations should be guided by regular monitoring of oral anticoagulant therapy and clinical status. Patients should carry anticoagulant treatment booklets.
Breast feeding. Drug concentrations were measured in the plasma and milk of 13 women receiving 2 to 12 mg of warfarin daily. Plasma concentrations varied from 1.6 to 8.5 micromoles/litre but none was detectable in the breast milk or in the plasma of the 7 infants who were breastfed (limit of detection 0.08 micromoles/litre). No anticoagulant effect was found in the 3 breast-fed infants tested. In another report of 2 women (dose of warfarin not specified), no evidence of the drug was found in the milk of one mother, and no anticoagulant effect was found in either infant. The American Academy of Pediatrics considers that warfarin is therefore usually compatible with breast feeding.
Genetic variation. The response to warfarin and dosing requirements vary widely between individuals and between different racial groups. Factors involved include age, indication for anticoagulation, diet, and use of interacting drugs, but much of the variability appears to be related to genetic polymorphism. Two genes appear to be particularly important: the gene for the cytochrome P450 isoenzyme CYP2C9, the major enzyme involved in warfarin metabolism; and the gene for vitamin K epoxide reductase (VKOR), which is involved in the synthesis of clotting factors and is the major target for warfarin and other coumarin anticoagulants. Although polymorphisms in either gene may affect dose requirements, patients with variant alleles for both genes appear to be particularly sensitive to warfarin; initial variability in response may be more strongly associated with VKOR. Identification of affected patients by genetic testing may be used to guide initial warfarin dosage, and a dosage algorithm has been suggested, although it requires validation. Similar effects have also been noted with other coumarins, including acenocoumarol and phenprocoumon.
Macular degeneration. Intra-ocular haemorrhage leading to loss of vision has been reported in patients with neovascular (wet) age-related macular degeneration receiving warfarin, and caution has been advised in such patients.
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