This medicine is indicated in adults for:
- Prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation.
- Prophylaxis after insertion of prosthetic heart valves.
- Prophylaxis of venous thrombosis and pulmonary embolism and for use in the treatment of these conditions to prevent their extension.
Kovar® is indicated for:
Kovar has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.
A baseline coagulation screen and liver function tests should be performed before initiating warfarin therapy.
Adults: The typical induction dose is 10 mg daily for 2 days but this should be tailored to individual requirements.
The daily maintenance dose is usually 3 to 9 mg taken at the same time each day. The exact maintenance dose depends on the prothrombin time, usually reported as the INR (international normalised ratio), or other appropriate coagulation tests.
Control tests should be made at regular intervals and the maintenance dose should be adjusted according to the results obtained.).
In emergencies, anticoagulant therapy should be initiated with heparin and warfarin together.
Elderly: As for adults, but dosage may need to be lowered. The elderly are generally more sensitive to the effects of warfarin and often require a smaller dose.
Dosage for children has not been established. Warfarin 1mg/ml Oral Suspension is not recommended for use in children.
Method of administration:
For oral administration only.
The dosage and administration of Kovar must be individualized for each patient according to the patient’s INR response to the drug. Adjust the dose based on the patient’s INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines regarding the duration and intensity of anticoagulation for the indicated conditions.
An INR of greater than 4.0 appears to provide no additional therapeutic benefit in mos patients and is associated with a higher risk of bleeding.
Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations.
The duration of treatment is based on the indication as follows:
In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).
Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.
The appropriate initial dosing of Kovar varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:
Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.
Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.
If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of Kovar is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.
Table 1 displays three ranges of expected maintenance Kovar doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.
Table 1: Three Ranges of Expected Maintenance Kovar Daily Doses Based on CYP2C9 and VKORC1 Genotypes †
|GG||5-7 mg||5-7 mg||3-4 mg||3-4 mg||3-4 mg||0.5-2 mg|
|AG||5-7 mg||3-4 mg||3-4 mg||3-4 mg||0.5-2 mg||0.5-2 mg|
|AA||3-4 mg||3-4 mg||0.5-2 mg||0.5-2 mg||0.5-2 mg||0.5-2 mg|
|†Ranges are derived from multiple published clinical studies. VKORC1 –1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose.|
Kovar has a narrow therapeutic range (index), and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during Kovar therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with Kovar, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR.
Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of Kovar therapy.
No dosage adjustment is necessary for patients with renal failure. Monitor INR more frequently in patients with compromised renal function to maintain INR within the therapeutic range.
The anticoagulant effect of Kovar persists beyond 24 hours. If a patient misses a dose of Kovar at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.
The intravenous dose of Kovar is the same as the oral dose. After reconstitution, administer Kovar for injection as a slow bolus injection into a peripheral vein over 1 to 2 minutes.
Kovar for injection is not recommended for intramuscular administration.
Reconstitute the vial with 2.7 mL of Sterile Water for Injection. The resulting yield is 2.5 mL of a 2 mg per mL solution (5 mg total). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is noted.
After reconstitution, Kovar for injection is stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is for single use only, discard any unused solution.
Some dental or surgical procedures may necessitate the interruption or change in the dose of Kovar therapy. Consider the benefits and risks when discontinuing Kovar even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of Kovar to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.
Since the full anticoagulant effect of Kovar is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with Kovar, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to Kovar may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap Kovar therapy with heparin for 4 to 5 days and until Kovar has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.
As heparin may affect the INR, patients receiving both heparin and Kovar should have INR monitoring at least:
Kovar may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.
Consult the labeling of other anticoagulants for instructions on conversion to Kovar.
Clinically significant bleeding
Use within 72 hours of surgery with risk of severe bleeding
Use within 48 hours postpartum.
Warfarin is contraindicated in pregnancy.
Drugs where interactions lead to a significantly increased risk of bleeding.
Kovar is contraindicated in:
Kovar is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism. Kovar can cause fetal harm when administered to a pregnant woman. Kovar exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If Kovar is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Kovar is contraindicated in patients with:
Most adverse events reported with warfarin are a result of over anticoagulation therefore it is important that the need for therapy is reviewed on a regular basis and therapy discontinued when no longer required.
Patients should be given a patient-held information booklet ('warfarin card') and informed of symptoms for which they should seek medical attention.
Commencement of therapy
If this preparation replaces or is replaced by another warfarin product, the patient should be monitored closely in the period immediately following the change.
When warfarin is started using a standard dosing regimen the INR should be determined daily or on alternate days in the early days of treatment. Once the INR has stabilised in the target range the INR can be determined at longer intervals.
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 for whom adherence may be difficult should be monitored more frequently.
For patients with any impairments that may influence their ability to take the correct dosage safely, the assistance of a carer to administer the dose may be required.
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. Patients with protein S deficiency may also be at risk and it is advisable to introduce warfarin therapy slowly in these circumstances.
Risk of haemorrhage
The most frequently reported adverse effect of all oral anticoagulants is haemorrhage.
Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age >65, highly variable INRs, history of gastrointestinal bleeding, uncontrolled hypertension, cerebrovascular disease, serious heart disease including congestive cardiac failure, risk of falling, anaemia, malignancy, trauma, renal insufficiency, impaired hepatic function, haemorrhagic blood dyscrasias, hypermetabolic states e.g. hyperthyroidism, or fever, acute illness, vitamin K deficiency state, diarrhoea concomitant drugs.
Genetic factors: genetic polymorphisms in the cytochrome P450 CYP2C9 gene result in impaired metabolism of S-warfarin. Affected individuals have an increased sensitivity to warfarin, manifesting as low dose requirements and an increased risk of bleeding. The variant alleles occur at a higher frequency in white populations than in other ethnic groups studies.
All patients treated with warfarin should have INR monitored regularly. 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 immediately to physicians signs and symptoms of bleeding.
Checking the INR and reducing or omitting doses depending on INR level is essential, following consultation with anticoagulation services if necessary. If the INR is found to be too high, reduce dose or stop warfarin treatment; sometimes it will be necessary to reverse anticoagulation. INR should be checked within 2-3 days to ensure that it is falling.
Any concomitant anti-platelet drugs should be used with caution due to an increased risk of bleeding.
Haemorrhage can indicate an overdose of warfarin has been taken.
If haemorrhage occurs overdose should be suspected. Bleeding may occur at therapeutic INR values, in which case the possibility of an underlying condition that predisposes the haemorrhage should be investigated.
Anticoagulation following an ischaemic stroke increases the risk of secondary haemorrhage into the infarcted brain. In patients with atrial fibrillation long term treatment with warfarin is beneficial, but the risk of early recurrent embolism is low and therefore a break in treatment after ischaemic stroke is justified. 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.
Minor surgical procedures with low risk of bleeding can be performed in general with an INR of <2.5. However the local recommendation should be considered.
For surgery, other surgical procedures, where there is a risk of severe bleeding, warfarin should be stopped 3-5 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 and heparin therapy should be started.
If surgery is required and warfarin cannot be stopped 3 days beforehand, anticoagulation should be reversed with low-dose vitamin K.
The timing for 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.
In most cases warfarin need not be stopped before routine dental surgery, e.g. tooth extraction.
Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality. The condition is mainly observed in patients with end-stage renal disease on dialysis or in patients with known risk factors such as protein C or S deficiency, hyperphosphataemia, hypercalcaemia or hypoalbuminaemia. Rare cases of calciphylaxis have been reported in patients taking warfarin, also in the absence of renal disease. In case calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with warfarin.
Due to a high risk of bleeding, patients with history of 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.
Many drugs and foods interact with warfarin and affect the prothrombin time. Any change to medication, including self-medication with OTC products, warrants increased monitoring of the INR. Patients should be instructed to inform their doctor before they start to take any additional medications including over the counter medicines, herbal remedies or vitamin preparations.
The anticoagulant effect of warfarin may be increased or decreased by concomitant use of herbal medicines. One such example is the interaction between warfarin and St.John's wort.
The rate of warfarin metabolism depends on thyroid status. Therefore patients with hyper- or hypo-thyroidism should be closely monitored on starting warfarin therapy.
Additional circumstances where changes in dose may be required
The following also may exaggerate the effect of warfarin suspension, and necessitate a reduction of dosage:
- Loss of weight
- Acute illness
- Cessation of smoking
The following may reduce the effect of warfarin suspension, and require the dosage to be increased:
- Weight gain
Acquired or inherited warfarin resistance should be suspected if larger than usual daily doses of warfarin are required to achieve the desired anticoagulant effect.
Ingredients in the formulation
The product contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Included as part of the "PRECAUTIONS" Section
Kovar can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors , certain concomitant drugs , and long duration of warfarin therapy.
Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.
Drugs, dietary changes, and other factors affect INR levels achieved with Kovar therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs.
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.
Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of Kovar therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.
Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue Kovar therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.
Fatal and serious calciphylaxis or calcium uremic arteriolopathy has been reported in patients with and without end-stage renal disease. When calciphylaxis is diagnosed in these patients, discontinue Kovar and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.
In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with Kovar, possibly in relation to episodes of excessive anticoagulation and hematuria. More frequent monitoring of anticoagulation is advised in patients with compromised renal function.
Anticoagulation therapy with Kovar may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue Kovar therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.
Do not use Kovar as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with Kovar may be considered after the platelet count has normalized.
Kovar can cause fetal harm when administered to a pregnant woman. While Kovar is contraindicated during pregnancy, the potential benefits of using Kovar may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue Kovar should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. Kovar exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
In the following clinical settings, the risks of Kovar therapy may be increased:
The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.
The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients to:
Advise patients to
Advise patients to:
Advise patients to:
Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.
Kovar is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of Kovar may outweigh the risks. Kovar can cause fetal harm. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of Kovar and possible risks to the fetus when prescribing Kovar to a pregnant woman.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Fetal/Neonatal Adverse Reactions
In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy.
Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Kovar and any potential adverse effects on the breastfed infant from Kovar or from the underlying maternal condition before prescribing Kovar to a lactating woman.
Monitor breastfeeding infants for bruising or bleeding.
Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated.
Kovar can cause fetal harm.
Verify the pregnancy status of females of reproductive potential prior to initiating Kovar therapy.
Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose of Kovar.
Adequate and well-controlled studies with Kovar have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of Kovar is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered Kovar should avoid any activity or sport that may result in traumatic injury.
The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended.
Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.
Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.
Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. Kovar is contraindicated in any unsupervised patient with senility. Observe caution with administration of Kovar to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of Kovar in elderly patients.
Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment. Instruct patients with renal impairment taking warfarin to monitor their INR more frequently.
Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Use caution when using Kovar in these patients.
Warfarin has no influence on the ability to drive and use machines.
Frequency categories are unknown for the following reported adverse reactions and therefore have not been included.
MedDRA system organ classa
Infections and infestations
Immune system disorders
Nervous system disorders
Cerebral haemorrhage; cerebral subdural haematoma
Respiratory, thoracic and mediastinal disorders
Gastrointestinal haemorrhage; rectal haemorrhage; haematemesis; pancreatitis; diarrhoea; nausea; vomiting; melaena
Skin and subcutaneous disorders
Rash; alopecia; purpura; erythematous swollen skin patches leading to ecchymosis, infarction and skin necrosis
Frequency not known: calciphylaxis
Jaundice; hepatic dysfunction
Renal and urinary disorders
Unexplained drop in haematocrit; haemoglobin decreased
a MedDRA is a dictionary of medical terminology used by the MHRA to enter data into the Yellow Card database. The dictionary is organized by system organ class
Skin necrosis is a rare but serious side effect of warfarin. It occurs mainly in obese, female patients, usually within 3 to 10 days of starting therapy, and is associated with the use of high induction doses. Patients with protein C or protein S deficiency are at particular risk. Initially, the lesions consist of painful, indurated, reddened areas, which progress through a stage of blood-filled blisters into well-demarcated blackened necrotic patches. Areas of skin with underlying fatty tissue, such as breasts, flanks and buttocks are most often affected. Pain in a particular area of skin is a premonitory symptom, and withdrawal of the oral anticoagulant at this stage, reversal of its effects with vitamin k or fresh frozen plasma, and the use of heparin may limit the extent of tissue damage.
'Purple toes' which is a rare complication of warfarin therapy. Typically, the syndrome presents 3 to 8 weeks after initiation of warfarin therapy as a sometimespainful blue-tinged discoloration of the plantar aspects and sides of the toes. Cholesterol emboli released from atheromatous plaques have been implicated as the cause. If the syndrome occurs, it is recommended that warfarin therapy be withdrawn, if possible, as the affected tissue may undergo ischaemic necrosis
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme www.mhra.gov.uk/yellowcard
The following serious adverse reactions to Kovar are discussed in greater detail in other sections of the labeling:
Other adverse reactions to Kovar include:
The benefit of gastric decontamination is uncertain. If the patient presents within 1 hour of ingestion of more than 0.25 mg/kg or more than the patient's therapeutic dose, consider activated charcoal.
In cases of life-threatening haemorrhage
Stop warfarin treatment, give prothrombin complex concentrate* (factors II, VII, IX, and X) or (if no concentrate available) fresh frozen plasma. Discuss with local haematologist or National Poisons Information Service, or both.
Non-life threatening haemorrhage
Where anticoagulation can be suspended, give slow intravenous injection of phytomenadione* (vitamin K1).
Where rapid re-anticoagulation is desirable (e.g., valve replacements) give prothrombin complex concentrate* (factors II, VII, IX, and X) or (if no concentrate available) fresh frozen plasma.
Monitor INR to determine when to restart normal therapy. Monitor INR for at least 48 hours post overdose.
For patients on long-term warfarin therapy without major haemorrhage
- INR >8Â·0, no bleeding or minor bleedingâ€”stop warfarin, and give phytomenadione* (vitamin K1) by slow intravenous injection or by mouth (for partial reversal of anticoagulation give smaller oral doses of phytomenadione 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.
- INR 6Â·0-8Â·0, no bleeding or minor bleedingâ€”stop warfarin, restart when INR <5Â·0
- INR <6Â·0 but more than 0Â·5 units above target valueâ€”reduce dose or stop warfarin, restart when INR <5Â·0
For patients 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 0Â·25 mg/kg;
b) the prothrombin time is already significantly prolonged (INR >4Â·0).
*For the dosages to be used for phytomenadione or prothrombin complex concentrate* (factors II, VII, IX, and X, please refer to the relevant product SPC.
The degree of reversal of anticoagulation must be decided on an individual basis. Full reversal with vitamin K may result in prolonged resistance to warfarin, giving rise to the possibility of valve thrombosis and thrombo-embolism in patients with prosthetic heart valves.
Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation.
The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of Kovar anticoagulation may be obtained by discontinuing Kovar therapy and, if necessary, by administration of oral or parenteral vitamin K1.
The use of vitamin K1 reduces response to subsequent Kovar therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of Kovar administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy.
Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of Kovar is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to Kovar overdosage.
Pharmacotherapeutic Category: Antithrombotic agent (Vitamin K Antagonist)
ATC Code: BO1 AA03
Warfarin is a synthetic anticoagulant of the coumarin series. It acts by inhibiting the formation of active clotting factors II, VII, IX and X.
An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of Kovar may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin Kdependent clotting factors and anticoagulation proteins: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, X - 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively.
Warfarin is readily absorbed from the gastro-intestinal tract. Its plasma half-life is about 40 hours. It is metabolised in the liver, and is excreted in the urine mainly as metabolites.
Kovar is a racemic mixture of the R- and S-enantiomers of warfarin. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.
Warfarin is essentially completely absorbed after oral administration, with peak concentration generally attained within the first 4 hours.
Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins.
The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4’-, 6-, 7-, 8-, and 10-hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance.
The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of Rwarfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.
Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; however, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.
Asian patients may require lower initiation and maintenance doses of warfarin. A non-controlled study of 151 Chinese outpatients stabilized on warfarin for various indications reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. Patient age was the most important determinant of warfarin requirement in these patients, with a progressively lower warfarin requirement with increasing age.
Warfarin has been shown to be teratogenic in animal studies and may cause abnormalities and foetal death when administered during pregnancy in humans.
Any unused product or waste material should be disposed of in accordance with local requirements.