Apo-Warfarin

Apo-Warfarin

warfarin

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Warfarin sodium.
Description
Each tablet contains warfarin sodium 1 mg, 2 mg or 5 mg, respectively.
Action
Pharmacotherapeutic Group: Anticoagulant.
Pharmacology: Pharmacodynamics: Apo-Warfarin and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX and X and the anticoagulant proteins C and S. Half-lives and these clotting factors are as follows: Factor II: 60 hrs; VII: 4-6 hrs; IX: 24 hrs; and X: 48-72 hrs. The half-lives of proteins C and S are approximately 8 and 30 hrs, respectively. The resultant in vivo effect is a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential co-factor for the post-ribosomal synthesis of the vitamin K-dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K-dependent clotting factor made by the liver by approximately 30-50%.
An anticoagulation effect generally occurs within 24 hrs after drug administration. However, peak anticoagulant effect may be delayed 72-96 hrs. The duration of action of a single dose of racemic warfarin is 2-5 days. The effects of Apo-Warfarin may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischaemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.
Clinical Trials: Atrial Fibrillation (AF): In 5 prospective randomized controlled clinical trials involving 3711 patients with nonrheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 1). The risk reduction ranged from 60-86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6-2.7% (see Table 1). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2-4.5) or low INR (1.4-3). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available. (See Table 1.)

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Myocardial Infarction: WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2-4 weeks post-infarction treated with warfarin to a target INR of 2.8-4.8. (But note that a lower INR was achieved and increased bleeding was associated with INR's >4; see Dosage & Administration.) The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table: See Table 2.

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Mechanical and Bioprosthetic Heart Valves: In a prospective, randomized, open-label, positive controlled study (Mok et al, 1985) in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin- (p<0.005) and pentoxifylline-aspirin- (p<0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6 and 7.9/100 patient-years, respectively. Major bleeding rates were 2.5, 0 and 0.9/100 patient-years, respectively.
In a prospective, open-label, clinical trial (Saour et al, 1990) comparing moderate (INR 2.65) vs high intensity (INR 9) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the 2 groups (4 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient-years) vs 0.95 events/100 patient-years in the moderate intensity group. In a randomized trial (Turpie et al, 1988) in 210 patients comparing 2 intensities of warfarin therapy (INR 2-2.25 vs INR 2.5-4) for a 3-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the 2 groups (major embolic events 2% vs 1.9%, respectively, and minor embolic events 10.8% vs 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs none in the lower intensity.
Pharmacokinetics: Apo-Warfarin is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.
Absorption: Apo-Warfarin is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hrs.
Distribution: There are no differences in the apparent volumes of distribution after IV and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6-12 hrs is distinguishable after rapid IV or oral administration of an aqueous solution. Using a one-compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see Use in lactation under Warnings). Approximately 99% of the drug is bound to plasma proteins.
Metabolism: The elimination of warfarin is almost entirely by metabolism, Apo-Warfarin is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, 2 diastereoisomer alcohols, 4'-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2 and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.
Excretion: The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20-60 hrs, with a mean of about 40 hrs. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life o R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37- 89 hrs, while that of S-warfarin ranges from 21-43 hrs. 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.
Asians: Asian patients may require lower initiation and maintenance dosages of warfarin. One non-controlled study in 151 Chinese patients reported a mean daily warfarin requirement of 3.3±1.4mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.
Elderly: There are no significant age-related differences in the pharmacokinetics of racemic warfarin. Limited information suggests that there is no difference in the clearance of S-warfarin in elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly compared to the young. Older patients (≥60 years) appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. As patient age increases, less warfarin is required to produce a therapeutic level of anticoagulation. The cause of this response to warfarin is not known.
Renal Dysfunction: Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.
Hepatic Dysfunction: Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
The administration of Apo-Warfarin via the IV route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72-96 hrs after dosing, indicating that the administration of IV Apo-Warfarin should not provide any increased biological effect or earlier onset of action.
Indications/Uses
For the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism.
For the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
To reduce the risk of death, recurrent myocardial infarction and thromboembolic events eg, stroke or systemic embolization after myocardial infarction in patient with poor LV function.
Dosage/Direction for Use
The dosage and administration of Apo-Warfarin must be individualized for each patient according to the particular patient's PT/INR response to the drug.
The dosage should be adjusted based upon the patient's PT/INR. (See Laboratory Control for full discussion on INR under Dosage & Administration.)
Venous Thromboembolism (including pulmonary embolism): Available clinical evidence indicates that an INR of 2-3 is sufficient for prophylaxis and treatment of venous thromboembolism and minimizes the risk of hemorrhage associated with higher INRs.
Atrial Fibrillation:
Five recent clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2-4.5) or low INR (1.4-3). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the American College of Chest Physicians' (ACCP) recommendation that an INR of 2-3 be used for long-term warfarin therapy in appropriate AF patients.
Post-Myocardial Infarction:
In post-myocardial infarction patients, Apo-Warfarin therapy should be initiated early (2-4 weeks post-infarction) and dosage should be adjusted to maintain an INR of 2.5-3.5 long-term. The recommendation is based on the results of the WARIS study in which treatment was initiated 2-4 weeks after the infarction. In patients thought to be at an increased risk of bleeding complications or on aspirin therapy, maintenance of Apo-Warfarin therapy at the lower end of this INR range is recommended.
Mechanical and Bioprosthetic Heart Valves:
In patients with mechanical heart valve(s), long-term prophylaxis with warfarin to an INR of 2.5-3.5 is recommended. In patients with bioprosthetic heart valve(s), based on limited data, the American College of Chest Physicians recommends warfarin therapy to an INR of 2-3 for 12 weeks after valve insertion. In patients with additional risk factors eg, atrial fibrillation or prior thromboembolism, consideration should be given for longer-term therapy.
Recurrent Systemic Embolism: In cases where the risk of thromboembolism is great eg, in patients with recurrent systemic embolism, a higher INR may be required.
An INR of >4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.
Initial Dosage: The dosing of Apo-Warfarin must be individualized according to patient's sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. Low initiation doses are recommended for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR response to Apo-Warfarin (see Precautions). Based on limited data, Asian patients may also require lower initiation and maintenance doses. It is recommended that Apo-Warfarin therapy be initiated with a dose of 2-5 mg/day with dosage adjustments based on the results of PT/INR determinations.
Maintenance: Most patients are satisfactorily maintained at a dose of 2-10 mg daily. Flexibility of dosage is provided by breaking scored tablets in half. The individual dose and interval should be gauged by the patient's prothrombin response.
Duration of Therapy: The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.
Missed Dose: The anticoagulant effect of Apo-Warfarin persists beyond 24 hrs. If the patient forgets to take the prescribed dose of Apo-Warfarin at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician.
Laboratory Control: The PT reflects the depression of vitamin K-dependent Factors VII, X and II. There are several modifications of the one-stage PT and the physician should become familiar with the specific method used in his laboratory. The degree of anticoagulation indicated by any range of PTs may be altered by the type of thromboplastin used; the appropriate therapeutic range must be based on the experience of each laboratory. The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician's judgment of the patient's reliability and response to Apo-Warfarin in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of 1-4 weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests are done when other warfarin products are interchanged with Apo-Warfarin and also if other medications are co-administered with Apo-Warfarin (see Precautions).
Different thromboplastin reagents vary substantially in their sensitivity to sodium warfarin-induced effects on PT. To define the appropriate therapeutic regimen, it is important to be familiar with the sensitivity to the thromboplastin reagent used in the laboratory and its relationship to the International Reference Preparation (IRP), a sensitive thromboplastin reagent prepared from human brain.
A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges. The INR system of reporting is based on a logarithmic relationship between the PT ratios of the test and reference preparation. The INR is the PT ratio that would be obtained if the International Reference Preparation (IRP), which has an ISI of 1, were used to perform the test. Early clinical studies of oral anticoagulants, which formed the basis for recommended therapeutic ranges of 1.5-2.5 times control mean normal PT, used sensitive human brain thromboplastin. When using the less sensitive rabbit brain thromboplastins commonly employed in PT assays today, adjustments must be made to the targeted PT range that reflect this decrease in sensitivity.
The INR can be calculated as: INR=(observed PT ratio)ISI.
where the ISI (International Sensitivity Index) is the correction factor in the equation that relates the PT ratio of the local reagent to the reference preparation and is a measure of the sensitivity of a given thromboplastin to reduction of vitamin K-dependent coagulation factors; the lower the ISI, the more "sensitive" the reagent and the closer the derived INR will be to the observed PT ratio.
The proceedings and recommendations of the 1992 National Conference on Antithrombotic Therapy review and evaluate issues related to oral anticoagulant therapy and the sensitivity of thromboplastin reagents and provide additional guidelines for defining the appropriate therapeutic regimen.
The conversion of the INR to PT ratios for the less intense (INR 2-3) and more intense (INR 2.5- 3.5) therapeutic range recommended by the ACCP for thromboplastins over a range of ISI values is shown in Table 3. (See Table 3.)

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Treatment During Dentistry and Surgery: The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists. PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of Apo-Warfarin to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation.
The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of Apo-Warfarin therapy. When discontinuing Apo-Warfarin even for a short period of time, the benefits and risks should be strongly considered.
Conversion from Heparin Therapy: Since the anticoagulant effect of Apo-Warfarin is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to Apo-Warfarin may begin concomitantly with heparin therapy or may be delayed 3-6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that Apo-Warfarin therapy be overlapped with heparin for 4-5 days, until Apo-Warfarin has produced the desired therapeutic response as determined by PT/INR. When Apo-Warfarin has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
Apo-Warfarin may increase the aPTT test, even in the absence of heparin. During initial therapy with Apo-Warfarin, the interference with heparin anticoagulation is of minimal clinical significance.
As heparin may affect the PT/INR, patients receiving both heparin and Apo-Warfarin should have blood for PT/INR determination drawn at least: 5 hrs after the last IV bolus dose of heparin, or; 4 hrs after cessation of continuous IV infusion of heparin, or; 24 hrs after the last SC heparin injection.
Administration: Should be taken on an empty stomach.
Overdosage
Symptoms: Suspected or overt abnormal bleeding (eg, appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries) are early manifestations of anticoagulation beyond a safe and satisfactory level.
Treatment: Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Apo-Warfarin therapy and if necessary, by administration of oral or parenteral vitamin K1. (See recommendations accompanying vitamin K1 preparations prior to use.) Such use of vitamin K1 reduces response to subsequent Apo-Warfarin therapy. Patients may return to a pre-treatment thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of Apo-Warfarin administration reverses the effect of vitamin K and a therapeutic PT/INR can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy.
If minor bleeding progresses to major bleeding, give 5-25 mg (rarely up to 50 mg) parenteral vitamin K1. In emergency situations of severe hemorrhage, clotting factors can be returned to normal by administering 200-500 mL of fresh whole blood or fresh frozen plasma, or by giving commercial Factor IX complex.
A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to Apo-Warfarin overdosage.
Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of Apo-Warfarin (warfarin sodium) treatment. Packed red blood cells may also be given if significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease.
Contraindications
Anticoagulation is contraindicated in any localised or general physical condition or personal circumstance in which the hazard of haemorrhage might be greater than the potential clinical benefits of anticoagulation: Haemorrhagic tendencies or blood dyscrasias; Recent or contemplated surgery of the central nervous system, the eye, and traumatic surgery resulting in large open surfaces; Bleeding tendencies associated with active ulceration or overt bleeding of the gastrointestinal, genitourinary or respiratory tracts; cerebrovascular haemorrhage; aneurysms (cerebral, dissecting aorta); pericarditis and pericardial effusions; bacterial endocarditis; Threatened abortion, eclampsia and preeclampsia. Inadequate laboratory facilities. Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient cooperation; Spinal puncture and other diagnostic or therapeutic procedures with a potential for uncontrollable bleeding; Miscellaneous: Major regional, lumbar block anaesthesia, malignant hypertension and known hypersensitivity to warfarin or to any of the components of Apo-Warfarin.
Use in pregnancy: Apo-Warfarin is contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal haemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy.
Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the 1st trimester. Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy and eye abnormalities have been observed. Mental retardation, blindness and other central nervous system abnormalities have been reported in association with 2nd and 3rd trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies eg, single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia and corneal leukoma, cleft palate, cleft lip, schizencephaly and microcephaly.
Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported.
Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking Apo-Warfarin, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks.
Warnings
As warfarin has a narrow therapeutic index, patients stabilized on Apo-Warfarin should be instructed not to change brands without prior approval of their doctor.
The most serious risks associated with anticoagulant therapy with sodium warfarin are haemorrhage in any tissue or organ and, less frequently (<0.1%), necrosis and/or gangrene of skin and other tissues. The risk of haemorrhage is related to the level of intensity and the duration of anticoagulant therapy. Haemorrhage and necrosis have, in some cases, been reported to result in death or permanent disability. Necrosis appears to be associated with local thrombosis and usually appears within a few days of the start of anticoagulant therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast or penis has been reported. Careful diagnosis is required to determine whether necrosis is caused by an underlying disease. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. See information on predisposing conditions. These and other risks associated with anticoagulant therapy must be weighed against the risk of thrombosis or embolization in untreated cases.
It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. Apo-Warfarin, a narrow therapeutic range (index) drug, may be affected by factors eg, other drugs and dietary vitamin K. Dosage should be controlled by periodic determinations of prothrombin time (PT)/International Normalized Ratio (INR) or other suitable coagulation tests. Determinations of whole blood clotting and bleeding times are not effective measures for control of therapy. Heparin prolongs the one-stage PT. When heparin and Apo-Warfarin are administered concomitantly, refer to the Conversion from Heparin Therapy under Dosage & Administration for recommendations.
Caution should be observed when Apo-Warfarin is administered in any situation or in the presence of any predisposing condition where added risk of haemorrhage or necrosis is present.
Anticoagulation therapy with Apo-Warfarin may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the "purple toes syndrome". Discontinuation of Apo-Warfarin therapy is recommended when such phenomena are observed.
Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including "purple toes syndrome", livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms simulating polyarteritis, or any other sequelae of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen and liver. Some cases have progressed to necrosis or death.
"Purple toes syndrome" is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3-10 weeks, or later, after the initiation of therapy with warfarin or related compounds. Major features of this syndrome includes purple color of plantar surfaces and sides of the toes that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of the color over time. While the "purple toes syndrome" is reported to be reversible, some cases progress to gangrene or necrosis which may require debridement of the affected area, or may lead to amputation.
Heparin-induced thrombocytopenia. Warfarin should be used with caution in patients with heparin-induced thrombocytopenia and deep vein thrombosis. Cases of venous limb ischemia, necrosis and gangrene have occurred in such patients 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 (Warkentin et al 1997).
A severe elevation (>50 sec) in activated partial thromboplastin time (PTT) with a PT/INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.
The decision to administer anticoagulants in the following conditions must be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the benefits: Severe to moderate hepatic or renal insufficiency; Infectious diseases or disturbances of intestinal flora: Sprue, antibiotic therapy; Trauma which may result in internal bleeding; Surgery or trauma resulting in large exposed raw surfaces; Indwelling catheters; Severe to moderate hypertension; Known or suspected deficiency in protein C-mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its co-factor, protein S, have been associated with tissue necrosis following warfarin administration. Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis. It has been reported that concomitant anticoagulation therapy with heparin for 5-7 days during initiation of therapy with Apo-Warfarin may minimize the incidence of tissue necrosis. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation.
Miscellaneous: Polycythaemia vera, vasculitis, severe diabetes.
Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported.
In patients with acquired or inherited warfarin resistance, decreased therapeutic responses to Apo-Warfarin have been reported. Exaggerated therapeutic responses have been reported in other patients.
Patients with congestive heart failure may exhibit greater than expected PT/INR response to Apo-Warfarin, thereby requiring more frequent laboratory monitoring and reduced doses of Apo-Warfarin.
Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Note recommendations accompanying these preparations.)
Topical preparations containing methyl salicylate should be used with care in patients on warfarin and excessive usage is to be avoided as potentially dangerous drug interaction can occur.
Use in lactation: Based on very limited published data, warfarin has not been detected in the breast milk of mother treated with warfarin. The same limited published data reported that some breast fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times although not as prolonged as their mothers. The decision to breast feed should be taken after careful consideration of the available alternatives. Women who are breast feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded. It is prudent to perform coagulation tests and to evaluate vitamin K status in infants at risk for bleeding tendencies before advising their mothers to breast feed. Effects in premature infants have not been evaluated.
Special Precautions
Periodic determination of PT/INR or other suitable coagulation test is essential.
Numerous factors, alone or in combination, including travel, changes in diet, environment, physical state and medication may influence response of the patient to anticoagulants. It is generally good practice to monitor the patient's response with additional PT/INR determinations in the period immediately after discharge from the hospital, and whenever other medications are initiated, discontinued or taken irregularly. The following factors are listed for reference; however, other factors may also affect the anticoagulant response.
Drugs may interact with Apo-Warfarin through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with Apo-Warfarin are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiological control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with Apo-Warfarin are mainly enzyme induction, enzyme inhibition and reduced plasma protein-binding. It is important to note that some drugs may interact by more than one mechanism.
The following factors, alone or in combination, may be responsible for increased PT/INR response: Endogenous Factors: Blood dyscrasias (see Contraindications); cancer; collagen vascular disease; congestive heart failure; diarrhea; elevated temperature; hepatic disorders (infectious hepatitis, jaundice); hyperthyroidism; poor nutritional state; steatorrhea; vitamin K deficiency.
Exogenous Factors: Potential drug interactions with Apo-Warfarin are listed as follows by drug class and by specific drugs.
Classes of Drugs: Adrenergic stimulants, central; Alcohol abuse reduction preparations; Analgesics; Anesthetics, inhalation; Antiarrhythmics*; Antibiotics*: Aminoglycosides (oral), Cephalosporins (parenteral), Macrolides, Miscellaneous, Penicillins (IV, high dose), Quinolones (fluoroquinolones), Sulfonamides (long-acting), Tetracyclines; Anticoagulants; Anticonvulsants*; Antidepressants*; Antimalarial Agents; Antineoplastics*; Antiparasitics/Antimicrobials; Antiplatelet drugs/effects; Antithyroid drugs*; β-adrenergic blockers; bromelains; Cholelitholytic agents; Diabetes agents, oral; Diuretics*; Fungal medications, systemic*; Gastric acidity and peptic ulcer agents*; Gastrointestinal, ulcerative colitis agents; gout treatment agents; hemorrheologic agents; hepatotoxic drugs; hyperglycemic agents; hypertensive emergency agents; hypnotics*; hypolipidemics*; monoamine oxidase inhibitors; narcotics, prolonged; nonsteroidal anti-inflammatory agents; psychostimulants; pyrazolones; salicylates; selective serotonin re-uptake inhibitors; steroids, adrenocortical*; steroids, anabolic (17-alkyl testosterone derivatives); thrombolytics; thyroid drugs; tuberculosis agents*; uricosuric agents; vaccines; vitamins*.
Specific Drugs Reported: Acetaminophen; alcohol*; allopurinol; aminosalicylic acid; amiodarone HCl; aspirin; atorvastatin; azithromycin; capecitabine; cefamandole; cefazolin; cefoperazone; cefotetan; cefoxitin; ceftriaxone; celecoxib; cerivastatin; chenodiol; chloramphenicol; chloral hydrate*; chlorpropamide; cholestyramine*; cimetidine; ciprofloxacin; cisapride; clarithromycin; clofibrate; Apo-Warfarin overdosage; cyclophosphamide*; danazol; dextran; dextrothyroxine; diazoxide; diclofenac; dicumarol; diflunisal; disulfiram; doxycycline; erythromycin; ethacrynic acid; fenofibrate; fenoprofen; fluconazole; fluorouracil; fluoxetine; flutamide; fluvastatin; fluvoxamine; gemfibrozil; glucagon; halothane; heparin; ibuprofen; ifosfamide; indomethacin; influenza virus vaccine; itraconazole; ketoprofen; ketorolac; levamisole; levofloxacin; levothyroxine; liothyronine; lovastatin; mefenamic acid; methimazole*; methyldopa; methylphenidate; methylsalicylate ointment (topical); metronidazole; miconazole; moricizine HCl*; nalidixic acid; naproxen; neomycin; norfloxacin; ofloxacin; olsalazine; omeprazole; oxaprozin; oxymetholone; paroxetine; penicillin G, IV; pentoxifylline; phenylbutazone; phenytoin*; piperacillin; piroxicam; pravastatin; prednisone*; propafenone; propoxyphene; propranolol; propylthiouracil*; quinidine; quinine; ranitidine*; rofecoxib; sertraline; simvastatin; stanozolol; streptokinase; sulfamethizole; sulfamethoxazole; sulfinpyrazone; sulfisoxazole; sulindac; tamoxifen; tetracycline; thyroid; ticarcillin; ticlopidine; tissue plasminogen activator (t-PA); tolbutamide; trimethoprim/sulfamethoxazole; urokinase; valproate; vitamin E; zafirlukast; zileuton.
Also: Other medications affecting blood elements which may modify hemostasis; dietary deficiencies; prolonged hot weather; unreliable PT/INR determinations.
The following factors, alone or in combination, may be responsible for decreased PT/INR response: Endogenous Factors: Edema; hereditary coumarin resistance; hyperlipidemia; hypothyroidism; nephrotic syndrome.
Exogenous Factors: Potential drug interactions with Apo-Warfarin (warfarin sodium) are as follows by drug class and by specific drugs.
Classes of Drugs: Adrenal cortical steroid inhibitors; antacids; antianxiety agents; antiarrhythmics*; antibiotics*; anticonvulsants*; antidepressants*; antihistamines; antineoplastics*; antipsychotic medications; antithyroid drugs*; barbiturates; diuretics*; enteral nutritional supplements; fungal medications, systemic*; gastric acidity and peptic ulcer agents*; hypnotics*; hypolipidemics*; immunosuppressives; oral contraceptives, estrogen-containing; steroids, adrenocortical*; tuberculosis agents*; vitamins*.
Specific Drugs Reported: Alcohol*; aminoglutethimide; amobarbital; atorvastain; azathioprine; butabarbital; butalbital; carbamazepine; chloral hydrate*; chlordiazepoxide; chlorthalidone; cholestyramine*; corticotropin; cortisone; Apo-Warfarin underdosage; cyclophosphamide*; dicloxacillin; ethchlorvynol; glutethimide; griseofulvin; haloperidol; meprobamate; 6-mercaptopurine; methimazole*; moricizine HCl*; nafcillin; paraldehyde; pentobarbital; phenobarbital; phenytoin*; pravastatin; prednisone*; primidone; propylthiouracil*; raloxifene; ranitidine*; rifampin; secobarbital; spironolactone; sucralfate; trazodone; vitamin C (high dose); vitamin K.
Also: Diet high in vitamin K; unreliable PT/INR determinations.
*Increased and decreased PT/INR responses have been reported.
Because a patient may be exposed to a combination of the previously mentioned factors, the net effect of Apo-Warfarin on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable.
It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.
Botanical (Herbal) Medicines: Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with Apo-Warfarin. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and Apo-Warfarin. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient's response with additional PT/INR determinations when initiating or discontinuing botanicals.
Specific botanicals reported to affect Apo-Warfarin therapy include the following: Bromelains, danshen, dong quai (Angelica sinesis), garlic, Ginkgo biloba, and ginseng are associated most often with an INCREASE in the effects of Apo-Warfarin; Coenzyme Q10 (ubidecarenone) and St John's wort are associated most often with a DECREASE in the effects of Apo-Warfarin.
Some botanicals may cause bleeding events when taken alone (eg garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of Apo-Warfarin. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of Apo-Warfarin.
Effect on Other Drugs: Coumarins may also affect the action of other drugs. Hypoglycaemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.
Special Risk Patients: Apo-Warfarin is a narrow therapeutic range (index) drug, and caution should be observed when warfarin sodium is administered to certain patients eg, the elderly or debilitated or when administered in any situation or physical condition where added risk of hemorrhage is present.
IM injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages.
Caution should be observed when Apo-Warfarin (or warfarin) is administered concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin can inhibit platelet aggregation and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.
Acquired or inherited warfarin resistance should be suspected if large daily doses of Apo- Warfarin are required to maintain a patient's PT/INR within a normal therapeutic range.
Information for Patients: The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well-instructed patients who communicate effectively with their physician. Patients should be advised: Strict adherence to prescribed dosage schedule is necessary. Do not take or discontinue any other medication, including salicylates (eg, aspirin and topical analgesics) and other over-the-counter medications and botanical (herbal) products (eg bromelains, coenzyme Q10, danshen, dong quai, garlic, ginkgo biloba, ginseng, St John's wort) except on advice of the physician. Avoid alcohol consumption. Avoid any activity or sport that may result in traumatic injury. Prothrombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that Apo-Warfarin is being taken. If the prescribed dose of Apo-Warfarin is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of Apo-Warfarin the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with Apo-Warfarin. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits eg, eating large amounts of green leafy vegetables. Contact physician to report any illness eg, diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: Pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with Apo-Warfarin is discontinued, patients should be cautioned that the anticoagulant effects of Apo-Warfarin may persist for about 2-5 days. Patients should be advised that all warfarin products represent the same medication and should not be taken concomitantly as overdosage may result. Carcinogenicity, Mutagenicity & Impairment of Fertility: Carcinogenicity and mutagenicity studies have not been performed with Apo-Warfarin. The reproductive effects of Apo-Warfarin have not been evaluated.
Use in pregnancy: Pregnancy Category X: Do not take Apo-Warfarin during pregnancy and do not become pregnant while taking it (see Contraindications).
Use in children: Safety and effectiveness in pediatric patients <18 years have not been established in randomized, controlled clinical trials. However, the use of Apo-Warfarin in pediatric patients is well documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category X: Do not take Apo-Warfarin during pregnancy and do not become pregnant while taking it (see Contraindications). Apo-Warfarin is contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal haemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy.
Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the 1st trimester. Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy and eye abnormalities have been observed. Mental retardation, blindness and other central nervous system abnormalities have been reported in association with 2nd and 3rd trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies eg, single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia and corneal leukoma, cleft palate, cleft lip, schizencephaly and microcephaly.
Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported.
Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking Apo-Warfarin, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks.
Use in lactation: Based on very limited published data, warfarin has not been detected in the breast milk of mother treated with warfarin. The same limited published data reported that some breast fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times although not as prolonged as their mothers. The decision to breast feed should be taken after careful consideration of the available alternatives. Women who are breast feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded. It is prudent to perform coagulation tests and to evaluate vitamin K status in infants at risk for bleeding tendencies before advising their mothers to breast feed. Effects in premature infants have not been evaluated.
Adverse Reactions
Potential adverse reactions to Apo-Warfarin may include: Fatal or nonfatal hemorrhage from any tissue or organ: This is a consequence of the anticoagulant effect. The signs, symptoms and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis.
Bleeding during anticoagulant therapy does not always correlate with PT/INR (see Treatment under Overdosage). Bleeding which occurs when the PT/INR is within the therapeutic range warrants diagnostic investigation since it may unmask a previously unsuspected lesion eg, tumor, ulcer, etc.
Necrosis of skin and other tissues (see Warnings).
Adverse reactions reported infrequently include: Hypersensitivity/allergic reactions, systemic cholesterol microembolization, purple toes syndrome, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, vasculitis, edema, fever, rash, dermatitis, including bullous eruptions, urticaria, abdominal pain including cramping, flatulence/bloating, fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache, dizziness, taste perversion, pruritus, alopecia, cold intolerance, and paresthesia including feeling cold and chills.
Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown.
Priapism has been associated with anticoagulant administration; however, a causal relationship has not been established.
Drug Interactions
See Precautions.
Storage
APO-WARFARIN should be stored between 15-25°C.
ATC Classification
B01AA03 - warfarin ; Belongs to the class of vitamin K antagonists. Used in the treatment of thrombosis.
Presentation/Packing
Tab 1 mg x 100's. 2 mg x 100's. 5 mg x 100's.
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