Approval Date.
Warfarin Sodium Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
-Warfarin sodium tablets can cause major or fatal bleeding.
-All patients treated with warfarin sodium tablets should be monitored regularly for International Normalized Ratio (INR).
-Medications, dietary changes, and other factors can affect INR levels while receiving warfarin sodium tablets.
-Instruct patients to take precautions to minimize the risk of bleeding and to report signs and symptoms of bleeding.
Drug Name]
Generic Name: Warfarin Sodium Tablets
English Name: Warfarin Sodium Tablets
Hanyu Pinyin：Huafalinna Pian
Ingredients
The main ingredient of this product is Warfarin Sodium.
Chemical name: 3-(α-Acetonylbenzyl)-4-hydroxycoumarin sodium salt
Chemical structure formula.
Molecular formula: C19H15NaO4
Molecular weight: 330.31
【Properties】.
This product is white or off-white tablet.
Indications
(1) Prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); (2) Prevention and treatment of thromboembolic complications after atrial fibrillation (AF) and/or heart valve replacement (3) Reduction of the risk of death, recurrence and thromboembolic events (such as stroke or embolism of the body circulation) after myocardial infarction.
Limitations of use
Warfarin sodium tablets have no direct effect on formed thrombi and do not reverse ischemic tissue damage. The purpose of anticoagulation therapy after thrombosis is to prevent further expansion of the formed thrombus and to prevent secondary thromboembolism that may lead to serious or even fatal consequences.
Specification
2.5mg
Dosage and Administration
Individualized dosing
The dose and course of warfarin sodium tablets must be individually adjusted according to the International Normalized Ratio (INR) level and clinical situation of each patient. For most patients, an INR > 4.0 provides no additional therapeutic benefit and may carry a higher risk of bleeding. It is recommended to refer to the latest clinical guidelines and to select the duration of dosing and the dose used on a case-by-case basis.
Single Indication.
Venous thromboembolism (including DVT and PE)
The dose of warfarin sodium tablets should be adjusted during treatment to maintain a target INR of 2.5 (range: 2.0-3.0). For the following indications the duration of treatment is
For patients with DVT or PE secondary to transient (reversible) risk factors, warfarin treatment for 3 months is recommended.
For patients with DVT or PE of unknown etiology, treatment with warfarin is recommended for at least 3 months. after 3 months, the risk-benefit ratio of long-term treatment is assessed individually for the patient.
For patients with more than two episodes of DVT or PE of unknown etiology, long-term treatment with warfarin is recommended. For patients on long-term anticoagulation therapy, the risk-benefit ratio of anticoagulation therapy should be periodically assessed on an individual basis.
Atrial fibrillation
In patients with non-valvular AF, the target INR for warfarin anticoagulation therapy is 2.5 (range: 2.0-3.0).
Long-term anticoagulation with warfarin is recommended in patients with persistent or paroxysmal nonvalvular atrial fibrillation who are at high risk for stroke (i.e., have any of the following risk factors: previous ischemic stroke, transient ischemic attack, or embolism of the body circulation, or two of the following risk factors: age >75 years, moderate or severe impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus).
Long-term anticoagulation with warfarin is recommended for patients with persistent or paroxysmal non-valvular atrial fibrillation who are at intermediate risk for stroke (with any of the following risk factors: age >75 years, moderate or severe impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus).
Long-term anticoagulation with warfarin is recommended for patients with atrial fibrillation combined with mitral stenosis.
Long-term anticoagulation with warfarin is recommended for patients with atrial fibrillation after prosthetic heart valve replacement. Depending on the type and location of the valve and other patient-specific factors, the target INR may be increased and aspirin may be used in combination.
Mechanical and Bioprosthetic Valves
In patients with aortic bileaflet mechanical valve implantation or Medtronic Hall (Minneapolis, MN) lateral tilting disc valve implantation who are in sinus rhythm and do not have left atrial dilatation, warfarin therapy is recommended with a target INR of 2.5 (range: 2.0-3.0).
In patients with mitral lateral disc and bileaflet mechanical valve implants, warfarin therapy is recommended with a target INR of 3.0 (range: 2.5-3.5).
For patients with caged ball or caged disc valve implantation, warfarin therapy is recommended with a target INR of 3.0 (range: 2.5-3.5).
For patients with mitral valve bioprosthetic implants, warfarin therapy is recommended for the first 3 months after valve implantation with a target INR of 2.5 (range: 2.0-3.0). In the presence of other risk factors for thromboembolism (atrial fibrillation, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range: 2.0-3.0) is recommended.
Post-myocardial infarction
For patients at high risk of myocardial infarction (e.g., large anterior wall infarction, severe heart failure, transthoracic echocardiography demonstrating intracardiac thrombus, atrial fibrillation, and history of thromboembolism), moderate-intensity warfarin (INR: 2.0-3.0) combined with low-dose aspirin (≤100 mg/day) is recommended for at least 3 months.
Recurrent Body Circulation Embolism and Other Indications
The anticoagulant therapeutic effects of warfarin have not been adequately evaluated in clinical trials in patients with valvular disease and mitral stenosis in combination with atrial fibrillation. However, moderate dose regimens (INR: 2.0-3.0) may be appropriate for these patients.
Initial and maintenance doses.
The initial dose of warfarin sodium tablets varies widely among patients. Factors affecting the initial dose include clinical factors such as age, race, weight, gender, concomitant medications and concomitant diseases, and genetic factors such as CYP2C9 and VKORC1 genotype. Lower initial and maintenance doses should be considered for elderly and/or frail patients and for Asian patients. Routine loading doses are not recommended in these populations due to the increased risk of bleeding and other complications and the inability to inhibit thrombosis more rapidly.
Genotype unknown
If the patient’s CYP2C9 and VKORC1 genotypes are unknown, the usual initial dose is 2-5 mg once daily. The required dose for each patient is determined by close monitoring of INR levels in conjunction with specific indications. A common maintenance dose is 2-10 mg daily.
Genotypes are known
Table 1 gives the 3 expected maintenance dose ranges observed in subgroups of patients with different combinations of CYP2C9 and VKORC1 variants. If the CYP2C9 and/or VKORC1 genotype of the patient is known, Table 1 should be consulted when selecting the initial dose. patients carrying the CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 genes may take longer (2-4 weeks) to achieve maximal INR effects with the same dosing regimen compared to patients who do not carry these CYP variants.
Table 1 Three expected maintenance daily dose ranges based on CYP2C9 and VKORC1 genotypes†
VKORC1CYP2C9*1/*1*1/*2*1/*3*2/*2*2/*3*3/*3GG5-7 mg5-7 mg3-4 mg3-4 mg3-4 mg0.5-2 mgAG5-7 mg3-4 mg3-4 mg3-4 mg3-4 mg0.5-2 mg0.5-2 mgAA3-4 mg3-4 mg0.5-2 mg0.5-2 mg0.5-2 mg0.5-2 mg† The above ranges were derived from multiple published clinical studies. The VKORC1-1639G>A (rs9923231) variant was used in the table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose.
Monitoring INR for optimal anticoagulation
Warfarin sodium tablets have a narrow therapeutic window and their activity may be influenced by several factors, such as medications and dietary vitamin K. Therefore, the anticoagulant effect must be closely monitored during treatment with warfarin sodium tablets. After administration of the initial dose, the INR must be measured daily until the INR stabilizes within the target range. after the INR stabilizes, the INR should be measured periodically to maintain the dose within the therapeutic range. The frequency of INR testing should be determined based on clinical circumstances, but a generally acceptable interval for INR measurement is 1 to 4 weeks. Additional INR testing is required when other warfarin products are used in place of this product, and when other drugs are used, discontinued, or taken irregularly. In addition, heparin is a common concomitant medication that increases the INR.
The clotting time and bleeding time of whole blood are not valid indicators for monitoring the therapeutic effect of warfarin sodium tablets.
Missed doses
The anticoagulant effect of warfarin sodium tablets lasts for more than 24 hours. If a patient does not take the prescribed dose of warfarin sodium tablets at the prescribed dosing time on a given day, the patient should take that dose as soon as possible on the same day and should not double the dose on the next day to make up for the missed dose.
Treatment during dental or surgical procedures
Some dental or surgical procedures may require interruption or adjustment of the therapeutic dose of warfarin sodium tablets. The benefits and risks of discontinuing warfarin sodium tablets, even for short periods of time, should be considered. Immediate INR needs to be measured prior to any dental or surgical procedure. for patients undergoing minimally invasive procedures, anticoagulation must be administered before, during or immediately after surgery and the dosage of warfarin sodium tablets adjusted to maintain the INR at the lower limit of the therapeutic range so that anticoagulation can be safely continued.
Conversion of other anticoagulants to warfarin sodium tablets anticoagulation
Heparin
Heparin is preferred for initial rapid anticoagulation as the full anticoagulant effect of warfarin sodium tablets is not achieved until several days later. During the initial treatment with warfarin sodium tablets, heparin has little interfering effect on anticoagulation therapy. When switching to warfarin sodium tablets, administration can be concurrent with heparin or delayed for 3 to 6 days. To ensure anticoagulant efficacy, full-dose heparin therapy should be given continuously in combination with warfarin sodium tablets for 4 to 5 days until it is determined by INR testing that warfarin sodium tablets are producing the desired therapeutic effect and then heparin can be discontinued.
Because heparin may affect INR, patients receiving the combination of heparin and warfarin sodium should be monitored for INR at least 5 hours after the last intravenous push of heparin, or 4 hours after discontinuation of continuous intravenous heparin infusion, or 24 hours after the last subcutaneous injection of heparin.
Warfarin sodium may prolong the activated partial thromboplastin time (aPTT) even without heparin. an INR within the expected range with a significantly prolonged aPTT (>50 seconds) has been identified as an indication of increased risk of postoperative bleeding.
Other anticoagulants
For instructions on whether to switch to warfarin sodium, refer to the instructions for other anticoagulants.
Adverse reactions]
(1) Serious adverse reactions
(1) Bleeding; (2) tissue necrosis; (3) defense against calcification; (4) acute kidney injury; (5) atherosclerotic embolism and cholesterol microembolism in the body circulation; (6) limb ischemia, necrosis and gangrene in patients with heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombotic syndrome (HITTS); (7) other clinical factors that increase the risk. (See [Precautions])
(2) Other adverse reactions
(1) Immune system disorders: allergic reactions (including urticaria and anaphylactic reactions); (2) Vascular system: vasculitis, purple toe syndrome; (3) Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis is associated with the combination of warfarin sodium tablets and ticlopidine; ④Gastrointestinal disorders: nausea, vomiting, diarrhea, abnormal taste, abdominal pain, feeling of fullness and flatulence; ⑤Dermal disorders: rash, dermatitis (including maculopapular rash), pruritus and alopecia; ⑥Respiratory disorders: tracheal or bronchial calcification; ⑦General symptoms: chills; ⑧Reproductive system: abnormal penile erection.
[Contraindicated
Pregnancy
Warfarin sodium tablets should not be used in pregnant women, except for those with mechanical heart valves with a high risk of thromboembolism (see [Precautions] and [Use in Pregnant and Lactating Women]). When used in pregnant women, it may cause fetal harm. Administration of warfarin sodium tablets during pregnancy causes a recognized serious congenital malformation (warfarin embryopathy and fetal toxicity), fatal fetal hemorrhage, and an increased risk of miscarriage and fetal death. If warfarin sodium tablets are taken during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazards to the fetus (see [Medication for Pregnant and Lactating Women]).
Other Prohibited Conditions.
(1) bleeding tendency or malignancy; (2) patients with recent or anticipated traumatic surgery of the central nervous system, eye, or resulting in large open wounds (see [Precautions]); (3) bleeding tendency associated with: (i) active ulceration or significant bleeding of the gastrointestinal, genitourinary, or respiratory tract; (ii) central nervous system bleeding; (iii) cerebral aneurysms, aortic coarctation aneurysms; (iv) pericarditis, pericardial pericardial effusion; (5) infective endocarditis; (4) preterm abortion, eclampsia and pre-eclampsia; (5) unmonitored potentially poorly adherent patients; (6) spinal puncture and other diagnostic measures or treatments that may result in uncontrolled bleeding; (7) hypersensitivity to warfarin or any other component of the product (see [Adverse Reactions]); (8) major regional block anesthesia or lumbar spine anesthesia; (9) malignant hypertension.
Precautions]
(1) Bleeding: Warfarin sodium tablets can cause hemorrhage or fatal bleeding, which is likely to occur during the first month of drug administration. Risk factors for bleeding include high intensity anticoagulation (INR > 4.0), age greater than or equal to 65 years, history of high INR variability, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment and certain genetic factors, certain concomitant medications (see [Drug Interactions]) and prolonged warfarin therapy.
Perform regular INR monitoring in all treated patients. Patients may benefit from more frequent INR monitoring in patients at high risk of bleeding, fine-tuning of dosing to target INR, and development of the shortest regimen appropriate to the clinical situation. However, maintaining INR in the therapeutic range does not exclude the risk of bleeding.
Medications, dietary changes, and other factors can affect the level of INR achieved with warfarin sodium tablet therapy. More frequent INR monitoring should be performed when starting or stopping other medications (including botanicals) or changing the dose of other medications (see [Drug Interactions]).
Instruct patients to take precautions to minimize the risk of bleeding and to report signs and symptoms of bleeding.
(2) Tissue necrosis: Warfarin sodium tablets can cause necrosis and/or gangrene of the skin and other tissues, a rare but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually occurs within a few days of starting treatment with warfarin sodium tablets. Treatment by debridement or excision of the affected tissue, limb, breast, or penis has been reported in severe cases of necrosis.
Careful clinical evaluation is required to determine whether necrosis is caused by the underlying disease. Although various treatments for necrosis have been tried, none have been consistently found to be effective. If necrosis occurs, treatment with warfarin sodium tablets should be discontinued. If anticoagulation therapy needs to be continued, other anticoagulants may be considered.
(3) Calcification defense: Warfarin sodium tablets can cause fatal severe calcification defense or calcific uremic small artery disease, which has been reported in patients with and without end-stage renal disease. When these patients are diagnosed with calcific defense, warfarin sodium tablets should be discontinued and the calcific defense treated as appropriate, and alternative anticoagulation therapy considered.
(4) Acute kidney injury: Acute kidney injury may occur with warfarin sodium tablets in patients with impaired glomerular integrity or a history of nephropathy, which may be associated with the development of excessive anticoagulation and hematuria. In patients with renal insufficiency, more frequent monitoring of anticoagulation is recommended.
(5) Systemic atherosclerotic embolism and cholesterol microembolism: Anticoagulation with warfarin sodium tablets may promote dislodgement of atherosclerotic plaques triggering new embolisms. Systemic atherosclerotic embolism and cholesterol microembolism may present with a variety of signs and symptoms depending on the site of embolism. The most susceptible organs are the kidneys, followed by the pancreas, spleen, and liver, and in some cases, progress to necrosis or patient death. A unique syndrome caused by microembolism of the foot is known as “purple toe syndrome” and treatment with warfarin sodium tablets should be discontinued if signs are observed. If anticoagulation therapy is to be continued, alternative medications may be used.
(6) Limb ischemia, necrosis and gangrene in patients with HIT and HITTS: Do not use warfarin sodium tablets as initial therapy for patients with heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombotic syndrome (HITTS). When heparin therapy is discontinued and warfarin therapy is started or continued, some patients with HIT and HITTS develop limb ischemia, necrosis, and gangrene, conditions that can lead to amputation and/or death at the affected site in some patients. Treatment with warfarin sodium tablets may be considered when platelet counts have normalized.
(7) Use in pregnant women with mechanical heart valves: When warfarin sodium tablets are used in pregnant women, they may cause harm to the fetus. Although warfarin sodium tablets are contraindicated during pregnancy, the potential benefit of using warfarin sodium tablets in pregnant women with mechanical heart valves at high risk of thromboembolism may outweigh the risks associated with their use. The initiation or continuation of warfarin sodium tablets should be evaluated with the patient in certain special circumstances, when the specific risks and benefits associated with the patient’s individual medical condition should be considered and evaluated with reference to the most recent medical guidelines. The use of warfarin sodium tablets during pregnancy is recognized to cause significant congenital malformations (warfarin embryopathy and fetal toxicity), fatal fetal hemorrhage and an increased risk of miscarriage and fetal death. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazards of the drug to the fetus (see [Medication for Pregnant and Lactating Women]).
(8) Other clinical factors that increase the risk
The risk of warfarin sodium tablet therapy may be increased in the following clinical situations: (1) Moderate to severe hepatic injury; hepatic injury may enhance the response to warfarin by decreasing the synthesis of clotting factors and the metabolism of warfarin. When warfarin sodium is used in these patients, signs of bleeding should be monitored more frequently. (ii) infectious disease or dysbiosis of the intestinal flora (e.g., oro-inflammatory diarrhea, antibiotic therapy); (iii) use of indwelling catheters; (iv) moderate to severe hypertension; (v) defective protein C-mediated anticoagulant response: warfarin sodium tablets decrease the synthesis of physiologic anticoagulant substances, protein C, and protein S; hereditary or acquired protein C or its cofactors and protein S deficiency are associated with tissue necrosis after warfarin administration. Combined anticoagulation with heparin for 5-7 days during initiation of treatment with warfarin sodium tablets may reduce the incidence of tissue necrosis in such patients; (6) Ophthalmic surgery: In cataract surgery, warfarin sodium tablets use is associated with a significant increase in minor complications of sharps and local anesthetic blocks, but not with surgical hemorrhagic complications that may threaten vision. Because discontinuation or reduction of warfarin sodium tablets may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium tablets before relatively invasive and less complex ophthalmic procedures (e.g., lens surgery) should be based on consideration of the risks versus benefits of anticoagulation; (7) erythrocytosis; (8) vasculitis; (9) diabetes mellitus; and (10) renal clearance is considered to be a secondary determinant, and no dose adjustment is required in patients with renal injury. Patients with renal injury should be instructed to monitor their INR more frequently with warfarin.(9) Endogenous Factors Affecting INR
The following factors may contribute to an increased INR response: diarrhea, liver disease, malnutrition, fat drainage, or vitamin K deficiency.
The following factors may lead to a decreased INR response: increased vitamin K intake or hereditary warfarin resistance.
Pregnant women and nursing mothers
(1) During pregnancy
①Risk summary
Warfarin sodium tablets should generally be contraindicated in pregnant women, except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism and for whom the benefits of using warfarin sodium tablets may outweigh the risks (see [Precautions]). Warfarin sodium tablets can cause fetal harm. Use of warfarin in the first trimester of pregnancy results in congenital malformations in approximately 5% of infants. Because these data are not from adequately well-controlled studies, the incidence of this major birth defect is not an adequate basis for comparison with the expected incidence in controls or the general population and does not reflect the incidence observed in clinical practice. Physicians prescribing warfarin sodium tablets to pregnant women should consider the benefits and risks associated with warfarin sodium tablets, as well as the possible risks to the fetus.
Adverse effects can occur with the use of this product during pregnancy regardless of the health status or drug use of the mother. The risk of significant infant birth defects and miscarriage in the pregnant population taking this product is not known. In the U.S. general population, the clinically confirmed expected risks of major birth defects and miscarriage following administration of this product in the pregnant population are 2% to 4% and 15% to 20%, respectively.
②Clinical Precautions
Fetal/Neonatal Adverse Reactions
In humans, warfarin crosses the placental barrier and the concentration in fetal plasma is close to maternal values. Warfarin use during the first trimester of pregnancy results in congenital malformations in approximately 5% of infants. Warfarin embryopathy is characterized by nasal hypoplasia with or without punctate epiphyseal dysplasia (cartilaginous dysplasia) and growth retardation (including low birth weight). Central nervous system and ocular developmental abnormalities have also been reported in association, including dorsal midline hypoplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline hypoplasia characterized by optic nerve atrophy. Mental retardation, blindness, cerebral cleft malformation, microcephaly, hydrocephalus and other adverse pregnancy outcomes have been reported after warfarin administration in mid to late pregnancy.
(2) Lactation
(1) Summary of risks
Limited published studies have shown that the breast milk of women treated with warfarin does not contain warfarin. Because of the potential for serious adverse effects, including bleeding in breastfed infants, physicians prescribing warfarin sodium tablets to breastfeeding women should consider the impact of breastfeeding on infant health and development in women taking the drug, the maternal clinical need for warfarin sodium tablets, and any possible adverse effects on the infant from warfarin sodium tablets and maternal status, and make a comprehensive assessment of whether to give warfarin sodium tablets to breastfeeding women for anticoagulation therapy.
② Clinical considerations
Monitor breastfed infants for bruising or bleeding.
③Human data
Based on published data from 15 breastfeeding mothers, warfarin was not detected in breast milk. Of the 15 term newborns, 6 breastfed infants had prothrombin times within the expected range and the remaining 9 infants did not obtain prothrombin times. The effect of prematurity was not evaluated.
(3) Females and males of childbearing age
The pregnancy status of women of childbearing age should be confirmed prior to initiation of warfarin sodium therapy. Women of childbearing potential are advised to use effective contraception during treatment and for at least 1 month after the last dose of warfarin sodium.
[Pediatric Dosage].
Adequate well-controlled studies of warfarin sodium tablets have not been conducted in any pediatric population, so the optimal dose, safety and efficacy in pediatric patients are not known. The use of warfarin sodium tablets in children is based on data and recommendations from adults and limited pediatric data from observational studies and pediatric registries. Pediatric patients taking warfarin sodium tablets should avoid any activity or exercise that may result in traumatic injury.
The hemostatic system of infants and children is developing and their physiology is variable in terms of thrombosis and response to anticoagulant drugs. The dose of warfarin in the pediatric population varies depending on the age of the patient and is usually highest per kilogram of body weight in infants and lowest per kilogram of body weight in adolescents in order to maintain target INRs. More frequent INR determinations are recommended because the required dose of warfarin in the pediatric population varies due to factors such as age, comorbid medications, diet, and available medical conditions, which may make it difficult to achieve and maintain the target INR range in pediatric patients. Variations in bleeding rates across populations and clinical care centers have been identified in pediatric observational studies and patient registries.
Infants and children receiving vitamin K supplementation, including infant formula, may be resistant to warfarin, while breastfed infants may be more sensitive to warfarin.
[Geriatric Dosage].
In the controlled clinical trials available for analysis, the total number of patients treated with warfarin sodium was 1885 (24.4%) in elderly patients over 65 years of age and 185 (2.4%) in patients over 75 years of age. No overall differences in efficacy or safety were observed between these older and younger patients, although it cannot be excluded that some older patients were more sensitive to this product.
Patients aged 60 years and older exhibited a greater anticoagulant response to INR than warfarin. Warfarin sodium tablets are contraindicated in any unsupervised elderly patient. More frequent bleeding monitoring is required for the use of warfarin sodium tablets in the elderly with any condition or physical condition that increases the risk of bleeding. Lower starting and maintenance doses of warfarin sodium tablets should be considered in elderly patients.
[Drug Interactions].
(1) General information
Drugs may interact with Warfarin Sodium Tablets through pharmacokinetic or pharmacokinetic mechanisms. Pharmacokinetic mechanisms of drug interactions with warfarin sodium tablets include synergistic effects (impaired hemostasis, reduced coagulation factor synthesis), competitive antagonism (vitamin K), and alteration of the physiological control pathway of vitamin K metabolism (genetic resistance). The main pharmacokinetic mechanisms of interaction with warfarin sodium tablets are enzyme induction, enzyme inhibition and reduced plasma protein binding. It is important to note that some drugs may interact with this product through multiple mechanisms.
INR monitoring should be performed more frequently when starting or discontinuing other drugs (including botanicals) or changing the dose of other drugs, including those used for short periods of time (e.g., antibiotics, antifungal drugs, corticosteroids).
Check the instructions for all concomitant medications for further information on adverse reactions related to this interaction or bleeding.
(2) CYP450 interactions
CYP450 isozymes associated with warfarin metabolism include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more active warfarin
S -enantiomer is metabolized by CYP2C9, while the
The S-enantiomer is metabolized by CYP2C9, while the R-enantiomer is metabolized by CYP1A2 and 3A4.
(i) Inhibitors of CYP2C9, 1A2 and/or 3A4 have the potential to enhance warfarin activity (increased INR) by increasing warfarin exposure.
(ii) Inducers of CYP2C9, 1A2 and/or 3A4 can potentially decrease warfarin activity (INR decrease) by decreasing warfarin exposure.
Selected CYP2C9, 1A2 and 3A4 inhibitors and inducers are shown in Table 2, but not all CYP2C9, 1A2 and 3A4 inhibitors and inducers are included in this table. The instructions for all combination doses may be consulted for further information on CYP450 interactions. The CYP450 inhibitory and inducing activity of a drug should be considered when starting, stopping, or changing the drug dose of a combination drug. If the combination drug is a CYP2C9, 1A2 and/or 3A4 inhibitor or inducer, the INR should be closely monitored.
Table 2 Examples of CYP450 and warfarin interactions
Enzyme inhibitor inducer CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfoxypyrone, tigecycline, voriconazole, and zarucest aripitant, bosentan, carbamazepine, phenobarbital, and rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine Ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil and zileuton montelukast, mirexazine, omeprazole, phenobarbital, phenytoin and smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenaline nilotinib, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, dirinavir/ritonavir, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, saquinavir, telithromycin, telanavir, voriconazole, and zileuton amodafinil, amprenavir, aripitant, bosentan (2) Drugs that increase the risk of bleeding, such as carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, and lufenamide
(3) Drugs that increase the risk of bleeding
Drugs known to increase the risk of bleeding are listed in Table 3. Because the risk of bleeding is increased when these drugs are used concomitantly with warfarin sodium tablets, closely monitor patients who are using warfarin sodium tablets in combination with any of the following drugs.
Table 3 Drugs that can increase the risk of bleeding
Drug classification of potent drugs anticoagulants agatropan, dabigatran, bivalirudin, dexiludin, heparin, and lepirudin antiplatelet drugs aspirin, cilozole, clopidogrel, dipyridamole, prasugrel, and ticlopidine nonsteroidal anti-inflammatory drugs celecoxib, diclofenac, diflunisal, fenofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meprobamate, piroxicam, and sulindac 5- serotonin reuptake inhibitors citalopram, desvenlafaxine, duloxetine hydrochloride, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, and verazodone (4) Antibiotics and antifungals
Changes in INR have been reported in patients on combined warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown a sustained effect of these drugs on warfarin blood concentrations.
The INR should be monitored closely when starting or discontinuing any antibiotic or antifungal drug in patients on warfarin.
(5) Botanical (herbal) products and foods
INR monitoring should be performed more frequently when starting or discontinuing botanicals.
There are few controlled studies evaluating metabolism and/or drug interactions between medicinal plants and warfarin sodium tablets. Due to the lack of manufacturing standards for medicinal plant preparations, the amount of active ingredients in botanical preparations may vary, which may further interfere with the assessment of potential interactions between medicinal plants and this product and the effect of their activity on anticoagulant effects.
Some medicinal plants may cause bleeding events when used alone (e.g., garlic and ginkgo) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties that could contribute to the anticoagulant effects of warfarin sodium tablets. Conversely, some medicinal plants can reduce the effects of warfarin sodium tablets (e.g. coenzyme Q10, St. John’s wort, ginseng). Some plants and foods can affect the activity of warfarin sodium tablets by acting on CYP450 (e.g., echinacea, grapefruit juice, ginkgo, golden sealwort, St. John’s wort).
The level of vitamin K in food may affect the therapeutic effect of warfarin sodium tablets. Patients taking warfarin sodium tablets are advised to maintain a normal balanced diet to maintain a steady intake of vitamin K. Patients taking Warfarin Sodium Tablets should avoid drastic changes in dietary habits, such as heavy consumption of green leafy vegetables.
[Drug overdose].
(1) Signs and symptoms
Bleeding (e.g., presence of blood in stool or urine, hematuria, excessive menstrual flow, black stool, petechiae, excessive bruising from superficial injury or persistent oozing, unexplained decrease in hemoglobin) is a sign of excessive anticoagulation.
(2) Treatment
Treatment of excessive anticoagulation depends on INR level, presence of bleeding and other clinical conditions. Its anticoagulant effect can be reversed by discontinuing warfarin sodium tablets and, if necessary, treated with oral or injectable vitamin K1. Vitamin K1 reduces the effect of subsequent warfarin sodium tablets and patients may return to their pre-treatment coagulation status after rapid reversal of the prolonged INR. Resumption of warfarin sodium tablets reverses the effect of vitamin K, and with careful dose adjustment the desired INR can be achieved again. for rapid re-anticoagulation, heparin is the preferred initial therapy.
For rapid reversal of the effects of warfarin sodium tablets, the treatment options are prothrombin complex (PCC), fresh frozen plasma, or activated coagulation factor VII. The use of blood products carries a risk of hepatitis and other viral diseases, and PCC and activated coagulation factor VII also increase the risk of thrombosis. Therefore, these preparations should only be used in cases of exceptional or life-threatening bleeding due to warfarin sodium tablet overdose.
[Pharmacological Toxicology].
The activity of warfarin is achieved by inhibiting the synthesis of vitamin K-dependent coagulation factors (including Factors II, VII, IX and X) and anticoagulant proteins C and S. Vitamin K is an important cofactor in the post-ribosomal synthesis of vitamin K-dependent coagulation factors, and vitamin K promotes the synthesis of γ-carboxyglutamate residues essential for protein bioactivity. Warfarin is thought to interfere with coagulation factor synthesis by inhibiting the C1 subunit of the vitamin K epoxide reductase (VKORC1) complex, thereby reducing the regeneration of vitamin K epoxide.
The anticoagulant effect of warfarin usually occurs within 24 hours of administration. However, the peak anticoagulant effect may occur with a delay of 72 to 96 hours. The duration of action of warfarin at a single racemic dose is 2 – 5 days. The effects of warfarin sodium may become more pronounced with the accumulation of daily maintenance doses, consistent with the half-life of the affected vitamin K-dependent coagulation factors and anticoagulant proteins. The half-lives of vitamin K-dependent clotting factors and anticoagulant proteins are: Factor II – 60 hours, Factor VII – 4 – 6 hours, IX – 24 hours, X – 48 – 72 hours, and Protein C and S are approximately 8 and 30 hours, respectively.
Non-clinical toxicology]
No carcinogenic, mutagenic or reproductive toxicity studies have been performed on warfarin.
Pharmacokinetics
Warfarin sodium is a racemic mixture of the R and S enantiomers of warfarin. the S-enantiomer has 2-5 times the anticoagulant activity of the R-enantiomer in humans, but is usually cleared more rapidly.
Absorption
Warfarin is largely completely absorbed after oral administration, with concentrations peaking within 4 hours.
Distribution
The volume of distribution of warfarin is approximately 0.14 L/kg. The plasma protein binding of the drug is approximately 99%.
Metabolism
Warfarin is eliminated almost exclusively by metabolism. Warfarin is metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes directed to inactive hydroxyl metabolites (major pathway) and reduced by reductase to lower metabolites with lower anticoagulant activity (warfarinol). Identified warfarin metabolites include dehydrowarfarin, two diastereoisomeric alcohols, 4′-, 6-, 7-, 8-, and 10-hydroxywarfarin. isozymes of CYP450 associated with warfarin metabolism include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9 is a polymorphic enzyme that may be responsible for the regulation of warfarin in vivo in human liver the major form of CYP450 that regulates anticoagulant activity in human liver. S-warfarin clearance is reduced in patients with one or more variant CYP2C9 alleles.
Excretion
The half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with an average of approximately 40 hours. the clearance of R-warfarin is generally half that of S-warfarin, and the half-life of R-warfarin is longer than that of S-warfarin because of the similar volume of distribution. the half-life of R-warfarin is 37-89 hours, compared to 21-43 hours for S-warfarin. 43 hours. Radiolabeling studies have shown that up to 92% of oral doses are found in the urine, but warfarin is rarely excreted in the urine as a prototype and is mainly excreted in the urine as a metabolite.
Geriatric patients
Patients aged 60 years and older showed a stronger than expected INR response to warfarin anticoagulation. The reason for the increased sensitivity to warfarin anticoagulation in this age group is unclear, but may be the result of a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests no difference in clearance of S -warfarin between older and younger patients; however, clearance of R -warfarin may be slightly reduced in older compared with younger patients. Therefore, as patients age, the anticoagulant effect that typically produces therapeutic levels requires the use of lower doses of warfarin.
Asian Patients
Asian patients may require lower starting and maintenance doses of warfarin. One uncontrolled study showed that 151 Chinese outpatients with various indications were able to maintain a stable warfarin dose of INR 2 to 2.5 at a mean of 3.3 ± 1.4 mg daily. Patient age was the most important determinant of warfarin requirement, which gradually decreased with age.
[Pharmacogenomics].
CYP2C9 and VKORC1 polymorphisms
The S-enantiomer of warfarin is mainly metabolized to 7-hydroxy warfarin by the polymorphic enzyme CYP2C9. The variant alleles CYP2C9*2 and CYP2C9*3 resulted in attenuated S-warfarin 7-hydroxylation by CYP2C9 enzyme in vitro. The frequency of CYP2C9*2 and CYP2C9*3 alleles in Caucasian populations was 11% and 7%, respectively.
Other CYP2C9 allele frequencies associated with reduced enzyme activity were lower, including the *5, *6, and *11 alleles in populations of African descent and the *5, *9, and *11 alleles in Caucasians.
Warfarin reduces regeneration from vitamin K epoxide in the vitamin K cycle by inhibiting the multiprotease complex VKOR. certain single nucleotide polymorphisms in the VKORC1 gene (e.g. -1639G>A) are associated with variation in warfarin dose requirements. variants in the VKORC1 and CYP2C9 genes generally explain most of the known variation in dose requirements for warfarin.
If information on CYP2C9 and VKORC1 genotypes is available, it may help in the selection of the initial dose of warfarin.
[Storage].
Store under shade and seal.
Package
Aluminum pillow package, 10 tablets/plate, 4 plates/bag.
Expiration date
24 months
【Execution standard
Drug Marketing Licensee】 Qilu Pharmaceutical Co.
Approval number
State Drug Certificate H37021314
Manufacturer
Company Name: Qilu Pharmaceutical Co.
Address
Address: No. 317 Xinluo Street, High-tech Zone, Jinan City
Zip code: 250100
Telephone number: 400-127-7799
Fax number: 0531-83126288, 83126545
Web
Address: http://www.qilu-pharma.com