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Instruction for use: Warfarin Nycomed
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Dosage form: tablets
Active substance: Warfarinum
ATX
B01AA03 Warfarin
Pharmacological group
Anticoagulant means of indirect action [Anticoagulants]
The nosological classification (ICD-10)
G45.9 Transient cerebral ischemic attack, unspecified: Acute cerebrovascular insufficiency; Spasm of cerebral vessels; Cerebral spasmodic syndrome; Spasm of the arteries of the brain; Spasm of cerebral vessels; Spasms of cerebral vessels
I22 Subsequent myocardial infarction: Atherosclerosis and the likelihood of reinfarction; Myocardial infarction re; Relapses myocardial infarction
I25.2 Transferred last myocardial infarction: Cardiac syndrome; Myocardial infarction; post-MI; Rehabilitation after myocardial infarction; Reocclusion of the operated vessel; Angina postinfarctnaya; Status after myocardial infarction; Status after myocardial infarction; myocardial infarction
I39 Endocarditis and cardiac valve disease in diseases classified elsewhere: Maranthine endocarditis; Libman-Saksa defeat
I48 Atrial fibrillation and flutter: Permanent atrial tachyarrhythmias; Relief frequent ventricular rate during atrial flutter or blink; atrial fibrillation; Paroxysm of atrial fibrillation and flutter; Paroxysm of atrial fibrillation; Paroxysmal atrial fibrillation; Atrial premature beats; Tahiaritmicheskoy atrial fibrillation; Tahisistolicheskoy atrial fibrillation; auricular flutter; Life-threatening ventricular fibrillation; Atrial fibrillation; Chronic atrial fibrillation; supraventricular arrhythmia; Paroxysmal atrial fibrillation and flutter; Paroxysmal fibrilloflutter; Atrial premature beats
I63.9 Brain infarction, unspecified: Lacunar strok; Lacunar infarction
I74 Embolism and arterial thrombosis: Thrombosis of effort (stress); Arterial thrombosis; Arteriothrombosis; Subacute and chronic arterial thrombosis; Subacute thrombosis of peripheral arteries; Postoperative thrombosis; Vascular thrombosis; Vascular embolism; Thrombosis of aortocoronary shunt; Arterial thrombosis; Thrombosis of arteries; Coronary artery thrombosis; Coronary thrombosis; Thrombosis of blood vessels; Thrombosis with ischemic stroke; Thrombosis with general surgical operations; Thrombosis in Oncology Operations; Vascular thrombosis; Thrombus formation in the postoperative period; Thrombotic complications; Thromboembolic diseases; Thromboembolic syndrome; Thromboembolic complication in the postoperative period; Thromboembolism of arteries; Partial vascular thrombosis; Embolism; Embolism of arteries
I82 Embolism and thrombosis of other veins: Recurrent venous thrombosis; Postoperative thrombosis; Venous thrombosis; Acute venous thromboembolism; Recurrent vein thrombosis; Venous thrombosis; Thrombosis of veins of internal organs; Venous thrombosis; Deep vein thrombosis; Thrombosis of blood vessels; Vascular thrombosis; Thrombosis of veins; Deep vein thrombosis; Thromboembolic diseases; Thromboembolism of veins; Severe venous thrombosis; Embolism; Embolism of veins; Thromboembolic complications
I82.9 Embolism and thrombosis of unspecified vein: Venous embolism; Venous thrombosis; Diseases caused by blood clots in the vessels; Acute vascular occlusion; Acute venous thrombosis; Acute thrombosis of veins; Thrombosis; Thromboembolism; Phlebothrombosis; Embolism
Z100 * CLASS XXII Surgical practice: Abdominal surgery; adenomectomy; Amputation; Coronary angioplasty; Angioplasty of the carotid arteries; Antiseptic skin treatment for wounds; Antiseptic Hand; Appendectomy; atherectomy; Balloon coronary angioplasty; Vaginal hysterectomy; The coronary bypass; Interventions in the vagina and cervix; Interventions on the bladder; Intervention in the mouth; Restoration and reconstructive surgery; Hand hygiene of medical personnel; Gynecologic surgery; Gynecological intervention; Gynecological surgery; Hypovolemic shock during operations; Disinfection of purulent wounds; Disinfection of wounds edges; Diagnostic intervention; Diagnostic procedures; Cervical Diathermocoagulation; Long-surgery; Replacing the fistula catheters; Infection in orthopedic surgery; Artificial heart valve; cystectomy; Short-term outpatient surgery; Short-term operation; Short surgical procedures; Krikotireotomiya; Blood loss during surgery; Bleeding during surgery and in the postoperative period; Kuldotsentez; laser photocoagulation; laser coagulation; retinal laser coagulation; Laparoscopy; Laparoscopy in Gynecology; CSF fistula; Small gynecological operations; Small surgical procedures; Mastectomy and subsequent plastic; mediastinotomy; Microsurgical operations on the ear; Mukogingivalnye operation; suturing; Minor surgery; neurosurgical operation; Immobilization of the eyeball in ophthalmic surgery; testectomy; pancreatectomy; Perikardektomiya; The period of rehabilitation after surgery; The period of convalescence after surgery; Percutaneous transluminal coronary angioplasty; Pleural thoracentesis; Pneumonia postoperative and posttraumatic; Preparation for surgical procedures; Preparation for surgery; Preparation of the surgeon's hands before surgery; Preparation of the colon for surgical procedures; Postoperative aspiration pneumonia in neurosurgical and thoracic surgery; Postoperative nausea; Postoperative bleeding; postoperative granuloma; postoperative shock; The early postoperative period; myocardial revascularization; Radiectomy; gastric Resection; bowel resection; uterine Resection; liver Resection; enterectomy; Resection of part of the stomach; Reocclusion of the operated vessel; Bonding tissues during surgical procedures; Removal of sutures; Condition after eye surgery; Condition after surgery; Condition after surgery in the nasal cavity; Condition after gastrectomy; Status after resection of the small intestine; Condition after tonsillectomy; Condition after removal of the duodenum; Condition after phlebectomy; Vascular surgery; Splenectomy; Sterilization of surgical instruments; Sterilization of surgical instruments; sternotomy; Dental surgery; Dental intervention in periodontal tissues; strumectomy; Tonsillectomy; Thoracic surgery; Thoracic surgery; total gastrectomy; Transdermal intravascular coronary angioplasty; Transurethral resection; Turbinektomiya; Removal of a tooth; cataract surgery; Removal of cysts; tonsillectomy; Removal of fibroids; Removing the mobile primary teeth; Removing polyps; Removing broken tooth; Removal of the uterus body; Removal of sutures; Fistula likvoroprovodyaschih ways; Frontoetmoidogaymorotomiya; Surgical infection; Surgical treatment of chronic limb ulcers; Surgery; The surgery in the anal area; The surgery on the colon; Surgical practice; The surgical procedure; Surgical interventions; Surgery on the gastrointestinal tract; Surgical procedures on the urinary tract; Surgical procedures on the urinary system; Surgical intervention of the genitourinary system; Surgical procedures on the heart; Surgical manipulation; surgery; Surgery on the veins; Surgical intervention; Vascular surgery; Surgical treatment of thrombosis; Surgery; cholecystectomy; Partial gastric resection; hysterectomy; Percutaneous transluminal coronary angioplasty; Percutaneous transluminal angioplasty; Coronary artery bypass; tooth Extirpation; Extirpation of milk teeth; pulpectomy; pulsative cardiopulmonary bypass; tooth Extraction; teeth Extraction; cataract extraction; Electrocoagulation; endourological intervention; episiotomy; Etmoidotomiya; Complications after tooth extraction
Z95.2 Presence of a prosthetic heart valve: Mechanical prosthesis of the heart valves; Prosthetic heart valves; Cardiac valve prosthetics
Z98.8 Other specified post-surgical conditions: Purulent complications in the postoperative period; Purulent complications of surgical operations; Postoperative liver dysfunction; Postoperative vomiting; Postoperative complications; Postoperative period; Early postoperative period
Composition
active substance: Warfarin sodium 2.5 mg
Auxiliary substances: lactose; corn starch; Calcium hydrogen phosphate dihydrate; Indigocarmine; Povidone 30; Magnesium stearate
Description of dosage form
Round, double radius shape, with a cross-shaped risk, light blue.
Characteristic
Bivalirudin is a single-chain polypeptide with a molecular weight of 2180.19, consisting of 20 amino acids and having a core structure of hirudin. As a direct inhibitor of thrombin, bivalirudin inhibits all catalyzed and thrombin-induced reactions, including fibrin formation, activation of clotting factors V, VIII and XIII, activation of protein C, and platelet aggregation. Bivalirudin has a high selectivity for thrombin with an inhibition constant (Ki) of 2.3 nM, and does not require the presence of co-factors.
Pharmachologic effect
Mode of action - Anticoagulant.
Pharmacodynamics
It blocks in the liver the synthesis of vitamin-K-dependent clotting factors (II, VII, IX, X), reduces their concentration in plasma and slows the process of blood coagulation.
The onset of anticoagulant action is observed 36-72 hours after the start of the drug with the development of maximum effect on the 5-7th day from the beginning of application. After discontinuation of the drug, the restoration of vitamin-K-dependent coagulation factors occurs within 4-5 days.
Pharmacokinetics
Quickly absorbed from the digestive tract almost completely. Binding to plasma proteins - 97-99%. Metabolised in the liver.
Warfarin is a racemic mixture, with the R and S isomers being metabolized in the liver in various ways. Each of the isomers is converted into 2 main metabolites.
The main catalyst of metabolism for the S-enantiomer of warfarin is the enzyme CYP2C9, and for the R-enantiomer of warfarin, CYP1A2 and CYP3A4. The left-handed isomer of warfarin (S-warfarin) has a 2-5 fold greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the latter is more T1 / 2. Patients with polymorphism of the CYP2C9 enzyme, including the alleles CYP2C9 * 2 and CYP2C9 * 3, may have increased sensitivity to warfarin and an increased risk of bleeding.
Warfarin is excreted from the body with bile in the form of inactive metabolites, which are reabsorbed into the digestive tract and excreted in the urine. T1 / 2 is from 20 to 60 hours. For the R-enantiomer, T1 / 2 is from 37 to 89 hours, and for the S-enantiomer is from 21 to 43 hours.
Indications for Warfarin Nycomed
Treatment and prevention of thrombosis and embolism of blood vessels:
Acute and recurrent venous thrombosis, pulmonary embolism;
Transient ischemic attacks and strokes;
Secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction;
Prevention of thromboembolic complications in patients with atrial fibrillation, damage to the heart valves or prosthetic heart valves;
Prevention of postoperative thrombosis.
Contraindications
Established or suspected hypersensitivity to the components of the drug;
Acute bleeding;
Pregnancy (I trimester and the last 4 weeks of pregnancy);
Severe liver or kidney disease;
Acute syndrome of disseminated intravascular coagulation;
Deficiency of proteins C and S;
Thrombocytopenia;
Patients with a high risk of bleeding, including patients with hemorrhagic disorders;
Varicose veins of the esophagus;
Aneurysm of arteries;
Lumbar puncture;
Peptic ulcer of the stomach and duodenum;
Severe wounds (including operating wounds);
Bacterial endocarditis;
Malignant hypertension;
Hemorrhagic stroke, intracranial hemorrhage.
Pregnancy and breast-feeding
Warfarin quickly penetrates the placenta, has a teratogenic effect on the fetus, leading to the development of warfarin syndrome in the fetus for the 6-12th week of pregnancy. Manifestations of this syndrome: nasal hypoplasia (saddle nasal deformity and other cartilage changes) and spot chondrodysplasia in radiographic examination (especially in the spine and long tubular bones), short brushes and fingers, atrophy of the optic nerve, cataracts leading to complete or partial blindness, Retardation of mental and physical development and microcephaly.
The drug may cause bleeding at the end of pregnancy and during labor. Taking the drug during pregnancy can cause congenital malformations and lead to fetal death. The drug cannot be administered in the first trimester of pregnancy and within the last 4 weeks. Use of warfarin is not recommended in other terms of pregnancy, except in cases of extreme necessity. Women of reproductive age should use the method of effective contraception during the period of application of warfarin.
Warfarin is excreted in breast milk, but when taking therapeutic doses of warfarin, no effect on the breastfed child is expected. Warfarin can be used during breastfeeding.
Data on the effect of warfarin on fertility are not available.
Side effects
Adverse reactions to the drug are ordered according to the system-organ class and are consistent with the terms of preferred use (in accordance with MedDRA). Within the category of system-organ class, the reactions are distributed according to the frequency of occurrence according to the following scheme: very often (≥1 / 10); Often (≥1 / 100 to <1/10); Infrequently (≥1 / 1000 to <1/100); Rarely (≥1 / 10000 to <1/1000); Very rarely (<1/10000).
Table 2
Side effects of using the drug
| Frequency | Side effects |
| On the part of the blood and lymphatic system | |
| Very frequent | Bleeding (in different organs) |
| Frequent | Hypersensitivity to warfarin after prolonged use |
| From the gastrointestinal tract | |
| Frequent | Vomiting, nausea, diarrhea |
| Î÷åíü ðåäêî | Melena |
| From the skin and subcutaneous tissues | |
| Rare | Vasculitis, skin necrosis, alopecia, rash, hives, itching |
| On the part of the CVS | |
| Rare | Purple Finger Syndrome |
| Vary rare | Cholesterol embolism |
| From the immune system | |
| Frequent | Hypersensitivity |
| From the side of the hepatic | |
| Rare | Increased level of hepatic enzymes, jaundice |
Examples of such complications include nasal bleeding, hemoptysis, hematuria, gum bleeding, bruising on the skin, vaginal bleeding, subconjunctival bleeding, rectal and other intestinal bleeding, intracerebral bleeding, prolonged or profuse bleeding after trauma or surgery. You can expect the development of bleeding, incl. Heavy, in any organ. Patients who received long-term anticoagulant treatment reported on the development of bleeding, leading to death, hospitalization, or the need for blood transfusion. Independent risk factors for significant bleeding during the use of warfarin include: advanced age, high levels of hypocoagulation, a history of history of history of gastrointestinal bleeding, concomitant diseases and atrial fibrillation. In patients with polymorphism CYP2C9 (see "Pharmacokinetics") there may be an increased risk of overly anticoagulant action and episodes of bleeding. These patients should carefully monitor the levels of Hb and INR.
Necrosis. Coumarin necrosis is a rare complication in the treatment with warfarin. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks or (rarely) in other places. Later, lesions become necrotic. In 90% of cases, necrosis develops in women. The lesions are observed from the 3rd to the 10th day of the drug administration, and the etiology assumes the deficiency of the antithrombotic protein C or S. Congenital insufficiency of these proteins can be the cause of complications, so treatment with warfarin should begin with small initial doses and simultaneously with the administration of heparin. If complication occurs, then warfarin is discontinued and heparin is continued until the lesions are healed or scarring.
Palmar-plantar syndrome. A very rare complication with warfarin therapy, its development is typical for men with atherosclerotic diseases. As suggested, warfarin causes hemorrhages in the area of atheromatous plaques, leading to microemboli. There are symmetrical purple lesions of the skin of the fingers and soles of the feet, accompanied by burning pains. After stopping the use of warfarin, these symptoms gradually disappear.
Other: hypersensitivity reactions, manifested as a skin rash and characterized by a reversible increase in levels of liver enzymes, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and calcification of the trachea.
Independent risk factors for serious bleeding during treatment with warfarin are: old age, high intensity of concomitant anticoagulant and antiplatelet therapy, history of strokes and gastrointestinal bleeding.
The risk of bleeding is increased in patients with polymorphism of the CYP2C9 gene.
Interaction
It is not recommended to start or stop taking other medicines, and also to change the doses of the medications.
At simultaneous appointment, it is also necessary to take into account the effects of cessation of induction and / or inhibition of the action of warfarin by other drugs.
The risk of severe bleeding increases with simultaneous administration of warfarin with drugs that affect platelet levels and primary hemostasis: acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (with the exception of COX-2 inhibitors), penicillin-type antibiotics in large doses.
Combined use of warfarin with preparations with a pronounced inhibitory effect on the cytochrome P450 system, for example, cimetidine and chloramphenicol, should be avoided, and the risk of bleeding increases within several days. In such cases, cimetidine cannot be replaced, for example, ranitidine or famotidine.
Table 3
Substances that decrease the effect of warfarin
| Name | Possible mechanism |
| Cardiovascular drugs | |
| Kolestyramine | Decrease in the absorption of warfarin and the effect on enterohepatic circulation |
| Boszentan | Induction of warfarin conversion in CYP2C9 / CYP3A4 in the liver |
| Gastrointestinal drugs | |
| Aprepitant Induction of warfarin conversion in CYP2C9 | Aprepitant Induction of warfarin conversion in CYP2C9 |
| Mesalazine The possibility of reducing the anticoagulant effect of warfarin | Mesalazine The possibility of reducing the anticoagulant effect of warfarin |
| Sucralfate The probability of decreasing the absorption of warfarin | Sucralfate The probability of decreasing the absorption of warfarin |
| Dermatological preparations | |
| Griseofulvin Decreased anticoagulant effect of coumarins | Griseofulvin Decreased anticoagulant effect of coumarins |
| Retinoids Possibility of reducing warfarin activity | Retinoids Possibility of reducing warfarin activity |
| Anti-infectives | |
| Dicloxacillin Increased metabolism of warfarin | Dicloxacillin Increased metabolism of warfarin |
| Rifampicin Increased metabolism of warfarin. It is necessary to avoid the joint use of these drugs | Rifampicin Increased metabolism of warfarin. It is necessary to avoid the joint use of these drugs |
| Antiviral agents (nevirapine, ritonavir) Increased metabolism of warfarin mediated by CYP2C9 | Antiviral agents (nevirapine, ritonavir) Increased metabolism of warfarin mediated by CYP2C9 |
| Nafcillin Reduction of the anticoagulant effect of warfarin | Nafcillin Reduction of the anticoagulant effect of warfarin |
| Means for muscle, joint and bone pain | |
| Phenazone Induction of enzyme metabolism, reduction of warfarin concentration in plasma. It may be necessary to increase the dosage of warfarin | Phenazone Induction of enzyme metabolism, reduction of warfarin concentration in plasma. It may be necessary to increase the dosage of warfarin |
| Rofecoxib The mechanism of interaction is unknown | Rofecoxib The mechanism of interaction is unknown |
| Means affecting the central nervous system | |
| Barbiturates (eg, phenobarbital) Increased metabolism of warfarin | Barbiturates (eg, phenobarbital) Increased metabolism of warfarin |
| Antiepileptic drugs (carbamazepine, valproic acid, primidone) Increased metabolism of warfarin | Antiepileptic drugs (carbamazepine, valproic acid, primidone) Increased metabolism of warfarin |
| Antidepressants (trazodone, mianserin) In four cases of clinical use, it was found that the interaction of trazodone and warfarin caused a decrease in PV and INR, but the mechanism of this interaction is unknown. The mechanism of interaction between warfarin and mianserin is also unknown | Antidepressants (trazodone, mianserin) In four cases of clinical use, it was found that the interaction of trazodone and warfarin caused a decrease in PV and INR, but the mechanism of this interaction is unknown. The mechanism of interaction between warfarin and mianserin is also unknown |
| Glutethimide Reduction of the anticoagulant effect of warfarin due to increased metabolism | Glutethimide Reduction of the anticoagulant effect of warfarin due to increased metabolism |
| Chlordiazepoxide Reducing the anticoagulant effect of warfarin | Chlordiazepoxide Reducing the anticoagulant effect of warfarin |
| Cytotoxic agents | |
| Aminoglutethimide Increased metabolism of warfarin | Aminoglutethimide Increased metabolism of warfarin |
| Azathioprine Reduction in the absorption of warfarin and increased metabolism of warfarin | Azathioprine Reduction in the absorption of warfarin and increased metabolism of warfarin |
| Mercaptopurine Decreased anticoagulant effect of warfarin | Mercaptopurine Decreased anticoagulant effect of warfarin |
| Mitotane Possible reduction of anticoagulant effect of warfarin | Mitotane Possible reduction of anticoagulant effect of warfarin |
| Immunosuppressive drugs | |
| Cyclosporin Warfarin increases the level of cyclosporine or enhances its effect, affecting the metabolism of cyclosporine | Cyclosporin Warfarin increases the level of cyclosporine or enhances its effect, affecting the metabolism of cyclosporine |
| Lipid-lowering drugs | |
| Colestyramine May reduce the anticoagulant effect of warfarin due to a decrease in its absorption | Colestyramine May reduce the anticoagulant effect of warfarin due to a decrease in its absorption |
| Diuretics | |
| Spironolactone, chlorthalidone Taking diuretics in case of pronounced hypovolemic effects can lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants | Spironolactone, chlorthalidone Taking diuretics in case of pronounced hypovolemic effects can lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants |
| Traditional medicine | |
| Hypericum perforatum (Hypericum perforatum) Strengthens the metabolism of warfarin, carried out by CYP3A4 and CYP1A2 (metabolism of R-warfarin), as well as carried out by CYP2C9 (metabolism of S-warfarin). The effect of induction of enzymes can persist for 2 weeks after the end of St. John's wort. In the event that the patient takes St John's wort preparations, the INR should be measured and discontinued. Monitoring of INR should be thorough, because His level may increase if the St. John's wort is discarded. After this, you can prescribe warfarin | Hypericum perforatum (Hypericum perforatum) Strengthens the metabolism of warfarin, carried out by CYP3A4 and CYP1A2 (metabolism of R-warfarin), as well as carried out by CYP2C9 (metabolism of S-warfarin). The effect of induction of enzymes can persist for 2 weeks after the end of St. John's wort. In the event that the patient takes St John's wort preparations, the INR should be measured and discontinued. Monitoring of INR should be thorough, because His level may increase if the St. John's wort is discarded. After this, you can prescribe warfarin |
| Ginseng (Panax ginseng) Probably induction of warfarin conversion in the liver. It is necessary to avoid the joint use of these drugs | Ginseng (Panax ginseng) Probably induction of warfarin conversion in the liver. It is necessary to avoid the joint use of these drugs |
| Food | Food |
| Foods containing vitamin K. Most of the vitamin K is found in green vegetables (for example, amaranth greens, cabbage, avocado, broccoli, Brussels sprouts, canola oil, leaf shayo, onion, coriander (cilantro), cucumber, chicory, kiwi fruit , Lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red seaweed, spring onions, soybeans, tea leaves (but not tea-drink), turnip greens, watercress, spinach), so When treating with warfarin, you should carefully take these foods to weaken the effect of warfarin | Foods containing vitamin K. Most of the vitamin K is found in green vegetables (for example, amaranth greens, cabbage, avocado, broccoli, Brussels sprouts, canola oil, leaf shayo, onion, coriander (cilantro), cucumber, chicory, kiwi fruit , Lettuce, mint, green mustard, olive oil, parsley, peas, pistachios, red seaweed, spring onions, soybeans, tea leaves (but not tea-drink), turnip greens, watercress, spinach), so When treating with warfarin, you should carefully take these foods to weaken the effect of warfarin |
| Vitamins | Vitamins |
| Vitamin C Decrease in the anticoagulant effect of warfarin | Vitamin C Decrease in the anticoagulant effect of warfarin |
| Vitamin K Warfarin blocks the synthesis of vitamin-K-dependent clotting factors | Vitamin K Warfarin blocks the synthesis of vitamin-K-dependent clotting factors |
| Name | Possible mechanism |
| Drugs affecting the blood and organs of hematopoiesis | |
| Abciximab, tirofiban, eptifibatid, clopidogrel, heparin Additional effect on the blood coagulation system | Abciximab, tirofiban, eptifibatid, clopidogrel, heparin Additional effect on the blood coagulation system |
| Drugs affecting the gastrointestinal tract and metabolism | |
| Cimetidine A pronounced inhibitory effect on the cytochrome P450 system (cimetidine can be replaced with ranitidine or famotidine), leading to a decrease in warfarin metabolism | Cimetidine A pronounced inhibitory effect on the cytochrome P450 system (cimetidine can be replaced with ranitidine or famotidine), leading to a decrease in warfarin metabolism |
| Glibenclamide Enhancing the anticoagulant effect of warfarin | Glibenclamide Enhancing the anticoagulant effect of warfarin |
| Omeprazole Increased anticoagulant effect of warfarin | Omeprazole Increased anticoagulant effect of warfarin |
| Drugs affecting CAS | |
| Amiodarone Decreased metabolism of warfarin after one week of joint intake. This effect can persist for 1-3 months after the abolition of amiodarone | Amiodarone Decreased metabolism of warfarin after one week of joint intake. This effect can persist for 1-3 months after the abolition of amiodarone |
| Ectaric acid May enhance the effect of warfarin due to the displacement of warfarin from protein bonds | Ectaric acid May enhance the effect of warfarin due to the displacement of warfarin from protein bonds |
| Lipid-lowering agents (fluvastatin, simvastatin, rosuvastatin, gemfibrozil, bezafibrate, clofibrate, lovastatin, fenofibrate) Competition for metabolism mediated by CYP2C9 and CYP3A4 | Lipid-lowering agents (fluvastatin, simvastatin, rosuvastatin, gemfibrozil, bezafibrate, clofibrate, lovastatin, fenofibrate) Competition for metabolism mediated by CYP2C9 and CYP3A4 |
| Propafenone Decreased metabolism of warfarin | Propafenone Decreased metabolism of warfarin |
| Quinidine Reduction in the synthesis of clotting factors | Quinidine Reduction in the synthesis of clotting factors |
| Diazoxide May replace warfarin, bilirubin, or other protein-bound protein substance | Diazoxide May replace warfarin, bilirubin, or other protein-bound protein substance |
| Digoxin Enhancing the anticoagulant effect | Digoxin Enhancing the anticoagulant effect |
| Propranolol Increased anticoagulant effect | Propranolol Increased anticoagulant effect |
| Ticlopidine Increased risk of bleeding. It is necessary to monitor the level of INR | Ticlopidine Increased risk of bleeding. It is necessary to monitor the level of INR |
| Dipyridamole Increased levels of warfarin or dipyridamole due to potentiation of effects. Increased risk of bleeding (hemorrhage) | Dipyridamole Increased levels of warfarin or dipyridamole due to potentiation of effects. Increased risk of bleeding (hemorrhage) |
| Dermatological products | |
| Miconazole (including in the form of a gel for the oral cavity) Decreased self-clearance of warfarin and an increase in the free fraction of warfarin in plasma; Decreased metabolism of cytochrome P450-mediated warfarin | Miconazole (including in the form of a gel for the oral cavity) Decreased self-clearance of warfarin and an increase in the free fraction of warfarin in plasma; Decreased metabolism of cytochrome P450-mediated warfarin |
| Genitourinary system and sex hormones | |
| Steroid hormones - anabolic and / or androgenic (danazol, testosterone) Decrease in the metabolism of warfarin and / or direct effect on the coagulation and fibrinolysis systems | Steroid hormones - anabolic and / or androgenic (danazol, testosterone) Decrease in the metabolism of warfarin and / or direct effect on the coagulation and fibrinolysis systems |
| Hormones for systemic use | |
| Means acting on the thyroid gland Enhancing the metabolism of vitamin-K-dependent clotting factors | Means acting on the thyroid gland Enhancing the metabolism of vitamin-K-dependent clotting factors |
| Glucagon Enhancing the anticoagulant effect of warfarin | Glucagon Enhancing the anticoagulant effect of warfarin |
| Anti-gouty agents | |
| Allopurinol Strengthening the anticoagulant effect of warfarin | Allopurinol Strengthening the anticoagulant effect of warfarin |
| Sulfinpyrazon Increased anticoagulant effect due to a decrease in its metabolism and weakening of bonds with proteins | Sulfinpyrazon Increased anticoagulant effect due to a decrease in its metabolism and weakening of bonds with proteins |
| Anti-infectives | |
| Penicillins in large doses (cloxacillin, amoxicillin) Possibility of increased bleeding probability, including bleeding from gums, nose, atypical bruising or dark stools | Penicillins in large doses (cloxacillin, amoxicillin) Possibility of increased bleeding probability, including bleeding from gums, nose, atypical bruising or dark stools |
| Tetracyclines The possibility of enhancing the anticoagulant effect of warfarin | Tetracyclines The possibility of enhancing the anticoagulant effect of warfarin |
| Sulfanilamidy (sulfametizol, sulfafurazol, sulfafenazol) The possibility of enhancing the anticoagulant effect of warfarin | Sulfanilamidy (sulfametizol, sulfafurazol, sulfafenazol) The possibility of enhancing the anticoagulant effect of warfarin |
| Quinolones (ciprofloxacin, norfloxacin, ofloxacin, grepafloxacin, nalidixic acid) Decreased metabolism of warfarin | Quinolones (ciprofloxacin, norfloxacin, ofloxacin, grepafloxacin, nalidixic acid) Decreased metabolism of warfarin |
| Macrolides (azithromycin, clarithromycin, erythromycin, roxithromycin) Decreased metabolism of warfarin | Macrolides (azithromycin, clarithromycin, erythromycin, roxithromycin) Decreased metabolism of warfarin |
| Antifungal agents (fluconazole, itraconazole, ketoconazole, metronidazole) Decreased metabolism of warfarin | Antifungal agents (fluconazole, itraconazole, ketoconazole, metronidazole) Decreased metabolism of warfarin |
| Chloramphenicol Reduction in the metabolism of warfarin, a pronounced inhibitory effect on the cytochrome P450 system | Chloramphenicol Reduction in the metabolism of warfarin, a pronounced inhibitory effect on the cytochrome P450 system |
| Cephalosporins (cefamandol, cefalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime) Strengthening the effect of warfarin due to suppression of the synthesis of vitamin-K-dependent factors of blood coagulation and other mechanisms | Cephalosporins (cefamandol, cefalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime) Strengthening the effect of warfarin due to suppression of the synthesis of vitamin-K-dependent factors of blood coagulation and other mechanisms |
| Sulfamethoxazole + trimethoprim Reducing the metabolism of warfarin and displacing warfarin from protein binding sites | Sulfamethoxazole + trimethoprim Reducing the metabolism of warfarin and displacing warfarin from protein binding sites |
| Anthelmintic means | |
| Levamisole Increased anticoagulant effect of warfarin | Levamisole Increased anticoagulant effect of warfarin |
| Counter-cough means of central action | |
| Codeine The combination of codeine and paracetamol increases the activity of warfarin | Codeine The combination of codeine and paracetamol increases the activity of warfarin |
| Means for muscle, joint and bone pain | |
| Acetylsalicylic acid Displacement of warfarin from plasma albumins, restriction of the metabolism of warfarin | Acetylsalicylic acid Displacement of warfarin from plasma albumins, restriction of the metabolism of warfarin |
| NSAIDs - including azaprospan, indomethacin, oxyphenbutazone, piroxicam, sulindac, tolmetin, feprazone, celecoxib (with the exception of COX-2 inhibitors) Competition for metabolism by cytochrome P450 enzymes CYP2C9 | NSAIDs - including azaprospan, indomethacin, oxyphenbutazone, piroxicam, sulindac, tolmetin, feprazone, celecoxib (with the exception of COX-2 inhibitors) Competition for metabolism by cytochrome P450 enzymes CYP2C9 |
| Leflunomide Restriction of metabolism of warfarin mediated by CYP2C9 | Leflunomide Restriction of metabolism of warfarin mediated by CYP2C9 |
| Paracetamol (acetaminophen) (especially after 1-2 inadvertent administration) Restriction of warfarin metabolism or effect on the formation of clotting factors (this effect does not occur when taking less than 2 g of paracetamol per day) | Paracetamol (acetaminophen) (especially after 1-2 inadvertent administration) Restriction of warfarin metabolism or effect on the formation of clotting factors (this effect does not occur when taking less than 2 g of paracetamol per day) |
| Phenylbutazone Decreased metabolism of warfarin, displacement of warfarin from protein binding sites. This combination should be avoided | Phenylbutazone Decreased metabolism of warfarin, displacement of warfarin from protein binding sites. This combination should be avoided |
| Narcotic analgesics (dextropropoxyphen) Increased anticoagulant effect of warfarin | Narcotic analgesics (dextropropoxyphen) Increased anticoagulant effect of warfarin |
| Drugs affecting the central nervous system | |
| Antiepileptic drugs (phosphenytoin, phenytoin) Displacement of warfarin from protein binding sites, increasing the metabolism of warfarin | Antiepileptic drugs (phosphenytoin, phenytoin) Displacement of warfarin from protein binding sites, increasing the metabolism of warfarin |
| Tramadol Competition for metabolism mediated by cytochrome P450 3A4 | Tramadol Competition for metabolism mediated by cytochrome P450 3A4 |
| Antidepressants: SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) Restriction of the metabolism of warfarin. It is believed that SSRIs restrict the cytochrome P450 isoenzyme CYP2C9. It is an enzyme that metabolizes the most potent isomer of S-warfarin. In addition, both SSRIs and warfarin bind strongly to albumin. In the presence of both, the possibility of displacing one of the compounds from albumin | Antidepressants: SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) Restriction of the metabolism of warfarin. It is believed that SSRIs restrict the cytochrome P450 isoenzyme CYP2C9. It is an enzyme that metabolizes the most potent isomer of S-warfarin. In addition, both SSRIs and warfarin bind strongly to albumin. In the presence of both, the possibility of displacing one of the compounds from albumin |
| Chloral hydrate The mechanism of interaction is unknown | Chloral hydrate The mechanism of interaction is unknown |
| Cytotoxic agents | |
| Fluorouracil Decreased synthesis of cytochrome P450 CYP2C9 enzymes that metabolize warfarin | Fluorouracil Decreased synthesis of cytochrome P450 CYP2C9 enzymes that metabolize warfarin |
| Capecitabine Reduction of isoenzymes CYP2C9 | Capecitabine Reduction of isoenzymes CYP2C9 |
| Imatinib Competitive suppression of the CYP3A4 isoenzyme and inhibition of the metabolism of warfarin mediated by CYP2C9 and CYP2D6 | Imatinib Competitive suppression of the CYP3A4 isoenzyme and inhibition of the metabolism of warfarin mediated by CYP2C9 and CYP2D6 |
| Ifosfamide CYP3A4 Suppression | Ifosfamide CYP3A4 Suppression |
| Tamoxifen Tamoxifen, an inhibitor of CYP2C9, may increase serum warfarin concentration due to a decrease in its metabolism | Tamoxifen Tamoxifen, an inhibitor of CYP2C9, may increase serum warfarin concentration due to a decrease in its metabolism |
| Methotrexate Increased warfarin effect due to decreased synthesis of procoagulant factors in the liver | Methotrexate Increased warfarin effect due to decreased synthesis of procoagulant factors in the liver |
| Tegafur Enhancing the anticoagulant effect of warfarin | Tegafur Enhancing the anticoagulant effect of warfarin |
| Trastuzumab Increased anticoagulant effect of warfarin | Trastuzumab Increased anticoagulant effect of warfarin |
| Flutamide Amplification of the anticoagulant effect of warfarin | Flutamide Amplification of the anticoagulant effect of warfarin |
| Cyclophosphamide The probability of changing the anticoagulant effect of warfarin, because Cyclophosphamide is an antitumor agent | Cyclophosphamide The probability of changing the anticoagulant effect of warfarin, because Cyclophosphamide is an antitumor agent |
| Cytotoxic drugs | |
| Etoposide May enhance the anticoagulant effect of coumarins | Etoposide May enhance the anticoagulant effect of coumarins |
| Immunomodulators | |
| Alpha and beta interferon An increase in the anticoagulant effect and an increase in serum warfarin concentration necessitates a reduction in the dose of warfarin | Alpha and beta interferon An increase in the anticoagulant effect and an increase in serum warfarin concentration necessitates a reduction in the dose of warfarin |
| Drugs for the treatment of addiction | |
| Disulfiram Reduction in the metabolism of warfarin | Disulfiram Reduction in the metabolism of warfarin |
| Diuretics | |
| Metolazone An increase in the anticoagulant effect of warfarin | Metolazone An increase in the anticoagulant effect of warfarin |
| Tienilic Acid Enhancing the anticoagulant effect of warfarin | Tienilic Acid Enhancing the anticoagulant effect of warfarin |
| Drugs for the treatment of bronchial asthma | |
| Zafirlukast Increase in the level or enhancement of the effect of zafirlukast against the background of taking warfarin due to changes in the metabolism of zafirlukast | Zafirlukast Increase in the level or enhancement of the effect of zafirlukast against the background of taking warfarin due to changes in the metabolism of zafirlukast |
| Reducing agents | |
| Troglitazone Decreased or weakened warfarin effect due to changes in warfarin metabolism | Troglitazone Decreased or weakened warfarin effect due to changes in warfarin metabolism |
| Vaccines | |
| Anti-influenza vaccine The possibility of enhancing the anticoagulant effect of warfarin | Anti-influenza vaccine The possibility of enhancing the anticoagulant effect of warfarin |
| Antimalarials | |
| Proguanil The possibility of enhancing the anticoagulant effect of warfarin according to individual reports | Proguanil The possibility of enhancing the anticoagulant effect of warfarin according to individual reports |
| Food | |
| Cranberry Cranberry reduces the metabolism of warfarin, mediated by CYP2C9 | Cranberry Cranberry reduces the metabolism of warfarin, mediated by CYP2C9 |
| Tonicity drinks containing quinine The use of a large number of tonicating beverages containing quinine may entail the need to reduce the dosage of warfarin. This interaction can be explained by a decrease in the synthesis in the liver of procoagulant factors quinine | Tonicity drinks containing quinine The use of a large number of tonicating beverages containing quinine may entail the need to reduce the dosage of warfarin. This interaction can be explained by a decrease in the synthesis in the liver of procoagulant factors quinine |
| Ginkgo biloba, garlic (Allium sativum), angelica sinensis, papaya (Carica papaya), sage (Salvia miltiorrhiza) Potentiation of anticoagulant / antiplatelet effect may increase risk of bleeding | Ginkgo biloba, garlic (Allium sativum), angelica sinensis, papaya (Carica papaya), sage (Salvia miltiorrhiza) Potentiation of anticoagulant / antiplatelet effect may increase risk of bleeding |
| Name | Name Possible mechanism |
| Drugs affecting CAS | |
| Dysopyramide May weaken or enhance the anticoagulant effect of warfarin | Dysopyramide May weaken or enhance the anticoagulant effect of warfarin |
| Supplements | |
| Coenzyme Q10 Coenzyme Q10 can enhance or inhibit the effect of warfarin because of the similarity of the chemical structure of coenzyme Q10 and vitamin K | Coenzyme Q10 Coenzyme Q10 can enhance or inhibit the effect of warfarin because of the similarity of the chemical structure of coenzyme Q10 and vitamin K |
| Other substances | |
| Alcohol (ethanol) Inhibition or induction of warfarin metabolism | Alcohol (ethanol) Inhibition or induction of warfarin metabolism |
Dosing and Administration
Inside.
1 time per day, preferably at the same time.
The duration of treatment is determined by the doctor in accordance with the indications for use.
Control during treatment. Before the start of therapy, MHO is determined. Further laboratory monitoring is carried out regularly every 4-8 weeks.
The duration of treatment depends on the clinical condition of the patient. Treatment can be canceled immediately.
Patients who had not previously taken warfarin: the initial dose was 5 mg / day (2 tablets per day) for the first 4 days. On the 5th day of treatment, MHO is determined and, in accordance with this indicator, a maintenance dose of the drug is administered. Usually the maintenance dose of the drug is 2.5-7.5 mg / day (1-3 tablets per day).
Patients who had previously taken warfarin: The recommended starting dose is a double dose of a known maintenance dose of the drug and is given within the first 2 days. The treatment is then continued with the aid of a known maintenance dose. On the 5th day of treatment, MHO monitoring and dose adjustment are performed in accordance with this indicator. It is recommended to maintain the MHO index from 2 to 3 in case of prophylaxis and treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, complicated heart valve diseases, prosthesis of heart valves with bioprostheses. Higher MHO values from 2.5 to 3.5 are recommended for prosthetic valve replacement with mechanical prostheses and complicated acute myocardial infarction.
Children: data on the use of warfarin in children are limited. The initial dose is usually 0.2 mg / kg / day with normal liver function and 0.1 mg / kg / day if liver function is impaired. The maintenance dose is selected in accordance with the MHO indices. The recommended levels of MHO are the same as those of adults. The decision to prescribe warfarin and supervision of treatment in children should be carried out by an experienced pediatrician. Doses are selected in accordance with Table. 1.
Table 1
Selection of a maintenance dose of warfarin according to the INR
| Day 1 | If the base INR value is from 1 to 1.3, then the shock dose is 0.2 mg / kg |
| Days 2 to 4, if the MHO value is: Actions: | Days 2 to 4, if the MHO value is: Actions: |
| From 1 to 1.3 Repeat the shock dose | From 1 to 1.3 Repeat the shock dose |
| From 1.4 to 1.9 50% of the impact dose | From 1.4 to 1.9 50% of the impact dose |
| From 2 to 3 50% of the impact dose | From 2 to 3 50% of the impact dose |
| From 3,1 to 3,5 25% of the impact dose | From 3,1 to 3,5 25% of the impact dose |
| > 3.5 Discontinue drug administration before reaching MHO <3.5, then resume treatment with a dose of 50% of the previous | > 3.5 Discontinue drug administration before reaching MHO <3.5, then resume treatment with a dose of 50% of the previous |
| Maintenance if the MHO value: Actions (weekly dose): | Maintenance if the MHO value: Actions (weekly dose): |
| From 1 to 1.3 Increase the dose by 20% | From 1 to 1.3 Increase the dose by 20% |
| From 1.4 to 1.9 Increase the dose by 10% | From 1.4 to 1.9 Increase the dose by 10% |
| From 2 to 3 No change | From 2 to 3 No change |
| From 3,1 to 3,5 Reduce the dose by 10% | From 3,1 to 3,5 Reduce the dose by 10% |
| > 3.5 Discontinue drug administration before reaching MHO <3.5, then resume treatment with a 20% lower dose than the previous one | > 3.5 Discontinue drug administration before reaching MHO <3.5, then resume treatment with a 20% lower dose than the previous one |
Patients with renal insufficiency: patients with impaired renal function need to reduce the dose of warfarin and carry out thorough monitoring (see "Special instructions").
Planned (elective) surgical interventions: pre-, peri- and post-operative anticoagulant therapy is performed as indicated below (if urgent cancellation of oral anticoagulant treatment is needed - see "Overdose").
1. Identify MHO one week prior to the scheduled operation.
2. Stop taking warfarin 1-5 days before surgery. In the case of a high risk of thrombosis, low molecular weight heparin is administered to the patient to prevent SC. The duration of the pause in taking warfarin depends on MHO. Acceptance of warfarin is discontinued:
- 5 days before surgery, if MHO> 4;
- 3 days before surgery, if MHO is from 3 to 4;
- 2 days before surgery, if MHO is from 2 to 3.
3. Determine the MHO in the evening before the operation and administer 0.5-1 mg of vitamin K1 orally or intravenously, if INR> 1.8.
4. Take into account the need for infusion of unfractionated heparin or preventive administration of low-molecular-weight heparin on the day of surgery.
5. Continue with the introduction of low-molecular-weight heparin for 5-7 days after surgery with concomitant reconstituted warfarin.
6. Continue taking warfarin from a normal maintenance dose on the same day in the evening after a small operation and the day the patient begins to receive enteral feeding after major surgery.
Overdose
The indicator of the effectiveness of treatment is on the border of the development of bleeding, so the patient can develop minor bleeding (including eg microhematuria, bleeding gums).
Treatment: in mild cases - reducing the dose of the drug or stopping treatment for a short time; With minor bleeding - stopping the drug before reaching the MHO target level. In case of severe bleeding, iv administration of vitamin K, administration of activated carbon, coagulation factor concentrate or freshly frozen plasma.
If oral anticoagulants are indicated for the purpose in the future, large doses of vitamin K should be avoided. Resistance to warfarin develops within 2 weeks.
Table 6
Treatment regimen for Overdose
| MHO level | Recommendations |
| In case of minor bleeding | |
| <5 Skip the next dose of warfarin and continue taking lower doses when the therapeutic level of MHO is reached | <5 Skip the next dose of warfarin and continue taking lower doses when the therapeutic level of MHO is reached |
| 5-9 Skip 1-2 doses of warfarin and continue taking lower doses when the therapeutic level of MHO is reached or skip 1 dose of warfarin and prescribe vitamin K at doses of 1-2.5 mg orally | 5-9 Skip 1-2 doses of warfarin and continue taking lower doses when the therapeutic level of MHO is reached or skip 1 dose of warfarin and prescribe vitamin K at doses of 1-2.5 mg orally |
| > 9 Stop taking warfarin, prescribe vitamin K in doses of 3-5 mg orally | > 9 Stop taking warfarin, prescribe vitamin K in doses of 3-5 mg orally |
| Discontinuation of the drug is indicated | |
| 5-9 (operation is planned) Stop taking warfarin and prescribe vitamin K in doses of 2-4 mg orally (24 hours before the planned operation) | 5-9 (operation is planned) Stop taking warfarin and prescribe vitamin K in doses of 2-4 mg orally (24 hours before the planned operation) |
| > 20 or severe bleeding Vitamin K in a dose of 10 mg by slow intravenous infusion, transfusion of the concentrates of factors of the prothrombin complex or fresh frozen plasma, or whole blood. If necessary, repeated administration of vitamin K every 12 hours | > 20 or severe bleeding Vitamin K in a dose of 10 mg by slow intravenous infusion, transfusion of the concentrates of factors of the prothrombin complex or fresh frozen plasma, or whole blood. If necessary, repeated administration of vitamin K every 12 hours |
After the treatment, prolonged observation of the patient is necessary, given that T1 / 2 warfarin is 20-60 hours.
Special instructions
A mandatory condition for therapy with warfarin is strict adherence to the patient's intake of the prescribed dose of the drug.
Patients suffering from alcoholism, as well as patients with dementia may be unable to comply with the prescribed mode of taking warfarin.
Conditions such as fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant lesions of the liver, may enhance the effect of warfarin. With hypothyroidism, the effect of warfarin can be reduced. In the case of renal failure or nephrotic syndrome, the free fraction of warfarin in the blood plasma increases, which, depending on the concomitant diseases, can lead to both an increase and a decrease in the effect. In the case of moderate hepatic insufficiency, the effect of warfarin is enhanced.
In all of the above conditions, careful monitoring of the MHO level should be carried out.
Patients receiving warfarin, as anesthetic drugs are recommended to appoint paracetamol, tramadol or opiates.
Patients with a mutation of the gene encoding the CYP2C9 enzyme have a longer T1 / 2 warfarin. These patients require lower doses of the drug, When taking conventional therapeutic doses, the risk of bleeding increases.
Do not take warfarin in patients with a rare hereditary intolerance to galactose, a deficiency of lactase, a syndrome of glucose-galactose malabsorption due to the presence of lactose in the formulation (as an auxiliary substance).
If it is necessary to initiate a rapid antithrombotic effect, it is recommended to begin treatment with the administration of heparin; Then for 5-7 days, combined therapy with heparin and warfarin should be conducted until the target MHO level is maintained for 2 days (see "Method of administration and dose").
In patients with protein C deficiency, there is a risk of skin necrosis at the beginning of warfarin therapy. Such therapy should begin without a shock dose of warfarin, even with heparin. Patients with protein S deficiency may also be at risk, and in these circumstances a slower initiation of warfarin therapy is recommended.
In the case of individual resistance to warfarin (it is very rare), from 5 to 20 shock doses of warfarin are needed to achieve a therapeutic effect. If the reception of warfarin in such patients is ineffective, other possible causes should be established - simultaneous administration of warfarin with other drugs (see "Interaction"), inadequate diet, laboratory errors.
Treatment of elderly patients should be carried out with special precautions, because The synthesis of coagulation factors and hepatic metabolism in such patients is reduced, resulting in an excessive effect of warfarin.
Caution is recommended in patients with impaired renal function, which should be used to monitor MHO levels more often in patients at risk of hypercoagulability, for example, severe arterial hypertension or kidney disease (see "Dosage and Administration").
Release form
Tablets, 2.5 mg: in plastic bottles, sealed with screw caps, under which are installed gaskets with tear-off rings, providing control of the first opening, 50 or 100 pieces each. 1 fl. In a cardboard box.
Manufacturer
Nycomed Denmark Apts. Langebjerg, 1, DK-4000, Roskilde, Denmark.
Claims of consumers should be sent to the address of OOO Takeda Pharmaceuticals. 119048, Moscow.
Conditions of supply of pharmacies
On prescription.
Storage conditions of the drug Warfarin Nycomed
At temperatures not higher than 25 ° C
Keep out of the reach of children.
The shelf life of the drug Warfarin Nycomed
5 years.
Do not use beyond the expiration date printed on the package.
