Orfarin

Warfarin sodium.

Each tablet contains warfarin sodium 3 mg and 5 mg, respectively.
Excipients/Inactive Ingredients: Lactose monohydrate, maize starch, gelatin, magnesium stearate, indigo carmine (E132) for 3 mg tablet, erythrosine (E127) for 5 mg tablet.

Pharmacotherapeutic Group: Oral anticoagulants. ATC Code: B01AA03.
Pharmacology: Pharmacodynamics: Warfarin or 4-hydroxycoumarin is an anticoagulant that prevents the vitamin K-dependent synthesis of clotting factors included anticoagulants factor protein C and protein S. Warfarin is racemic mixture. Of its isomers, S-warfarin is approximately 5 times as potent an anticoagulant as R-warfarin. The effect of warfarin is based on its ability to prevent the reduction and activity of vitamin K in the synthesis of coagulation factors II, VII, IX and X. In therapeutic doses, warfarin prevents the synthesis of vitamin K-dependent coagulation factors by 30 to 50% and reduces the biological activity of coagulation factors. It takes 72 to 96 hours for the full effect of warfarin to appear. During this time the coagulation factors already synthesised are eliminated.
Pharmacokinetics: The bioavailability of oral warfarin is over 95% and peak plasma concentration is achieved in 3 to 9 hours. Meals slow down but do not reduce the absorption. Warfarin binds strongly to serum albumin, the free fraction varies between 0.5 and 3%. The volume of distribution of warfain is approximately 0.14 L/kg. Warfarin crosses the placenta but is not excreted in the breast milk. Warfarin is metabolised in the liver catalysed by CYP2C9 (S-warfarin) and CYP1A2 and CYP3A (R-warfarin) into inactive metabolites which are principally excreted in the urine and to a lesser extent into the bile. Enterohepatic circulation does exist. The elimination half life of S-warfarin is 18 to 35 hours and that of R-warfarin 20 to 60 hours.
Toxicology: Preclinical Safety Data: Animal studies have shown warfarin to be teratogenic. In other respects, available preclinical safety data do not reveal further relevant information for humans.

Treatment and prevention of deep venous thrombosis and pulmonary embolism.
Prevention of thromboembolic complications (stroke or systemic embolism) after myocardial infarct.
Prevention of thromboembolic complications (stroke or systemic embolism) in patients with atrial fibrillation, cardiac valvular disease or prosthetic heart valves.

The target INR range of oral anticoagulant therapy: Prophylaxis of thromboembolic complications in patients with prosthetic heart valves: INR 2.5-3.5. Other indications: INR 2.0-3.0.
Adults: Patients in normal weight and the spontaneous INR under 1.2 are administered 10 mg of warfarin on three consecutive days. The dosing is continued according to the table as follows based on the INR measured on the fourth day.
In open care and for patients with inherited protein C or protein S deficiency the recommended initial dose is 5 mg of warfarin (*) in three days. The dosing is continued according to the table as follows, based on the INR-measured on the fourth day. (See Table 1.)
For elderly patients, for those small in size, for those with the spontaneous INR over 1.2, or for those who have a disease (see Precautions) or medication (see Interactions) affecting the efficacy of anticoagulant therapy, the recommended initial dose is 5 mg of warfarin (*) for two days. The dosing is continued according to table 2, based on the INR measurement performed on the third day. (See Table 2.)

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INR measurements are carried out daily until the therapeutic level has been achieved (usually this takes 5 to 6 days). Intervals of INR measurements are then extended weekly. In long-term follow-up the measurement intervals are dependent i.a. on the patient's compliance and clinical status, targeting, however, on 4-weekly measurement intervals. If large fluctuations exist in the INR values or if the patient has a disease affecting liver function or the absorption of vitamin K, the measuring interval must be shorter than this. Many medicines may potentiate or weaken the effect of warfarin, which must be considered in the follow-up when initiating or discontinuing other medications. In long-term follow-up the adjustments required based on the INR measurements are made to the weekly dose. Thereafter the effect of the adjustment is checked by measuring the INR after 1 or 2 weeks of the adjustment. After this, the intervals are targeted on the same 4-weekly measurement intervals.
Children: The initiation and follow up of anticoagulant therapy in children is carried out by pediatricians. Dosage can be adjusted according to Table 2. (See Table 2.)

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Elective Surgery: Pre-, peri- and postoperative anticoagulant therapy the following dosage can be applied (if an urgent reversal of oral anticoagulant effect is needed, see Overdose).
Determine the INR one week prior to the scheduled surgery. Discontinue warfarin 1 to 5 days prior to surgery. If the patient is in high risk of thromboembolism, subcutaneous low molecular weight heparin should be given at therapeutic doses. The effect of heparin can be monitored by measuring the prophylactic effect of FXa when the effective therapeutic level is 0.3 to 0.7 anti-FXa activity units/mL.
The extent of warfarin pause depends on the INR value. Discontinue warfarin: 5 days prior to surgery if the INR > 4.0; 3 days prior to surgery if the INR=3.0 to 4.0; 2 days prior to surgery if the INR=2.0 to 3.0.
Determine the INR in the evening before surgery. If INR >1.8, administer 0.5 to 1 mg vitamin K₁ intravenously or orally.
Consider the need for unfractionated heparin infusion or prophylactic low molecular weight heparin during the day of surgery.
Continue subcutaneous low molecular weight heparin for 5 to 7 days concomitantly with reintroduced warfarin therapy.
Initiate warfarin with maintenance doses in the evening after minor surgery, and on the day the patient begins enteral nutrition after major surgery.

In mild cases and when the overdosage has been gradual, it usually suffices to stop the warfarin therapy temporarily. If the patient has taken a large amount of warfarin, gastric lavage is not recommended because of the risk of complications. Medicinal charcoal is administered repeatedly to prevent the absorption and enterohepatic circulation of warfarin. If medicinal charcoal is administered, vitamin K must be administered parenterally (IV). If bleeding complications occur, warfarin effect can be reversed by giving vitamin K, coagulation factor concentrate or fresh frozen plasma. If warfarin therapy is indicated also in the future, large doses of vitamin K exceeding 10 mg must be avoided, because after that the patient will be resistant to the effect of warfarin for up to two weeks.
The following scheme can be used in treating overdosage. (See Table 3.)

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Hypersensitivity to warfarin or to any of the excipients.
Pregnancy (see Use in Pregnancy & Lactation).
Bleeding tendency (von Willebrand disease, hemophilia, thrombocytopenia and platelet function disorders).
Severe hepatic insufficiency and hepatic cirrhosis.
Untreated or uncontrolled hypertension.
Recent intracranial bleeding. Other conditions predisposing to intracranial bleeding eg, aneurysms.
Tendency to fall.
Surgery of the central nervous system or the eye.
Conditions predisposing to the gastrointestinal or urinary tract bleeding eg, previous gastrointestinal bleeding complications, diverticulosis or malignancies.
Infectious endocarditis (see Precautions), pericarditis or pericardial effusion.
Dementia, psychoses, alcoholism and other situations where the compliance may be poor and the treatment cannot be carried out safely in practice.

If a rapid antithrombotic effect is needed, heparin treatment must be initiated. After this, heparin treatment is continued along with the initiated warfarin treatment for at least 5 to 7 days until the INR has been at target level (see Dosage & Administration) for at least two days.
Resistance to warfarin is a very rare phenomenon. Only a few case reports have been published on that. These patients need 5- to 20-fold warfarin doses to achieve therapeutic response. If the response of the patient to warfarin treatment is significantly poorer than normal, other causes imparing the effect of the treatment must be first be ruled out, eg, missing drug intake, interaction with food or other medicinal products and potential laboratory errors.
To avoid coumarin necrosis (see Adverse Reactions), patients with a hereditary deficiency of protein C or S should first start heparin for 5 to 7 days along with warfarin therapy. Warfarin therapy is initiated at a dose of 5 mg.
Special caution must be exercised when treating elderly patients. The patients compliance and the abilities to follow strict rules on drug intake must be ascertained. Hepatic metabolism of warfarin as well as the synthesis of coagulation factors are slowed down in the elderly. This may be easily result in an excessive therapeutic response. Warfarin therapy must be initiated cautiously (see Dosage & Administration). Concomitant medications must be taken into account to avoid harmful interactions (see Interactions).
Hyperthyroidism, fever and uncompensated heart failure may enhance the warfarin effect. In hypothyroidism, the warfarin effect may be reduced. In moderate hepatic insufficiency, the effect of warfarin is enhanced. In renal insufficiency and nephrotic syndrome, the free fraction of warfarin in plasma is elevated (depending on the other primary diseases, it may either enhance or reduce the warfarin effect). The clinical situation of the patient and the INR values must be carefully monitored under all these circumstances.
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption should not take this medicine.
Effects on the Ability to Drive or Operate Machinery: No effect.

Warfarin crosses the placenta. Maternal warfarin therapy may cause warfarin embryopathy (nasal hypoplasia and chondrodysplasia punctata) if warfarin is administered during the organogenesis (weeks 6 t 12 of pregnancy), and even after the abnormalities in the development of central nervous system are possible. Warfarin can induce fetal hemorrhage, which has relevance especially during delivery. Warfarin embryopathy has been estimated to occur in 4 to 6% of pregnancies, if warfarin is used throughout the pregnancy, and its likelihood increases if larger than 5 mg daily doses are used. Warfarin is contraindicated during the week 6 to 12 of pregnancy and after the middle of the third trimester. During other phases of pregnancy, the risks to the fetus from warfarin use must be carefully weighed against the risk to the mother and fetus from not using warfarin. Antithrombotic therapy during the pregnancy must be individually planned under the supervision of a specialist clinician.
Since warfarin is not excreted in the breast milk, breast feeding can be continued during warfarin therapy.

Commonly reported (1-10%) undesirable effects of warfarin treatment are the bleeding complications. The over-all rate for bleeding is about 8% per year for total bleeding, consisting of minor bleeding (6% per year), severe bleedings (1% per year) and fatal (0.255 per year). The most common risk factor for intracranial bleeding is untreated or uncontrolled hypertension. Likelihood of bleeding increases as the INR elevates significantly above the target range. If bleeding occurs when the INR is within the target range, there usually exist another comorbid condition which should be investigated. Other common undesirable effects are nausea, vomiting and diarrhoea.
Coumarin necrosis is a rare complication of warfarin therapy. It manifests initially as swelling and darkening skin lesions usually in the lower extremities or buttocks, but may appear elsewhere as well. Later the lesions become necrotic. 90% of the patients are women. Lesions appear on the 3rd to 10th day after starting warfarin therapy and relative deficiency of antithrombotic proteins C and S is considered as an etiologic factor. Hereditary deficiency of protein C or S may predispose the patient to the complication. For this reason, warfarin therapy must be initiated in these patients concomitantly with heparin and using small doses of warfarin. If these adverse reactions occurs, warfarin therapy must be discontinued and heparin therapy continued until the lesions have healed or become scarred.
Purple toe-syndrome is an even more rare complication of warfarin therapy. Patients, usually male, typically have arteriosclerosis. Warfarin is thought to cause hemorrhages to the atheromatous plaques leading to microembolization. This cause symmetrical purple skin lesions in the toes and soles which is associated with burning pain. Warfarin therapy must be discontinued and thereafter the skin lesions disappear slowly.
Other rare adverse events reported during warfarin treatment are vasculitis, tracheal calcification, reversible hepatic enzyme elevation, cholestatic hepatits, reversible alopecia, rash, priapism and allergic reactions (manifested usually as skin rash).

Warfarin iteracts with many drugs. Drugs may reduce the absorption or enterohepatic circulation of warfarin (cholestyramine). Drugs may induce (antiepileptics or antituberculotics) or inhibit the hepatic metabolism of warfarin (e.g, amiodarone or metronidazole). In certain instances cessation of inhibition or induction of liver enzymes can also change the balance of warfarin therapy. Certain drugs may displace warfarin from the plasma protein bonds, which increases the free fraction and, unless the patient has some liver disease or some other medication inhibiting warfarin metabolism, this generally enhances the elimination of warfarin. The best known pharmacodynamic interactions are associated with the simultaneous use of drugs affecting the platelets (acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most of the non-steroidal anit-inflammatory drugs, but not the coxibs). Primary and secondary hemostasis predisposes the patient to severe bleeding complications. Penicillins in large doses may have the same effect. Vitamin K-dependent synthesis of the coagulation factor is reduced and the warfarin effect is potentiated by certain drugs, such as anabolic steroids, azapropazone, erythromycin, and some cephalosporins. An ample supply of dietary vitamin K reduces the warfarin effect. Correspondingly, reduced absorption of vitamin K due to e.g. diarrhoea may potentiate the warfarin effect. In patients with inadequate supply of vitamin K, antibiotics may reduce the ability of the intestinal bacteria to produce vitamin K₂, which leads to an enhanced warfarin effect. Heavy use of alcohol with concomitant hepatic failure potentiates the warfarin effect. The quinine contained in Tonic-water may also potentiate the warfarin effect.
Cranberry juice and other cranberry products may potentiate the effect of warfarin and therefore concomitant use should be avoided. If the patient needs relief of pain while on warfarin, paracetamol or opiates are recommended.
Warfarin may potentiate the effect of oral sulphonyluera antibiotics. 
The following drugs have been reported to potentiate or reduce the warfarin effect: Increased Effect:  Acetylsalicylic acid, allopurinol, amiodarone, amoxicillin, argatroban, azapropazone, azithromycin, bezafibrate, capecitabine, carboxyuridine, celecoxib, clarithromycin, chloral hydrate, cefamandole, cefalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, clofibrate, codeine, cyclophosphamide, dexstropropoxphene, (dextro) thyroxine, digoxin, disulfiram, doxycycline, erythromycin, etoposide, fenofibrate, feprazone, fluconazole, fluorouracil, flutamide, flutamide, fluvastatin, fluvoxamine, gatifloxacin, gemfibrozil, grepafloxacin, ifosfamide, indometacin, influenza vaccine, interferon alpha and beta, isoniazid, itraconazole, ketoconazole, latamoxef, leflunomide, lepirudin, levofloxacin, lovastatin, metolazone, methotrexate, metronidazole, miconazole (also oral gel), moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (the effect evident after 1 to 2 weeks of continuous use), phenylbutazone, piroxicam, proguanil, propafenone, propranolol, quinine, quinidine, rofecoxib, roxithromycin, simvastatin, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfaphenazole, sulfinpyrazone, sulfofenur, sulindac, (anabolic and androgenic) steroid hormones, tamoxifen, tegafur, tetracycline, tolmetin, tramadol, trastuzumab, troglitazone, valproic acid, vitamin A, vitamin E, zafirlukast.
There are reports suggesting that noscapine as wellas glucosamine with or without chondroitin sulphate may increase the INR patients on warfarin.
Decreased Effect: Azathioprine, (barbiturates), carbamazepine, chlordiazepoxide, chlortalidone, cloxacillin, ciclosporin, dicloxacillin, disopyramide, griseofulvin, mercaptopurine, mesalazine, mitotaine, nafcillin, nevirapine, phenobarbital, primidone, rifampicin, spironolactone, trazodone, vitamin C.
Herbal medication can either potentiate the warfarin effect e.g. ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis, contains coumarins), papaya (Carica papaya) or danshen (Salvia miltiorrhiza, decreases the warfarin elemination), or reduce it, e.g. ginseng (Panax spp). The effect of warfarin can be reduced by concomitant use of the herbal preparation of St. John's wort (Hypericum perforatum). This is due to induction of drug metabolizing enzymes by St. John's wort. Herbal preparation containing St. John's wort should therefore not be combined with warfarin.
The inducing effect may persist for as long as 2 weeks after cessation of treatment with St John's wort. If a patient is already taking St John's wort check the INR and stop St John's wort. Monitor INR closely as this may rise on stopping St John's wort. The dose of warfarin may need adjusting. Ingestion of vitamin K containing foodstuffs during warfarin treatment should be as steady as possible. The most abundant vitamin K sources are green vegetables and leaves, such as: Amaranth leaf, avocado, broccoli, Brussels sprout, cabbage, canola oil, chayote leaf,chives, coriander, cucumber skin (but not cucumber without skin), endives, kale leaf, kiwifruit, lettuce leaf, mint leaf, mustard greens, olive oil, parsley, peas, pistachio nuts, purple seaweed laver, spinach leaf, spring onion, soybeans, soybean oil, tea leaves (but not tea), turnip greens, or watercress.
Topical preparations containing methyl salicylate should be used with care in patients on warfarin and excessive usage is to be avoided as potentially dangerous drug interaction can occur.

Incompatibilities: Not applicable.

Store below +25°C in a tightly closed original container.
Shelf-Life: 2.5 years.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AA03 - warfarin ; Belongs to the class of vitamin K antagonists. Used in the treatment of thrombosis.

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