COUMADIN - PACKAGE LEAFLET - LEAFLETS

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Coumadin - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Warfarin (warfarin sodium)

Coumadin 5mg divisible tablets

Why is Coumadin used? What is it for?

COUMADIN is an anticoagulant, that is, it helps prevent the formation of clots (lumps) in the blood.

COUMADIN is a medicine with a narrow therapeutic index, which means that small variations in the dose can have serious consequences, in fact too much medicine can cause bleeding, too little medicine can lead to the formation of dangerous blood clots.

Your doctor has prescribed COUMADIN for you to prevent blood clots. These clots are dangerous because they can block normal blood flow. For example, if a clot travels to the brain it can cause a stroke (interruption of blood flow to the brain).

COUMADIN is used to treat and prevent clots:

in the legs and lungs
associated with an irregular and fast heartbeat, called "atrial fibrillation";
associated with heart valve replacement.

If you have had a heart attack (heart attack) COUMADIN is used for:

decrease the risk of having another heart attack;
decrease the risk of stroke;
decrease the risk of clots going to the legs or lungs.

Talk to your doctor if you don't feel better or if you feel worse.

Contraindications When Coumadin should not be used

Do not take COUMADIN

If you are allergic to warfarin sodium or any of the other ingredients of this medicine (listed in the section What it contains).
If you have a risk of bleeding or ongoing bleeding.
If you are pregnant or could be.
If you are a woman of childbearing age who does not use contraceptives
If you are pregnant and at risk of losing your baby or have very high blood pressure.
If you have recently undergone or are about to undergo an operation, even under local anesthesia (interruption of pain in an area of the body).
If you need to have a procedure in the hospital, including a puncture in the back.
If you have very high blood pressure which can cause eye damage (malignant hypertension).
If you are taking St. John's wort preparations - Hypericum perforatum (herbal medicine to treat depression) (see section Other medicines and Coumadin).

Precautions for use What you need to know before taking Coumadin

Talk to your doctor or pharmacist before taking COUMADIN
If you notice any unusual bleeding or if you have any signs or symptoms of bleeding (see Possible side effects).
If you have or have had in the past international normalized ratio (INR) values, a blood clotting index, greater than 4.0 or highly variable.
If you have ever had stomach and intestinal bleeding.
If you have high blood pressure.
If you suffer from a disease of the blood vessels of the head.
If you suffer from a decrease in hemoglobin, a protein that carries oxygen to tissues, in the blood (anemia).
If you have a malignant tumor (cancer).
If you suffer from kidney disease.
If someone in your family suffers from a blood disorder.
If you have been told that you will have to take COUMADIN for a long time.
If you are elderly (age 65 or older). Your doctor will decide what dose is right for you. This dose may change from time to time.
If her toes turn blue and hurt. Stop taking COUMADIN and contact your doctor who will prescribe another medicine (see section Possible side effects).
If you suffer from a decrease in the number of platelets, a type of blood cell, following treatment with heparin, a medicine to thin the blood.
If you have mild to severe liver disease. Your doctor will decide what dose is right for you.
If you have vomiting, diarrhea or an infection while taking COUMADIN.
If you notice that part of your body or skin becomes black during therapy with COUMADIN (skin or tissue necrosis) (see section Possible side effects)
If they have applied a catheter (small, flexible tube).
If you have a disease involving protein C, a protein naturally present in the body that makes the blood thinner.
If he has to undergo an "eye operation".
If he hits his head or takes a bad fall.
If you have an increase in blood cells which can be seen in blood tests
If you suffer from "inflammation of the blood vessels.
If you have diabetes mellitus (increased blood sugar levels).
If he eats little.
If you suffer from a vitamin K deficiency.
If you are taking medicines or foods that contain vitamin K (see sections Other medicines and COUMADIN; COUMADIN with food, drink and alcohol).
If your body does not react adequately to warfarin treatment.
If you are going to have an operation, including at the dentist. Tell any healthcare professional who cares for you (including dentist) that you are taking COUMADIN as therapy with COUMADIN must be stopped or decreased before, during and immediately after the surgery.

Interactions Which drugs or foods can change the effect of Coumadin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Tell your doctor if you notice any changes in your health, make changes to the medicines you are taking, to your lifestyle (travel, environmental conditions, physical activity).

In particular, tell your doctor if you are taking:

herbal preparations, especially Hypericum perforatum (used to treat depression) (see Do not take COUMADIN)
Medicines to treat infections (amoxicillin, benzylpenicillin, penicillin G, piperacillin, ticarcillin, cefaclor, cefamandol, cefazolin, cefixime, cefotetan, cefonicid, cefotiam, cefoxitin, ceftriaxone, cefuroxime, roxicycline, ticromacycline, ticromacycline , telithromycin, neomycin, ciprofloxacin, levofloxacin, nalidixic acid, moxifloxacin, norfloxacin, pefloxacin, ofloxacin, pyrimethamine, sulfafurazolo, Sulfamethizole, sulfamethoxazole / trimethoprim, sulfisoxazole, aminosalicylic acid, isoniazid, chloramphenicol, vancomycin, clindamycin, dicloxacillin, nafcillin, rifampin, rifapentine )
medicines to treat infections caused by fungi (miconazole, econazole, fluconazole, ketoconazole, itraconazole, voriconazole, griseofulvin)
medicines to prevent and treat infections caused by parasites (proguanil, metronidazole, nimorazole, tinidazole, quinine)
medicines to treat infections caused by viruses (delavirdine, efavirenz, etravirine, nevirapine, atazanivir, ritonavir, peginterferon alfa-2b, ribavirin, darunavir)
medicines to treat organ rejection in transplant patients (cyclosporine)
Medicines to treat inflammation and pain (paracetamol, acetylsalicylic acid, diflunisal, propoxyphene, tramadol, diclofenac, indomethacin, ketorolac, sulindac, phenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozamic acid, celecoxib, lumofenecox, ethnecoxy meclophenamic acid, lornoxicam, iroxicam, glucosamine, dexamethasone, methylprednisolone, prednisone, cortisone)
medicines to thin the blood (prasugrel, ticlopidine, abciximab, tirofiban, heparin, argatroban, bivalirudin, desirudin, lepidurin)
medicines to dissolve blood clots (streptokinase, alteplase)
medicines to treat depression (desvenlafaxine, duloxetine, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, viloxazine, trazodone)
medicines to treat epilepsy, a disease characterized by uncontrolled body movements and loss of consciousness (valproic acid, valproate, fosphenytoin, phenytoin, phenobarbital, primidone, carbamazepine)
medicines to treat mental disorders and anxiety (haloperidol, chlordiazepoxide)
medicines to treat Parkinson's disease, a disease of the central nervous system manifested for example by tremor, muscle stiffness, slowing of movement, difficulty in maintaining balance (entacapone, tolcapone, ropinirole)
medicines to treat dementia, a disease characterized by memory loss, orientation in space and time, difficulty speaking (Ginko biloba, memantine)
medicines that stimulate the brain (methylphenidate)
medicines to treat insomnia (chloral hydrate, glutethymide, butobarbital, pentobarbital, secobarbital)
medicines to treat lung diseases (zafirlukast)
medicines to treat cough (noscapine, oxolamine)
medicines to treat disorders related to menopause (permanent interruption of the female cycle) in women (tibolone, lasofoxifene, raloxifene)
medicines to treat tumors (tamoxifen, toremifene, megestrol, bicalutamide, flutamide, nilutamide, cyclophosphamide, ifosfamide, carboplatin, capecitabine, fluorouracil, tegafur, paclitaxel, trastuzumab, etoposide, erlotinib, geostatinatinide, imostatinide, imostatinib mercaptopurine, mitotane)
contraceptive medicines (pill) (medroxyprogesterone, oral contraceptives containing estrogen)
medicines to treat sexual disorders (testosterone)
medicines to treat irregular periods in women (danazol)
medicines that increase metabolism (metandienone, oxandrolone, oxymethanolone, stanozolol)
vaccines (flu shot)
vitamins (vitamin E, C, K)
medicines to treat skin diseases (isotretion, etretinate, benzethonium chloride)
medicines to treat alcohol dependence (disulfiram)
ointments to treat pain (methyl salicylate ointment, trolamine salicylate ointment)
medicines to treat obesity (orlistat)
medicines to treat high blood sugar levels (diabetes) (exenatide)
medicines to treat low blood sugar (glucagon)
medicines to treat diseases of the thyroid gland, a gland in the neck (levothyroxine, liothyronine, thyroid extracts, methimazole, propylthiouracil)
medicines to treat the inability to hold urine (urinary incontinence) (tolterodine)
medicines to treat enlarged prostate, the gland that produces semen in men (tamsulosin)
medicines to treat rheumatoid arthritis, a disease characterized by joint inflammation, swelling, difficulty moving and pain (leflunomide, azathioprine)
medicines to treat heart rhythm disorders (quinidine, propafenone, amiodarone, disopyramide)
medicines to treat high blood pressure (propanolol, pentoxifylline, benziodarone)
medicines to treat high blood pressure in the pulmonary artery (bosentan)
medicines to treat heart disease (ethacrynic acid, thienyl acid, spironolactone, chlorthalidone)
medicines to treat the lack of production of coenzyme Q10, a substance useful to the body (ubiquinone or ubidecarenone
medicines to treat high blood fat levels (benzafibrate, clofibrate, ciprofibrate, fenofibrate, gemfibrozil, atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, colesevelam, cholestyramine)
medicines to treat heartburn (cimetidine, ranitidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, sucralfate)
medicines to treat vomiting (aprepitant, fosaprepitant)
medicines to treat stones or pebbles, in the gallbladder, the organ that stores bile, an important substance in digestion processes (chenodiol)
medicines to treat digestive disorders (cisapride)
medicines to treat inflammation of the gut (olsalazine)
medicines to treat build-ups of uric acid that cause painful joints (gout) allopurinol, benzbromarone, sulfinpyrazone)
corticotropin, diagnostic medicine
medicines containing alcohol (see section COUMADIN with food, drink and alcohol)

Warnings It is important to know that:

COUMADIN with food, drink and alcohol

Do not start a diet without first consulting your doctor.
Do not make sudden changes in your eating habits, such as starting to eat large amounts of foods that contain vitamin K (green leafy vegetables such as spinach, lettuce, broccoli, cauliflower, Brussels sprouts and, to a lesser extent, cereals, meat and dairy products)
If the baby is taking formula milk, COUMADIN therapy may be affected.
Do not take garlic, Ginko biloba, ginseng, echinacea, grapefruit juice and hydraste while taking COUMADIN. For a complete list of foods and herbs to avoid ask your doctor.
Avoid alcohol consumption.

Pregnancy and breastfeeding

Pregnancy

Do not take COUMADIN during pregnancy, if you think you are pregnant or if you might become pregnant

If you are a woman of childbearing age who does not use contraceptives.

In fact, this medicine can cause harm to the unborn child.

If you take COUMADIN, talk to your doctor before planning a pregnancy.

Feeding time

COUMADIN does not pass into breast milk and infants who were breastfed by mothers taking COUMADIN had no changes in prothrombin time. Take COUMADIN with caution while breastfeeding and monitor the newborn for bruising and bleeding.

Driving and using machines

Coumadin therapy does not affect your ability to drive or operate machinery.

COUMADIN contains lactose

This medicine contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Coumadin: Posology

Always take this medicine exactly as your doctor has told you and at the same time each day. You can take COUMADIN both with meals and between meals. The dose you take may vary over time, depending on your response to COUMADIN and the condition of your liver.

To decide what dose to give you, your doctor will order a blood test to measure your prothrombin time (PT); Prothrombin time values are often recorded as INR (International Normalized Ratio), which is a standard way of expressing them.
Tests to evaluate the PT / INR are very important, as they help the doctor understand how long it takes for the blood to clot and decide if he needs to change the dose of COUMADIN.
When you start therapy with COUMADIN you will need to carry out the PT / INR checks very often, later they may be thinned out. However, this will not happen if you suffer from kidney disease. These tests, and regular visits to your doctor, are very important for the success of COUMADIN therapy. Throughout the course of therapy with COUMADIN you will need to check your PT / INR periodically (about once a month) and keep it in the best range for your health condition.

If in doubt, consult your doctor or pharmacist.

The tablet can be divided into equal parts.

Overdose What to do if you have taken too much Coumadin

If you take more COUMADIN than you should

If you have taken too much COUMADIN contact your doctor or a healthcare facility immediately for appropriate support.

If you forget to take COUMADIN

Always try to take COUMADIN as prescribed by your doctor. If you happen to miss a dose, tell your doctor right away. Take the missed dose on the same day as soon as you remember. If it is time for your next dose, do not take the missed one as well, but go on with your normal dosing schedule.

If you stop taking COUMADIN

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Coumadin

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects include:

bleeding (haemorrhage) in various parts of the body (around the heart, adrenal gland, eye, intestine, back of the abdomen, liver, head, lung)
part of the body or skin becomes black (skin or other tissue necrosis),
obstruction of a blood vessel due to fat (systemic atheroemboli and cholesterol microemboli). In this case, you may find that your toes turn blue and hurt (Blue Toe Syndrome) *.

If you experience any of the side effects mentioned above, STOP the treatment with COUMADIN and contact your doctor.

In addition, the side effects that may be observed, indicated by frequency, are not known (frequency cannot be estimated from the available data).

Decrease in hemoglobin, a protein that carries oxygen to tissues, in the blood (anemia) *
Chest pain*
Swelling in the belly area (distension of the abdomen), pain in the belly *, diarrhea, metallic taste in the mouth (dysgeusia), difficulty swallowing (dysphagia) *, gas (flatulence), bleeding gums, vomiting blood ( haematemesis), blood in stools (hematochezia), dark, foul-smelling stools (melaena), nausea, vomiting
Weakness (asthenia) *, chills, fatigue *, malaise *, pain *, paleness *, swelling caused by fluid retention (swelling) *
Liver infection (hepatitis)
Allergic (anaphylactic) reaction, allergy (hypersensitivity)
Abnormal blood tests (increased liver enzyme)
Joint pain (arthralgia) *, collection of blood around a joint (haemarthrosis), pain in the muscles (myalgia) *
Dizziness *, headache *, numbness (paraesthesia) *, total or partial loss of range of motion (paralysis) *, collection of blood around the spine (vertebral hematoma)
Deep sleep with reduced response to normal stimuli (lethargy) *
Blood in the urine (hematuria)
Excessive blood loss during the female period (menorrhagia), vaginal bleeding
Nosebleeds (epistaxis), difficulty in breathing (dyspnoea) *, blood with a cough (hemoptysis), bleeding in the chest (hemothorax), calcium salt deposition in the lung (lung calcification)
Loss of hair and hair (alopecia), skin irritation (dermatitis), skin irritation with blisters (bullous dermatitis), bruising (ecchymosis), skin spots (petechiae), itching, skin rash, redness of the skin accompanied by itching (urticaria)
Obstruction of an artery due to a gas bubble (arterial embolism), drop in blood pressure (hypotension) *, decrease in blood pressure with severe reduction in heart function (shock) *, fainting (syncope) *, inflammation of blood vessels (vasculitis)

Side effects marked with an asterisk (*) are symptoms or medical conditions resulting from bleeding.

There may also be variations, found in blood tests, in the levels of hemoglobin (a protein that carries oxygen to tissues), hematocrit (percentage of blood occupied by red blood cells) and enzymes that indicate the state of the liver and biliary (hepatobiliary) tract.

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Do not store above 30 ° C. Store in the original packaging. Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after Expiry. The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Description of what COUMADIN looks like and contents of the pack

COUMADIN comes in the form of breakable tablets.

COUMADIN is available in packs of 30 tablets each containing 5 mg of warfarin sodium.

What COUMADIN contains

The active ingredient is warfarin sodium.

The other ingredients are starch, magnesium stearate, stearic acid, lactose

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information on Coumadin can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications Pregnancy 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE DE THE FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIATION DRUGS, FURTHER DETAILED INSTRUCTIONS ON QUALITY PREPARATION

01.0 NAME OF THE MEDICINAL PRODUCT

COUMADIN 5 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient: 5 mg warfarin sodium

Excipient with known effect: lactose

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Tablets

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Prophylaxis and therapy of pulmonary embolism, deep vein thrombosis, arterial thromboembolism associated with chronic atrial fibrillation, mechanical or biological heart valve prostheses, intracardiac mural thrombosis, acute myocardial infarction. Prophylaxis of reinfarction.

04.2 Posology and method of administration

Dosage

Initial dose

The dose of COUMADIN should be individualized according to the patient's response to the drug, as indicated by daily monitoring of prothrombin time (PT) and expressed according to the International Normalized Ratio (INR). A high loading dose may increase the risk of bleeding and other complications, does not offer faster protection against thrombus formation and is therefore not recommended. Low starting doses are recommended in patients who are elderly, debilitated or who may have a greater than expected INR in response to COUMADIN. It is recommended that COUMADIN therapy be initiated using doses of 2.5 to 5 mg per day with dose adjustments based on INR determinations.

Maintenance dose

Most patients are maintained at doses of 2.5 to 10 mg per day with satisfactory results. Individual dose and dosing intervals should be determined based on the patient's INR values.

The duration of therapy is individual; in general, anticoagulant therapy should be continued until the risk of thrombosis and embolism is overcome.

For information purposes, the therapeutic ranges of INR recommended for each indication are given below (see also New Guide to Oral Anticoagulant Therapy of the Federation of Anticoagulant Surveillance Centers 1997).

Indications Therapeutic range (INR) Duration Treatment and secondary prevention of pulmonary embolism: In the absence of persistent thromboembolic risk 2-3 3-6 months In the presence of thrombophilic conditions or relapsing episodes 2-3 to be determined on a case-by-case basis Treatment and secondary prevention of deep vein thrombosis: In the absence of persistent thromboembolic risk 2-3 3-6 months In the presence of thrombophilic conditions or relapsing episodes 2-3 to be determined on a case-by-case basis Prevention of deep vein thrombosis 1,5-2,5 7-10 days For high-risk patients, for example in orthopedic surgery, as a second choice as an alternative to low molecular weight heparin Arterial thromboembolism 3-4,5* indefinite Chronic atrial fibrillation of recent onset to undergo cardioversion 2-3 at least 2 weeks first at least 3 weeks after cardioversion Valve prostheses: mechanical 3-4,5* indefinite biological 2-3 3 months Intracardiac mural thrombosis 2-3 until the thrombosis disappears Heart attack Prevention of thromboembolic risk 2-3 3 months Prevention of reinfarction 3-4,5* at least 3 years

Due to limited data, in patients with biological heart valves, warfarin therapy (INR 2-3) is recommended for 12 weeks after valve insertion. Longer term therapy should be considered for patients. with additional risk factors, such as atrial fibrillation or previous thromboembolism.

* Unless otherwise medically indicated, in most patients, an INR greater than 4.0 does not appear to provide additional therapeutic benefit and is associated with a higher bleeding risk.

In case of INR greater than 5 the patient should immediately stop taking warfarin and consult a doctor.

Special populations

Renal impairment

No dosage adjustment is required in patients with renal impairment although more frequent monitoring may be appropriate in order to keep the warfarin dose within the therapeutic range.

Hepatic impairment

Hepatic dysfunction may potentiate the response to warfarin due to the decrease in its metabolism and due to impaired synthesis of clotting factors. A reduction in dosage is therefore necessary.

Pediatric population

There is insufficient information from controlled clinical trials on use in children.

The safety and efficacy of COUMADIN in children and adolescents below 18 years of age have not been established.

Elderly patients

Low starting doses are recommended in elderly and / or debilitated patients.

COUMADIN with heparin

Given that there is an interval of about 12-18 hours between the administration of the initial dose and the therapeutic prolongation of the prothrombin time and a delay of 36-72 hours for the achievement of the global anticoagulant effect, in emergency situations (eg. pulmonary), initially administer sodium heparin together with COUMADIN. Concomitant therapy with unfractionated heparin influences the results of the INR test so it is recommended to perform the test at least six hours after heparin discontinuation.

04.3 Contraindications

COUMADIN is contraindicated in the following circumstances:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Pregnancy

In women of childbearing potential who are not using contraceptive measures (see section 4.6 "Pregnancy and lactation").

Hemorrhagic tendencies and blood dyscrasias

Recent or planned surgery associated with a high risk of bleeding

Bleeding tendencies associated with active ulceration or ongoing bleeding of the: gastrointestinal, genitourinary and respiratory tract; central nervous system hemorrhage; cerebral aneurysm, dissecting aneurysm of the aorta; pericarditis, pericardial effusion; bacterial endocarditis

Threat of abortion, eclampsia and preeclampsia

Unsupervised patients with an associated high risk of non-adherence to treatment

Spinal puncture and other diagnostic or therapeutic procedures with the risk of uncontrollable bleeding

Major lumbar or regional anesthesia

Malignant hypertension

St. John's wort (Hypericum Perforatum): Hypericum perforatum preparations should not be taken concomitantly with warfarin due to the risk of decreased plasma levels and decreased therapeutic efficacy of warfarin (see section 4.5 "Interactions with other medicinal products and other forms of interaction") .

04.4 Special warnings and appropriate precautions for use

Hemorrhage

COUMADIN can cause major or fatal bleeding. Bleeding is most likely to occur in the first month. Risk factors for bleeding include high anticoagulation intensity (INR> 4.0), age 65 years or more, history of high variability of INR values, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy , trauma, kidney damage, certain genetic factors and prolonged warfarin therapy.

In most patients, it appears that an INR greater than 4.0 does not provide additional therapeutic benefit and is associated with a higher bleeding risk.

Periodic INR determinations should be made in all patients on therapy. Patients at increased risk of bleeding may benefit from more frequent INR checks, careful dose adjustments to achieve the desired INR, and from a shorter duration of therapy, appropriate to the clinical condition.However, maintaining the INR in the therapeutic range does not eliminate the risk of bleeding.

Medicines, dietary changes and other factors may affect the INR levels achieved with COUMADIN therapy. The INR should be monitored more frequently in case of initiation or discontinuation of therapy with other drugs, including herbal medicines or in case of modification of dosages with other drugs (see section 4.5 "Interactions with other medicinal products and other forms of interaction").

Patients should be educated about measures to minimize the risk of bleeding and to report the signs and symptoms of bleeding.

A sharp increase (> 50 seconds) in activated partial thromboplastin time (APTT) with a PT / INR in the desired range was identified as an index of increased risk of postoperative bleeding.

Tissue necrosis

Necrosis and / or gangrene of the skin and other tissues is an uncommon but serious risk (amputation of the involved tissue, limb, breast, or penis.

A careful clinical evaluation is required to determine if necrosis is caused by a latent disease. Although several treatments have been tried, no therapy for necrosis has been considered uniformly effective. Treatment with COUMADIN should be discontinued in case of necrosis. anticoagulant therapy must be continued, alternative drugs should be considered.

Systemic atheroemboli and cholesterol microemboli

Anticoagulant therapy with COUMADIN may increase the release of atheromatous embolic plaques. Systemic atheroemboli and cholesterol microemboli can manifest with a series of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys, followed by the pancreas, spleen and liver. Some cases have resulted in necrosis or death. A distinctive syndrome of microemboli is the blue toe (foot) syndrome. Treatment with COUMADIN should be discontinued if such phenomena are observed. If continued anticoagulation therapy is required, alternative medications should be considered.

Heparin-induced thrombocytopenia

COUMADIN should not be used as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombotic syndrome (HITTS). Cases of limb ischaemia, necrosis and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy initiated or continued. In some patients, the consequences have led to amputation of the involved parts and / or death. Treatment with COUMADIN can be considered following normalization of the platelet count.

Other factors that may influence the response to COUMADIN therapy

Moderate to severe hepatic impairment

Infectious diseases or disorders in the intestinal flora (e.g. sprue, antibiotic therapy)

Use of fixed catheters

Deficit in the anticoagulant response mediated by protein C: COUMADIN reduces the synthesis of natural anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following administration of warfarin. Concomitant anticoagulant therapy with heparin for 5-7 days during the initiation of COUMADIN therapy may minimize the incidence of tissue necrosis in these patients. Warfarin therapy should be discontinued when there is a suspicion that it may be causing the development of necrosis and heparin anticoagulation should be considered.

Eye surgery: in cataract surgery, the use of COUMADIN was associated with a significant increase in minor complications due to needle or blockage of local anesthesia, but was not associated with operative bleeding complications potentially dangerous for the view. Since discontinuation or reduction of COUMADIN therapy can lead to severe thromboembolic complications, the decision to discontinue COUMADIN prior to less invasive and complex eye surgery, such as lens surgery, must be based on the risks of weighted anticoagulation therapy. towards the benefits.

True polycythemia

Vasculitis

Diabetes mellitus

Poor nutritional status

Vitamin K deficiency

Increased intake of vitamin K Hereditary resistance to warfarin

Patients with congestive heart failure may exhibit a greater than expected PT / INR, therefore more frequent laboratory checks and reduced doses of COUMADIN are required.

Ongoing treatment of dental and surgical operations

Certain dental or surgical procedures may require discontinuation or dose modification of COUMADIN therapy. Risks and risks should be considered.

benefits in case of interruption of therapy with COUMADIN, even for short periods. The INR should be determined immediately before any dental or surgical procedure. In patients undergoing minimally invasive procedures who need to be anticoagulated before, during or immediately after such procedures, a dose adjustment of COUMADIN in order to maintain the INR at the lowest level of the therapeutic range it can safely allow the maintenance of anticoagulation.

Pediatric population

No adequate and well controlled studies have been conducted in the pediatric population and the optimal dose, safety and efficacy in this population are not known.

Use in the elderly

Patients 60 years of age or older appear to show a greater than expected INR response to the anticoagulant effect of warfarin. Care should be taken when administering warfarin to elderly patients in any situation or physical condition where an added risk persists. low starting doses of warfarin are recommended for elderly patients.

Pharmacogenetics

Genetic variability in particular in relation to genes encoding CYP2C9 and VKORC1 proteins can significantly influence the dose of warfarin required to achieve the desired clinical effect. If an association with these polymorphisms is known, extreme caution should be exercised.

Important information about some of the ingredients:

This medicine contains lactose therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Numerous factors, alone or in combination, including changes in medications, herbal preparations, and diet, can affect the patient's response to anticoagulants, including warfarin.

Medicinal products can interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms. The pharmacodynamic mechanisms underlying the drug interactions with COUMADIN are synergism (reduced haemostasis, reduced synthesis of coagulation factors), competitive antagonism (vitamin K), alterations in the physiological control of vitamin K metabolism (hereditary resistance). The pharmacokinetic mechanisms to The basis of drug interactions with COUMADIN are predominantly due to enzyme induction, enzyme inhibition and reduced plasma protein binding It is important to note that some drugs may interact with COUMADIN by more than one mechanism.

PT / INR determinations should be made more frequently when initiating or discontinuing therapy with other drugs, including herbal preparations, or when changing the dosage of other drugs, herbal preparations, or if you change the dosage of other drugs, including drugs used for a short time (such as antibiotics, antifungals, corticosteroids).

In order to obtain further information on interactions with COUMADIN or adverse reactions related to bleeding, consult the product information of all drugs used concomitantly.

Interactions with CYP450

CYP450 isoenzymes involved in warfarin metabolism include CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4. The more potent S-enantiomer of warfarin is metabolised by CYP2C9, while the R-enantiomer is metabolised by CYP1A2 and 3A4.

CYP2C9, 1A2, and / or 3A4 inhibitors have the potential to enhance the effect (increase INR) of warfarin by increasing warfarin exposure.

Inducers of CYP2C9, 1A2, and / or 3A4 have the potential to decrease the effect (decrease in INR) of warfarin by decreasing exposure to warfarin.

Medicines that increase the risk of bleeding

Drugs belonging to specific classes known to increase the risk of bleeding are presented below.

As the risk of bleeding is increased when such medicinal products are co-administered with warfarin, patients receiving any of these medicinal products with COUMADIN should be closely monitored.

Anticoagulants

Antiplatelet agents

Thrombolytics

Non-steroidal anti-inflammatory drugs (NSAIDs)

Serotonin reuptake inhibitors

Antibiotics and antifungals

There have been reports of INR changes in patients receiving warfarin and antibiotics or antiphingins, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma warfarin concentrations. The INR should be monitored carefully when initiating o An antibiotic or antifungal is stopped in patients being treated with COUMADIN.

Broad-spectrum antibiotics can potentiate the effects of warfarin by reducing the intestinal flora that produces vitamin K.

Drugs affecting INR

Drugs that can interact with COUMADIN and cause an increase in INR values include:

Pharmacological class Specific Drug Reported Cardiovascular system Antiarrhythmics class Ia quinidine class Ic propafenone class III amiodarone Antihypertensive agents beta-blocking agents propanolol Antithrombotics antiplatelet agents thienopyridines prasugrel, ticlopidine glycoprotein IIb / IIIa antagonists abciximab, tirofiban anticoagulants heparinics heparin direct thrombin inhibitors argatroban, bivalirudin, desirudin, lepirudin thrombolytics streptokinase, alteplase Diuretics derivatives of aryloxyacetic acid ethacrynic acid, thienyl acid Peripheral vasodilators purine derivatives pentoxifylline Vasodilators benziodarone Lipid modifying agents bundles benzafibrate, clofibrate, ciprofibrate, fenofibrate, gemfibrozil HMG CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastine, simvastatin others ezetimibe Gastrointestinal system Antacids H2 receptor antagonists cimetidine, ranitidine proton pump inhibitors esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Cholelitholytics chenodiol Prokinetic agents cisapride Intestinal anti-inflammatory agents olsalazine Musculoskeletal system Antigout agents inhibitors of uric acid production allopurinol uricosurics benzbromarone, sulfinpyrazone Nervous system Antidepressants monoamine oxidase inhibitors desvenlafaxine, duloxetine, venlafaxine serotonin and norepinephrine reuptake inhibitors citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline selective serotonin reuptake inhibitors viloxazine, trazodone Antiepileptics derivatives of fatty acids valproic acid, valproate derivatives of hydantoin fosphenytoin, phenytoin Anti-Parkinson agents dopaminergic agents entacapone, tolcapone, ropinirole Anti dementia agents ginkgo biloba, memantine Central nervous system stimulants methylphenidate Hypnotics aldehydes and derivatives chloral hydrate derivatives of piperidindione glutethymide Respiratory System Treatments for obstructive airway diseases leukotriene receptor antagonists zafirlukast Cough suppressants opiate alkoloids and derivatives noscapina others oxolamine Endocrine system Corticosteroids glucocorticoids dexamethasone, methylprednisolone, prednisone Sex hormones estrogen tibolone antiestrogens tamoxifen, toremifene progestogens medroxyprogesterone, megestrol androgens testosterone antiandrogens bicalutamide, flutamide, nilutamide antigonadotropins danazol anabolic steroids metandienone, oxandrolone oxymethanolone, stanozolol Antidiabetics incretin-mimetic exenatide Hyperglycemic agents glucagon Thyroid therapies thyroid hormones levothyroxine, liothyronine, thyroid extracts antithyroid agents methimazole, propylthiouracil Genitourinary system Urinary antispasmodics tolterodine Drugs for benign prostatic hypertrophy alpha adrenoreceptor antagonists tamsulosin Immune system Selective immunosuppressants leflunomide Infections Antibacterials penicillins amoxicillin, benzylpenicillin, penicillin G, piperacillin, ticarcillin cephalosporins cefaclor, cefamandal, cefazolin, cefixime, cefotetan, cefonicid, cefotiam, cefoxitin, ceftriaxone, cefuroxime tetracyclines doxycycline, tetracycline, tigecycline macrolides azithromycin, clarithromycin, erythromycin, roxithromycin, telithromycin aminoglycosides neomycin quinolones ciprofloxacin, levofloxacin, nalidixic acid, moxifloxacin, norfloxacin, pefloxacin, ofloxacin sulfonamides sulfadoxine, sulfafurazole, sulfamethizole, sulfamethoxazole / trimethoprim, sulfisoxazole anti tuberculosis agents aminosalicylic acid, isoniazid amphenicol chloramphenicol glycoproteins vancomycin lincosamides clindamycin Antifungals derivatives of imidazole miconazole triazole derivatives econazole, fluconazole, ketoconazole, itraconazole, voriconazole Pesticides biguanides proguanil derivatives of nitroimidazole metronidazole, nimorazole, tinidazole methanolquinolones quinine Antivirals non-nucleoside reverse transcriptase inhibitors delavirdine, efavirenz, etravirine, nevirapine protease inhibitors atazanavir, ritonavir Inflammation and pain Analgesics anilides acetaminophen (paracetamol) salicylic acid and derivatives aspirin (acetylsalicylic acid), diflunisal opioids propoxyphene, tramadol Non-steroidal anti-inflammatory drugs derivatives of acetic acid diclofenac, indomethacin, ketorolac, sulindac derivatives of propionic acid phenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin coxib celecoxib, etoricoxib, lumiracoxib, rofecoxib fenamati mefenamic acid, meclophenamic acid oxicam lornoxicam, piroxicam others glucosamine Antineoplastics Alkylating agents analogues of nitrogen mustard cyclophosphamide, ifosfamide, platinum derivatives carboplatin Antimetabolites pyrimidine analogs capecitabine, fluorouracil, tegafur Microtubule inhibitors taxans paclitaxel Monoclonal antibodies trastuzumab Topoisomerase inhibitors etoposide Tyrosine kinase inhibitors erlotinib, gefitinib, imatinib, sorafenib Others romidepsin, vorinostat Vaccines flu shot Vitamins Vitamin E Others alcohol, benzethonium chloride, disulfiram, methyl salicylate ointment, trolamine salicylate ointment, orlistat

Drugs that can interact with COUMADIN and cause a decrease in INR values include:

Pharmacological class Specific Drug Reported Cardiovascular system Antiarrhythmics class Ia disopyramide Diuretics aldosterone antagonists spironolactone sulfonamides chlorthalidone Lipid modifying agents sequestrants of bile acids colesevelam, cholestyramine Pulmonary artery antihypertensive agents bosentan Others ubiquinone (ubidecarenone) Gastrointestinal system Antacids H2 receptor antagonists ranitidine others sucralfate Antiemetics antagonists of NK1 aprepitant, fosaprepitant Nervous system Antidepressants others trazodone Antiepileptics barbiturates and derivatives phenobarbital, primidone carboxymides carbamazepine hydantoins phenytoin Antipsychotics butyrophenones haloperidol Anxiolytics benzodiazepines chlordiazepoxide Hypnotics barbiturates butobarbital, pentobarbital, secobarbital Endocrine system Corticosteroids glucocorticoids cortisone, prednisone Sex hormones oral contraceptives oral contraceptives containing estrogen selective estrogen modulators lasofoxifene, raloxifene Thyroid therapies antithyroid agents methimazole, propylthiouracil Pituitary hormones ACTH corticotropin Enzyme inhibitors aminoglutethimide Immune system Immunostimulants interferons peginterferon alfa-2b Immunosuppressants calcineurin inhibitors cyclosporine others azathioprine Infections Antibacterials penicillins dicloxacillin, nafcillin anti-tuberculosis agents rifampicin, rifapentine Antifungals antibiotics griseofulvin Antivirals nucleosides and nucleotides ribavirin non-nucleoside reverse transcriptase inhibitors efavirenz, nevirapine protease inhibitors darunavir, ritonavir Inflammation and pain Non-steroidal anti-inflammatory drugs others glucosamine Antineoplastics Alkylating agents cyclophosphamide Antimetabolites mercaptopurine Others mitotane Vitamins C vitamin vitamin K Others alcohol, etretinate, isotretinoin

Herbal preparations and foods

Care should be taken when herbal preparations are taken together with COUMADIN. There are few adequate and well-controlled studies evaluating the potential for metabolic and / or drug interactions between herbal preparations and COUMADIN. Due to the lack of standardization of the production of herbal medicines, the amount of active substance may vary.This could further confuse the ability to evaluate potential interactions and effects on anticoagulant action.

Some herbal preparations can cause bleeding when taken alone (for example, garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet and / or fibrinolytic properties. These effects are expected to be additive to the anticoagulant effects of COUMADIN. . Conversely, some herbal products may decrease the effect of COUMADIN (eg coenzyme Q10, St. John's wort, ginseng). Some herbal preparations and foods may interact with COUMADIN through interactions with CYP450 (for example, echinacea, grapefruit juice, ginko, hydraste, St. John's wort).

The patient's response should be monitored with further INR determinations if any herbal preparation is started or stopped.

Some herbal preparations that can affect clotting are listed below for reference, although this list should not be considered exhaustive. Many herbal preparations have several common names and scientific names. The most widely known common names of herbal preparations are given below.

Herbal preparations that contain coumarins with a potential anticoagulant effect Agrimoniaa Celery Passionflower Chinese angelica (Angelica sinensis) Chamomile (German and Roman) Thorny ash (northern) Anise Dandelion cod Quassia Arnica Fenugreek Red clover Asafoetida (Ferula assafoetida) Horse chestnut Sweet clover Water clover (Menyanthes trifoliata) b Horseradish Woodruff (Asperula odorata) Boldo Licoriced Dipteryx odorata Buchu (Agathosma Betulina) Meadowsweet (Filipendula ulmaria) b Capsicoc Nettle Cassiad Various herbal preparations with anticoagulant properties Fucus vesiculosus Pau d "Arco Herbal preparations that contain salicylates and / or have antiplatelet properties Agrimoniaa Cranberry Meadowsweet (Filipendula ulmaria) b Aspen tree Dandelion cod Policosanol Black Cohosh rubifolia Feverfew (Tanacetum parthenium) Tamarind Water clover (Menyanthes trifoliata) b Garlic and Willow Cassiad Ginger Canada tea Clove Ginko biloba a thousand leaves Ginseng (Panax spp) e Licoriced Herbal preparations with fibrinolytic properties Bromelain Garlic and Capsicoc Ginseng (Panax spp) e Salvia miltiorrhiza Herbal preparations with coagulating properties Alpha-alpha (Medicago sativa) Green vegetables (broccoli, kale, spinach, turnip greens and Brussels sprouts) St. John's wort (Hypericum perforatum) Agrimoniaa

a Contains coumarins, has antiplatelet properties, and may have coagulating properties due to the possible content of vitamin K.

b Contains coumarins and salicylates.

c Contains coumarins and has fibrinolytic properties.

d Contains coumarins and has antiplatelet properties.

e It has antiplatelet and fibrinolytic properties.

The therapeutic efficacy of warfarin could be reduced by the simultaneous administration of preparations based on St. John's wort (Hypericum perforatum). This is due to the induction of the enzymes responsible for the metabolism of drugs by these preparations which therefore must not be administered concomitantly with warfarin. The induction effect may persist for at least 2 weeks after stopping treatment with Hypericum perforatum products.

If a patient is taking Hypericum perforatum products concomitantly with warfarin, the INR values should be monitored and therapy with the latter should be discontinued.

Monitor INR values closely, as they may increase after stopping Hypericum perforatum. The warfarin dosage may need to be adjusted.

04.6 Pregnancy and lactation

Pregnancy

COUMADIN is contraindicated in pregnancy in women who are pregnant or may become pregnant as the drug crosses the placental barrier and may cause fatal fetal bleeding into the uterus (see section 4.3 "Contraindications").

Cases of congenital malformations have also been reported in children whose mothers were treated with warfarin during pregnancy. Exposure to COUMADIN during pregnancy causes a known series of major congenital malformations (warfarin embryopathy and fetotoxicity), fetal haemorrhage , and an increased risk of miscarriage and fetal mortality. The effects of COUMADIN on reproduction and development have not been evaluated in animals. If this medicine is used during pregnancy, or if a patient becomes pregnant while taking this medicine. medicine, the patient should be informed of the potential risks to the fetus.

In humans, warfarin crosses the placenta and fetal plasma concentrations approach maternal values. Warfarin exposure during the first trimester of pregnancy caused a series of congenital malformations in approximately 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without pointed epiphyses (punctate chrondrodysplasia) and growth retardation (including low birth weight). dorsal median, characterized by agenesis of the corpus callosum; Dandy-Walker malformation, cerebellar midline atrophy and ventral midline dysplasia, characterized by optic atrophy. Warfarin exposure during the second and third trimesters has been associated with mental retardation, blindness, schizoencephaly, microcephaly, hydrocephalus and other adverse pregnancy outcomes.

Feeding time

Based on published data on 15 lactating mothers, warfarin was not detected in human milk. Among the 15 infants born at term, 6 nursing infants showed prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects on preterm infants have not been evaluated.

Therefore, caution should be exercised when COUMADIN is administered to breastfeeding women as the risk to the newborns / infants cannot be excluded. It is advisable to check the coagulation parameters of the newborn and to monitor for bruises and bleeding.

04.7 Effects on ability to drive and use machines

COUMADIN has no or negligible influence on the ability to drive or use machines

04.8 Undesirable effects

The following serious adverse reactions have been reported with COUMADIN:

Hemorrhage

Haemorrhage, from minor to severe bleeding (including fatal outcomes), may occur during therapy with COUMADIN. The bleeding can take place in any tissue or organ, and can manifest as internal or external bleeding with associated symptoms and complications.

Typically, the following body systems can be affected:

upper gastrointestinal tract (gingival bleeding, haematemesis) or lower (melaena, hematochezia, rectal bleeding)

Retroperitoneal hemorrhage may also occur.

respiratory tract (epistaxis, haemoptysis), including rare cases of pulmonary alveolar haemorrhage

genitourinary tract (haematuria, vaginal bleeding, menorrhagia)

skin (contusion, bruising and petechiae)

Central nervous system haemorrhage may also occur, including intracranial haemorrhage or vertebral hematoma, ocular haemorrhage, intra-articular haemorrhage, pleural haemorrhage, pericardial haemorrhage, adrenal haemorrhage, and hepatic haemorrhage.

Some bleeding complications may present as signs and symptoms that are not immediately identified as resulting from bleeding. These adverse reactions are marked in the table below with an asterisk (*).

Necrosis of the skin and other tissues

Systemic atheroemboli and cholesterol microemboli

The following adverse reactions have been reported from post-marketing experience with warfarin. As these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequencies.

Adverse reactions are listed in the following table by system organ class, MedDRA terminology and frequency.

Frequencies are defined as: very common (ge; 1/10); common (ge; 1/100,

System and organ classification Frequency MedDRA Term Disorders of the blood and lymphatic system Not known Anemia* Cardiac pathologies Not known Chest pain *, pericardial haemorrhage Endocrine pathologies Not known Adrenal hemorrhage Eye disorders Not known Ocular haemorrhage Gastrointestinal disorders Not known Abdominal distension, abdominal pain *, diarrhea, dysgeusia, dysphagia *, flatulence, gingival bleeding, haematemesis, haematochezia, melaena, nausea, rectal haemorrhage, retroperitoneal haemorrhage, vomiting General disorders and administration site conditions Not known Asthenia *, chills, fatigue *, malaise *, pain *, paleness *, swelling *, pyrexia Hepatobiliary disorders Not known Hepatic haemorrhage, hepatitis, jaundice Disorders of the immune system Not known Anaphylactic reaction, hypersensitivity Diagnostic tests Not known Hepatic enzyme increased Musculoskeletal and connective tissue disorders Not known Arthralgia *, haemarthrosis, myalgia * Nervous system disorders Not known Dizziness *, headache *, intracranial haemorrhage, paraesthesia *, paralysis *, vertebral hematoma Psychiatric disorders Not known Lethargy * Renal and urinary disorders Not known Hematuria Diseases of the reproductive system and breast Not known Menorrhagia, vaginal bleeding Respiratory, thoracic and mediastinal disorders Not known Epistaxis, dyspnoea *, hemoptysis, hemothorax, pulmonary alveolar haemorrhage, lung calcification Skin and subcutaneous tissue disorders Not known Alopecia, dermatitis, bullous dermatitis, ecchymosis, petechiae, pruritus, rash, skin necrosis, urticaria Vascular pathologies Not known Blue toe (foot) syndrome *, arterial embolism, fat embolism, haemorrhage, hypotension *, necrosis, shock *, syncope *, vasculitis

* Medical symptoms or conditions resulting from bleeding complications.

Laboratory results

Changes in hemoglobin levels, hematocrit and hepatobiliary enzymes may occur.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse

04.9 Overdose

Signs and symptoms: Suspected or manifest abnormal bleeding (eg, blood in stool or urine, hematuria, excessive menstrual flow, melaena, petechiae, bruising, or persistent bleeding from superficial wounds) is an early sign of a " anticoagulation to an unsatisfactory level of safety.

Treatment: Excessive anticoagulation, with or without bleeding, can be controlled by discontinuing COUMADIN therapy and, if necessary, by administering 1-2 mg of vitamin K1 (phytomenadione) parenterally or orally. Such use of vitamin K 1 reduces response to subsequent COUMADIN therapy. Following rapid reversal of an elevated PT / INR, patients may return to the thrombotic state they had before treatment. Resuming COUMADIN dosing reverses the effect of vitamin K, and, with careful dosage adjustments, a therapeutic PT / INR can be achieved again. If rapid anticoagulation is indicated, heparin may be preferable for initiation therapy.

If a small bleeding progresses to a larger one, give 5 to 25 mg (rarely up to 50 mg) of vitamin K1 parenterally.

In emergency situations due to severe bleeding, clotting factors can be restored to normal levels by administering 15 mg / kg of fresh whole blood or fresh frozen plasma, or by administering 30-50 units / kg prothrombin complex concentrate.

The use of blood products is associated with the risk of hepatitis and other viral diseases and with an increased risk of thrombosis. Therefore, the use of these preparations should be reserved only in case of extensive bleeding, due to an overdose of COUMADIN, which danger the patient's life.

Purified factor IX preparations should not be used because they do not increase the levels of prothrombin and factor VII and X, which are depressed, together with factor IX, as a result of treatment with COUMADIN. In case of conspicuous blood loss, massed erythrocytes can be administered. In elderly patients or patients with heart disease, blood or plasma transfusions should be carefully monitored to avoid precipitating a "pulmonary embolism."

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agent - Vitamin K antagonist ATC code: B01AA03

The active ingredient of COUMADIN (warfarin sodium) is the sodium salt of 3 - (- acetonylbenzyl) -4-hydroxycoumarin and belongs to the group of indirect dicumarolic anticoagulants.

COUMADIN and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent coagulation factors, which include Factors II, VII, IX and X and anticoagulant proteins C and S. The half-lives are: Factor II 60 hours; Factor VII 4-6 hours; Factor IX 24 hours; Factor X 48-72 hours; Protein C 8 hours and Protein S 30 hours. The resulting effect in vivo is a sequential depression of Factor VII, IX, X and II activity. Vitamin K is an essential factor for the post-ribosomal synthesis of vitamin K dependent coagulation factors. Vitamin K promotes the biosynthesis of carboxyglutamic acid residues, essential for the biological activity of proteins. Warfarin is thought to interfere with the synthesis of clotting factors by inhibiting the regeneration of vitamin K1 epoxide. The degree of depression depends on the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor by 30 to 50%.

The anticoagulant effect generally appears within 24 hours after drug administration, but the peak anticoagulant effect may also occur after 72-96 hours. The duration of action of a single dose of racemic warfarin is 2-5 days.

The drug has no direct effect on stabilized thrombosis, nor does it reverse ischemic damage; however, when thrombosis has occurred, the goal of anticoagulant treatment is to prevent further extension and related complications, which can lead to serious, even fatal consequences.

05.2 Pharmacokinetic properties

COUMADIN is a racemic mixture of the R and S enantiomers. In humans, the S enanatiomer has an anticoagunate activity 5 times greater than the R enantiomer, but generally has a faster clerance.

After oral administration, absorption is substantially complete and maximum plasma concentrations are reached within 1-9 hours. Approximately 97% is bound to plasma albumin. COUMADIN usually induces hypoprothrombinemia within 36-72 hours and its duration of action may persist for 4-5 days, thereby producing a smooth and long-lasting response curve.

Up to 92% of the orally administered dose is recovered in the urine, mainly in the form of metabolites.