iMeds.se

Warfarin Orion

Document: Warfarin Orion tablet ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCT


Warfarin Orion 2.5 mg tablets


2. QUALITATIVE AND QUANTITATIVE COMPOSITION


1 tablet contains 2.5 mg warfarin sodium.


Excipients with known effect: lactose 51.4 mg/tablet


For a full list of excipients, see section 6.1.


3. PHARMACEUTICAL form


Tablet


White to off-white, round biconvex tablet, 7 mm in diameter and with a cross-line on one side.


The tablet can be divided into equal doses.


4. Clinical particulars


4.1 Therapeutic indications



4.2 Posology and method of administration


Posology:

Warfarin Orion is absorbed rapidly and completely. The same dose can therefore be administered orally, parenterally or intravenously.


Initial dose: Day 1 and 2: 3(24) Warfarin Orion 2.5 mg tablets (7.5 mg (510 mg)), depending on patient’s weight, age and overall health, etc. Day 3: Preliminary maintenance dose, based on the effect of the initial dose on the coagulative activity (International Normalized Ratio, INR value) on day 3.


For patients with no need for a rapid treatment effect, e.g. when there is no concomitant treatment with heparin or low-molecular-weight heparin, it is possible to initiate with the estimated maintenance dose and to first check the INR value on days 34. This helps to avoid possible hypercoagulation, which can appear during the adjustment phase because of an imbalance between pro- and anticoagulation factors.


Maintenance dose: The maintenance dose is normally 14 tablets (2.510 mg) daily, but individual differences are large (dose can vary from less than ½ a tablet to 10 tablets in some patients).


The entire daily dose should be taken at one time and at the same time every day. Dosage boxes (pill organizers) may be useful. Effective prevention of thrombosis is generally only achieved after 5 days of treatment, provided the INR value has reached the recommended therapeutic level.


Managing anticoagulation treatment

Sensitivity to Warfarin Orion varies from person to person and even within the same patient. Therefore the treatment intensity should be checked on a regular basis. This is done by measuring prothrombin complex (PC) levels in blood samples, and the value is expressed as the International Normalized Ratio (INR), with a normal value of 1.0. Sensitivity to Warfarin Orion increases with age and lower body weight. Some patients may have increased sensitivity because of acquired causes such as pronounced heart failure or impaired hepatic function (see 4.3 and 5.2) or concomitant drug treatments (see 4.5).


INR values are checked every day to every other day during the first week, and subsequently once or twice a week until the patient is on the maintenance dose. Once a stable level is achieved, the interval between checks can often be extended to 46 weeks or sometimes longer periods.


Therapeutic levels of INR

For patients with venous thrombosis, pulmonary embolism, atrial fibrillation, secondary prophylaxis after myocardial infarction in combination with acetylsalicylic acid, and for patients with a later model of a prosthetic mechanical aortic valve, the recommended target value is INR 2.5 (± 0.5).


For patients with a prosthetic mechanical mitral valve or a double prosthetic valve, patients with failures at normal treatment intensity, and after myocardial infarction, a higher intensity, equivalent to a target value of INR 3.0 (± 0.5), may be recommended.

It should be pointed out that the above therapeutic areas are only general outlines and should be modified depending on the condition being treated, the degree of relative contraindications, local treatment guidelines, and the patient’s ability to cooperate.


Combination with heparin

In acute cases, it is recommended that Warfarin Orion be combined with heparin or low-molecular-weight heparin to ensure a rapid anticoagulation effect. INR should be therapeutic for at least 2 days before discontinuation of heparin, unfractionated or low-molecular-weight heparin.


A treatment card, patient information and a Warfarin Orion tag to wear can be requested from Orion Pharma.


Paediatric population

Data from controlled clinical trials are very limited. The initial dose is 0.10.2 mg/kg per day for children with normal hepatic function, which is then adjusted based on INR values. The maintenance dose is dependent on age and reduces with increasing age from < 1 year to 1118 years.


Treatment with Warfarin Orion is not recommended for newborns on account of the risk of simultaneous vitamin K deficiency. There is no definitive therapeutic INR range for younger children. In practice, therapeutic values for adults have been used, with a target value of INR 2.5 (± 0.5). Treatment of children, and especially small children, requires specialist knowledge.


Elderly

Elderly patients require lower doses than younger adults. The initial dose should be 2 (13) Warfarin Orion 2.5 mg tablets (5 mg (2.57.5 mg)), which is then adjusted based on INR values. Warfarin pharmacokinetics is unaffected by age. The reduced dose requirement is due to pharmacodynamic changes.


Impaired renal function: Patient with impaired renal function, depending on the comorbidity, may require lower or higher dose of Warfarin Orion (see 4.4 and 5.2).


Impaired hepatic function: Patients with impaired hepatic function may need lower dose of Warfarin Orion. Impaired hepatic function can enhance the effect of warfarin through inhibited synthesis of clotting factors and reduced metabolism of warfarin (see 4.3 and 4.4).


Patients with genetically abnormal enzyme types

Substantially deviating INR response may be due to genetic factors, particularly genetic reduction of the activity of the enzyme CYP2C9 and increased susceptibility of VKOR (the pharmacological target of warfarin) to the inhibition of warfarin.


Patients with the alleles CYP2C9*2 or CYP2C9*3 in the enzyme CYP2C9 have reduced metabolism of (S)-warfarin and may therefore require lower initial and maintenance doses (see sections 4.4, 4.8, 5.1 and 5.2). A meta-analysis showed that the average daily dose of warfarin was 20% lower in patients with a CYP2C9*2 allele and 34% lower in those with a CYP2C9*3 allele. Patients with two of these genes (homozygotes) needed a dose reduction of 36% and 78%, respectively. It can also take longer to reach steady state for warfarin and its therapeutic effect.

Also genetic differences in the gene VKORC1 that encodes the vitamin K epoxide reductase enzyme, the target of warfarin, have been shown to influence the dose requirement by increasing the sensibility to warfarin. In studies, a factor of approximately two has been reported for the difference between the highest and lowest average dose for different haplotype groups. Caucasians are relatively evenly distributed between the groups, while Asians mostly have genes that require a reduced dose.

Genotyping may be considered when treating particularly sensitive patients for whom it is particularly important to avoid an excessive anticoagulative effect.


4.3 Contraindications


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

First trimester and last four weeks of pregnancy (see also section 4.6)


Warfarin is contraindicated in patients with an increased risk of bleeding:


4.4 Special warnings and precautions for use


If a rapid antithrombotic effect is needed, heparin treatment must be initiated first. 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 section 4.2) for at least two days.


There is a large risk for interactions when warfarin is used concomitantly with other drugs. An intensified monitoring of the therapeutic response to warfarin is therefore recommended when treatment with other drugs is initiated or withdrawn during warfarin treatment (see section 4.5).


Elimination of warfarin is slower in patients with certain mutations in the gene for the enzyme CYP2C9 metabolising (S)-warfarin. These patients only require a low maintenance dose and have a risk of excessive bleeding if a high initial dose is given. In addition, it will take longer to achieve the new efficacy level after adjusting the dose. Also patients with genetic variations of the enzyme VKOR may require lower doses due to increased sensitivity to warfarin (see sections 4.2, 5.1 and 5.2).


Resistance to warfarin is a very rare phenomenon. Only 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 poor, other more plausible causes should be ruled out: patient incompliance, interaction with other medicaments or food, and also laboratory errors.


To avoid coumarin necrosis (see section 4.8) patients with a hereditary deficiency of antithrombotic protein C or S must first be treated with heparin. Concomitantly initiating warfarin loading doses must not exceed 5 mg. Heparin treatment must be continued for 5 to 7 days as described in previous paragraph.


Special caution must be exercised when treating elderly patients. The patient compliance and the capabilities of following strict rules on dosage must be ascertained. Hepatic metabolism of warfarin, as well as the synthesis of clotting factors, is slowed down in the elderly. This may easily result in an excessive warfarin effect. Treatment must be initiated cautiously (see section 4.2).

Tooth extractions can usually be carried out at INR 22.2. In other surgical procedures, caution should be observed and the INR should be adjusted to a level suitable for the procedure.


Drastic changes in dietary habits should be avoided as the amount of vitamin K in food may affect therapy with warfarin. Conditions which may affect therapy are transition to a vegetarian diet, extreme dieting, depression, vomiting, diarrhea, steatorrhea or malabsorption of other causes.


If bleeding occurs during warfarin treatment, regardless of the current INR level, local causes should be suspected. Bleeding from the gastrointestinal tract could be due to ulcer or tumor and bleeding from the urogenital tract could be caused by tumor or infection.


Hyperthyreosis, fever and uncompensated cardiac insufficiency may enhance the warfarin effect. In hypothyreosis 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, which depending on the comorbidity of the patient may lead to either enhanced or reduced warfarin effect. The clinical situation of the patient and the INR values must be carefully monitored under all these circumstances.


Due to local or regional treatment recommendations and different bioanalytical methods, there may be variations in therapeutic INR.


Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality. The condition is mainly observed in patients with end-stage renal disease on dialysis or in patients with known risk factors such as protein C or S deficiency, hyperphosphataemia, hypercalcaemia or hypoalbuminaemia. Rare cases of calciphylaxis have been reported in patients taking warfarin, also in the absence of renal disease. In case calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with warfarin.


The tablets contain lactose (see section 2). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.


4.5 Interaction with other medicinal products and other forms of interaction


Warfarin is a mixture of enantiomers. (R)-warfarin is metabolised primarily by CYP1A2 and CYP3A4. (S)-warfarin is metabolised primarily by CYP2C9.


Drugs that compete as substrates for these cytochromes or inhibit their activity may increase warfarin plasma concentrations and INR, potentially increasing the risk of bleeding. When these drugs are co-administered, warfarin dosage may need to be reduced and the level of monitoring increased.


Conversely, drugs which induce these metabolic pathways may decrease warfarin plasma concentrations and INR, potentially leading to reduced efficacy. When these drugs are co-administered, warfarin dosage may need to be increased and the level of monitoring increased.


The following table gives some guidance about the expected effect of other medical products on warfarin.


Interacting drug

Effect of initiation

Effect of withdrawal*

Inducers of CYP1A2, CYP2C9 or CYP3A4

Decreased warfarin plasma concentrations with risk for subtherapeutic treatment.

Increased warfarin plasma concentrations with risk for supratherapeutic treatment.

Inhibitors (substrates) of CYP1A2, CYP2C9 or CYP3A4

Increased warfarin plasma concentrations with risk for supratherapeutic treatment.

Decreased warfarin plasma concentrations with risk for subtherapeutic treatment.

* For substances that act as inducers, the effect can persist for several weeks after withdrawal.


Absorption or enterohepatic recirculation of warfarin may be affected by some medications, e.g. colestyramine. Induction (e.g. antiepileptics or antituberculotics) or inhibition (e.g. amiodarone or metronidazole) of the hepatic metabolism of warfarin can take place. Cessation of induction or inhibition has to be taken into account as well.


Warfarin can be displaced from the plasma protein bonds, which increases the free fraction and, unless the patient has hepatic failure, the metabolism and elimination of warfarin are enhanced leading to a reduced effect.


Medications affecting the platelets and primary hemostasis (e.g. acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, and most of the non-steroidal anti-inflammatory drugs) may result in a pharmacodynamic interaction and predispose the patient for severe bleeding complications. Penicillins in large doses have the same effect on primary hemostasis.


Anabolic steroids, azapropazone, erythromycin, and some cephalosporins reduce directly the vitamin K dependent synthesis of the clotting factors and potentiate the warfarin effect. An ample supply of dietary vitamin K reduces the warfarin effect. Reduced absorption of vitamin K due to e.g. diarrhoea may potentiate the warfarin effect. Patients with inadequate supply of foodstuffs containing vitamin K are dependent on vitamin K2 produced by the intestinal bacteria. In these patients, many antibiotics may reduce the synthesis of vitamin K2, leading to an enhanced warfarin effect. Heavy use of alcohol with concomitant hepatic failure potentiates the warfarin effect. 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 temporary relief of pain while on warfarin, the recommended medications are paracetamol or opioids.


Warfarin may potentiate the effect of oral sulphonylurea antidiabetics.


Following medications have been reported to change the warfarin effect:


Increased effect:


All non-steroidal anti-inflammatory agents (NSAIDs) and anticoagulants


Analgesics: Dexstropropoxyphene, paracetamol (the effect evident after 1 to 2 weeks of continuous use), tramadol


Antiarrhythmics: Amiodarone, propafenone, quinidine


Antibacterials: Amoxicillin, azithromycin, cefalexin, cefamandole, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, chloramphenicol, ciprofloxacin, clarithromycin, clindamycin, doxicycline, erythromycin, gatifloxacin, grepafloxacin, isoniazid, latamoxef, levofloxacin, metronidazole, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, roxithromycin, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfaphenazole, tetracycline


Antifungals: Fluconazole, itraconazole, ketoconazole, miconazole (also oral gel)


Antigout drugs: Allopurinol, sulfinpyrazone


Antineoplastic and immunomodulating agents: Cabecitabine, cyclophosphamide, etoposide, fluorouracil, flutamide, ifosfamide, leflunomide, mesna, methotrexate, sulofenur, tamoxifen, tegafur, trastuzumab


Cardiovascular drugs: Digoxin, metolazone, propranolol


Gastrointestinal drugs: Cimetidine, omeprazole


Lipid regulating drugs: Bezafibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, lovastatin, simvastatin


Vitamins: Vitamin A, vitamin E


Others: Carboxyuridine, chloral hydrate, codeine, disulfiram, ethacrynic acid, fluvoxamine, influenza vaccine, interferon alpha and beta, phenytoin, proguanil, quinine, (anabolic and androgenic) steroid hormones, thyroid hormones, troglitazone, valproic acid, zafirlukast


There are reports suggesting that noscapine as well as glucosamine with or without chondroitin sulphate may increase the INR in patients on warfarin.


Decreased effect:


Antibacterials: Cloxacillin, dicloxacillin, flucloxacilline, nafcillin, rifampicin


Antiepileptics: Carbamazepine, phenobarbital, primidone


Antineoplastic and immunomodulating agents: Azathioprine, ciclosporin, mercaptopurine, mitotane


Anxiolytic sedatives, hypnotics, and antipsychotics: Barbiturates, chlordiazepoxide


Diuretics: Chlortalidone, spironolactone


Others: Aminoglutethimide, colestyramine, disopyramide, griseofulvin, mesalazine, nevirapine, trazodone, vitamin C


Herbal medications 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 elimination), or reduce it, e.g. ginseng (Panax spp.). The effect of warfarin can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolizing enzymes by St. John’s wort. Herbal preparations 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.


Smoking may increase warfarin clearance, and smokers may require slightly higher doses than nonsmokers. On the other hand, smoking cessation may enhance warfarin effects. Therefore, it is necessary to monitor INR closely when a chronic smoker undergoes smoking cessation.


4.6 Fertility, pregnancy and lactation


Pregnancy

Warfarin crosses the placenta. Warfarin is contraindicated during the first trimester as teratogenic effects (fetal warfarin-syndrome and CNS-malformations) have been reported with use during early pregnancy. Fetal warfarin syndrome is characterized by nasal hypoplasia, stippling in the epiphyseal regions, limb hypoplasia, optic atrophy, microcephaly, mental and growth retardation, as well as cataract that could lead to total or partial blindness. Use of warfarin is also contraindicated during the last four weeks of pregnancy as coumarin-derivatives have been associated with an increased risk of maternal and fetal bleeding, and fetal lethality especially during delivery. If possible, warfarin should be avoided during the whole period of pregnancy.


In special circumstances treatment may be considered by specialist clinician.


Breastfeeding

Warfarin is not excreted in the breast milk. Breastfeeding can be continued during warfarin treatment.


4.7 Effects on ability to drive and use machines


Warfarin Orion has no or negligible influence on the ability to drive and use machines.


4.8 Undesirable effects


Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥ 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

Common

Rare

Very rare

Not known

Vascular disorders

Bleeding

Coumarin necrosis, purple toe -syndrome

Vasculitis

Respiratory, thoracic and mediastinal disorders

Tracheal calcification

Gastrointestinal disorders

Nausea, vomiting, diarrhoea


Hepatobiliary disorders

Reversible hepatic enzyme elevation, cholestatic hepatitis

Skin and subcutaneous tissue disorders

Reversible alopecia, rash

Calciphylaxis

Reproductive system disorders, male

Priapism

General disorders and administration site conditions

Allergic reactions (manifested usually as skin rash)

Investigations

Cholesterol embolism

Commonly reported (110 %) 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 bleedings (6 % per year), severe bleedings (1 % per year) and fatal (0.25 % 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 exists another comorbid condition which should be investigated.


Coumarin necrosis 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 of warfarin treatment, and the aetiology involves a relative deficiency of antithrombotic proteins C and S. Hereditary deficiency of these proteins may predispose to the complication. For this reason, the warfarin treatment in these patients must be initiated concomitantly with heparin and using small initial doses of warfarin. If the complication occurs, warfarin treatment must be discontinued and heparin treatment must be continued until the lesions heal or become scarred.


Purple toe syndrome is an even more rare complication of warfarin treatment. Patients are usually male and typically have an arteriosclerotic disease. Symmetric purple lesions of skin in toes and soles occur and the lesions are associated with burning pain. Warfarin treatment must be discontinued and the skin lesions usually slowly disappear.


Persons with genetic variations of the polymorphic enzymes CYP2C9 and VKOR (see section 4.2, 4.4, 5.1 and 5.2) resulting in increased susceptibility for warfarin have an increased risk for excessive anticoagulative effect of warfarin treatment, which can increase the risk of bleeding complications. Haemoglobin levels and INR must be monitored carefully.


Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via [to be completed nationally].


4.9 Overdose


Toxicity data are contradictory. A potentially toxic dose for children is 0.5 mg/kg. The lowest reported lethal dose for adults is 615 mg/kg.


Symptoms: All symptoms are due to disturbance of coagulation. Symptoms of bleeding from almost any organ are possible. Sometimes the only finding is pathological laboratory data. In some cases symptoms are minor bleedings such as mucous membrane bleeding, haematuria. Pronounced poisoning may lead to e.g., haemoptysis, haematemesis, melaena, petechiae, ecchymoses, intracranial haemorrhage, haemorrhagic shock.


Treatment: If justified gastric lavage and charcoal may be used. INR is monitored repeatedly for several days. Based on coagulation tests and clinical symptoms, 10 mg vitamin K is given intravenously 14 times/day (half the dose for children under 12 years). In the event of severe poisoning, higher doses of vitamin K are given, and, in the event of severe bleeding, supplementation with clotting factors in the form of plasma (preferably freshly frozen) or clotting factor concentrate (prothrombin complex concentrate), and possibly tranexamic acid. Always discuss cases with local haematologist or poison center if in doubt. Only clotting factors (and not vitamin K) are given to patients receiving anticoagulant therapy and where a complete reversal is not desirable.


The half-life for warfarin is 2055 hours. Overdoses thus require prolonged observation and treatment with vitamin K. The table below suggests measures for treatment of overdose:

Clinical situation

Dose adjustment/other treatment

No bleeding, INR > 4

Wait 1 day. Adjust the dose.

No bleeding, INR > 6

Wait 12 days. Adjust the dose.

New check quickly.

No bleeding, INR > 8

Consider vitamin K. 12 mg s.c., i.v. or orally.

Wait 2 days. Check next day. Adjust the dose.

Minor bleeding

Wait with warfarin 12 days. Possibly vitamin K as per above.

Severe bleeding

Reduce INR quickly to 1.51.6.


10 ml/kg fresh frozen plasma is estimated to reduce INR from 7 to 4 or 4 to 2.2. One unit of coagulation factor concentrate is equivalent to 1 ml plasma. The effect is instantaneous, but diminishes after 6 hours. If the effect of warfarin can be suspended, 510 mg vitamin K (i.v.) is administered concomitantly with plasma/coagulation factor concentrate. A lower dose of vitamin K (25 mg) is given, if it is expected that treatment with warfarin will continue. It takes 612 hours until the vitamin K is effective, with peak effect after 24 hours.

Intoxication/poisoning

If bleeding, see above.

10 mg vitamin K 34 times daily until the effect of warfarin is estimated to be eliminated. Treatment may be required for several days.

5. PHARMACOLOGICAL PROPERTIES


5.1 Pharmacodynamic properties


Pharmacotherapeutic group: Anticoagulant.

ATC-code: B01AA03.


Warfarin Orion contains warfarin sodium, which is a synthetic coumarin anticoagulant. Warfarin sodium is a readily soluble salt and differs from other preparations in this group because it can be given orally and parenterally.


Warfarin induces an anticoagulative effect by competitively blocking (vitamin K epoxide reductase and vitamin K reductase) the reduction of vitamin K and its 2,3-epoxide to vitamin KH2. Vitamin KH2 is required in order for some vitamin K-dependent coagulation proteins (prothrombin factor VII, IX and X) to be able to be carboxylated with gamma glutamic acid and thus become coagulatively active. The naturally occurring vitamin K-dependent coagulation inhibitors protein C and its cofactor protein S are also affected to a corresponding degree. By inhibiting the conversion of vitamin K, treatment with warfarin results in the liver producing and excreting partially carboxylated and decarboxylated coagulation protein.


Genetic differences in the gene for vitamin K epoxide reductase (VKORC1) have been shown to be relevant for the necessary dose of warfarin, see sections 4.2, 4.4, 4.8 and 5.2.


The half-life for the clotting factors varies from 47 hours for factor VII to 50 hours for factor II. This means that the system first achieves a new equilibrium after several days. Effective prevention of thrombosis is generally achieved after five days of treatment and the therapeutic effect subsides over 45 days after the end of treatment. The anticoagulative effect of warfarin can be counterbalanced with a lower dose of vitamin K, while higher doses can lead to warfarin resistance that can last more than one week. The effect of warfarin can be affected by pharmacodynamic factors as well as pharmacokinetic factors such as absorption and metabolic clearance, i.e. the same dose can have different effects on different people, with a few appearing resistant and possibly requiring 510 times the normal dose, and a not insignificant proportion of patients needing only very low doses.


5.2 Pharmacokinetic properties


Warfarin Orion is a racemic mixture of (S)-warfarin and (R)-warfarin. (S)-warfarin is 25 times more potent than the (R) form in terms of anticoagulative effect. Warfarin's kinetics is not dose-dependent.


Absorption

Warfarin is absorbed quickly and completely.


Distribution

Warfarin’s distribution volume is relatively small, with an apparent distribution volume of 0.14 l/kg. Warfarin has high protein binding, with a binding rate of 9899 %.


Biotransformation

Warfarin is almost completely eliminated via metabolism to inactive metabolites. (R)-warfarin is metabolised by, among other things, CYP1A2, CYP3A4 and carbonyl reductase, while (S)-warfarin is metabolised almost completely via the polymorphic enzyme CYP2C9. Patients with abnormal forms of CYP2C9 such as the alleles CYP2C9*2 and CYP2C9*3 metabolise (S)-warfarin less effectively and therefore have an increased risk for excessive anticoagulation and bleeding complications. For further information, see the section Special patient groups below.


Elimination

The half-life for (R)-warfarin varies between 37 and 89 hours, while for (S)-warfarin it varies between 21 and 43 hours. Studies of radioactively-labelled warfarin have shown that up to 90 % of an oral dose is found in urine, mainly in the form of metabolites. After the conclusion of warfarin therapy, the prothrombin level normalises after approx. 45 days.


Special patient groups


The elderly: Limited data indicates that warfarin’s pharmacokinetics is not age-dependent (see 4.2).


CYP2C9 genotype: (S)-warfarin is primarily eliminated by metabolism catalysed by the enzyme CYP2C9. CYP2C9 presents genetic polymorphism. The alleles *1, *2 and *3 are most common in the Caucasian population. The allele *1 provides ”normal” enzyme activity. The alleles *2 and *3 provide reduced enzyme activity and thus reduced clearance (and increased half-life) of warfarin. The most marked reduction of clearance is obtained in patients with two *3 alleles. Among Caucasians, this genotype is present in 0.5% of the population. Allele frequency and the significance of the genotype for the warfarin dose needed are presented below.

Relative allele frequency per ethnicity

*1

*2

*3

Caucasians

74.3%

14.3%

10.9%

African Americans

95.3%

0.0%

0.8%

Japanese

98.4%

0.0%

1.6%

Genotype

Observed reduction in the dose level needed

*1/*1

0% (reference)

*1/*2

20%

*1/*3

34%

*2/*2

36%

*2/*3

57%

*3/*3

78%

Impaired renal function: Renal clearance does not appear to affect the anticoagulative effect of warfarin. The initial dose does not therefore need to be adjusted in patients with impaired renal function (see 4.4).


Impaired hepatic function: Impaired hepatic function can enhance the effect of warfarin through inhibited synthesis of clotting factors and reduced metabolism of warfarin (see 4.2 and 4.3).


5.3 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.


6. PHARMACEUTICAL PARTICULARS


6.1 List of excipients


Lactose, anhydrous

Maize starch

Calcium phosphate

Povidone

Magnesium stearate


6.2 Incompatibilities


Not applicable.


6.3 Shelf life


3 years.


6.4 Special precautions for storage


This medicinal product does not require any special storage conditions.


6.5 Nature and contents of container


HDPE bottle, HDPE screw cap.

Pack size: 100 tablets.


6.6 Special precautions for disposal


No special requirements.


7. MARKETING AUTHORISATION HOLDER


Orion Corporation

Orionintie 1
FI-02200 Espoo
Finland


8. MARKETING AUTHORISATION NUMBERS


To be completed nationally.


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


To be completed nationally.


10. DATE OF REVISION OF THE TEXT


27.10.2016