AZENMAROL 4

Composition: Each tablet contains:
Acenocoumarol . . . . . . . . . . . . . . . . . . . . . 4 mg
Presentation:
Cardboard box containing 3 blisters of 10 tablets; Cardboard box containing 10 blisters of 10 tablets.
Indications:
– Heart disease causing embolism: Prevention of thromboembolic complications caused by atrial fibrillation, mitral valve disease, artificial valve.
– Myocardial infarction: Prevention of thromboembolic complications in myocardial infarction complications, such as thrombus adherent to cardiac wall, severe left ventricular dysfunction, left ventricular dysrhythmia causing embolism as a follow-up therapy alternative to heparin. Prevention of recurrence of myocardial infarction in patients who cannot take aspirin.
– Treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrence as alternative to heparin.
– Prevention of venous thrombosis, pulmonary embolism in hip replacement surgery.
– Prevention of catheter-related thrombosis.

Additional information

Dosage and administration

Dosage:
The dosage must be adjusted to achieve the treatment target that interferes with the clotting mechanism to a limit where blood clots do not occur, and spontaneous bleeding is avoided. Dosage depends on response to the treatment of individual patient.
Oral usual dose: 4 mg / day on the first day, followed by 4-8 mg / day on the second day. Maintenance dose is from 1-8mg / day depending on the biological response. Dose should be titrated in 1 mg increments.
Biological monitoring and dose adjustment:
Appropriate biological investigation is a measure of prothrombin time expressed by International Normalized Ratio (INR). Prothrombin time permits to measure factors II, X, and VII which are reduced by vitamin K antagonistic drugs. Factor IX is also reduced by vitamin K antagonistic drugs but not measured by prothrombin time.
INR is a manner to display Quicktime where the sensitivity of reagent (thromboplastin) used for the test is considered resulting in reduction of erratic changes between laboratories.
The INR reference value for a patient not taking a vitamin K antagonist is 1.0. When the drug is used in following circumstances, INR target level that should be achieved is 2.5 in most cases. This level fluctuates between 2 and 3. INR below 2 reflects insufficient anticoagulants. INR over 3 show that a surplus dose is used. INR over 5 shows that there is risk of bleeding.
Frequency of biological examination testing: The first testing is 48 ± 12 hours after administration of the first dose of vitamin K antagonist to detect an increase in individual sensitivity. If the INR is above 2, that is the signal of overdose when balance is achieved, the dose must be reduced. Following examinations are performed daily or on alternative days until IRN is stable, thereafter, the intervals are gradually prolonged dependent on response, the longest is 12 weeks. Sometimes balance of treatment is only obtained after several weeks. After every change of doses, INR should be examined after 1 or 2 days and repeatedly until the stability is achieved.
In general, if INR is 2 – 3 the prevention or treatment of venous thromboembolism is recommended, including pulmonary embolism, atrial fibrillation, valvular heart disease, or bioprosthetic heart valve disease, INR of 2.5 to 3.5 in postmyocardial infarction, mechanical heart valve patients, or in some patients with thrombotic or antiphospholipid syndrome. Higher INR may be recommended for recurrent venous thromboembolism.
Elderly patients: The starting dose should be lower than the recommended adult dose. The mean stable dose in treatment is usually only 1/2 to 3/4 of an adult dose.
Conversion from heparin therapy: Due to the delayed anticoagulant effect of vitamin K antagonist drugs, heparin should be maintained at a constant dose for required period, i.e until the INR has been in the target range on at least two consecutive days. In the case of heparin-induced thrombocytopenia, vitamin K antagonist should not be given immediately after stopping heparin as there is increased risk of blood clots due to S protein (anticoagulant protein) is early reduced. Vitamin K antagonist is only indicated after administration of antithrombin drugs (danaparoid or hirudin).
The anticoagulant should be discontinued 5 days before surgery. On the day before surgery if INR is ≥ 1.5 oral administration of parenteral vitamin K of 1 – 5mg is required. If there is adequate haemostasis, acenocoumarol can be resumed, at the normal maintenance dose, in the evening of surgery day or tomorrow morning.
Patients who stop this drug before surgery are regarded as at high risk of thrombosis and may be given bridging anticoagulant therapy with low molecular weight heparin (treatment doses). Low molecular weight heparin should be stopped at least 24 hours before surgery. If surgery has high risk of bleeding, low molecular weight heparin must not be used for at least 48 hours after surgery.
Patient on acenocoumarol therapy requiring urgent surgery that can be delayed for 6-12 hours can be given intravenously 5 mg of vitamin K to reverse anticoagulant effect. If the surgery can not be delayed, both vitamin K injection and mixture of lyophilized prothrombin (e.g 25 units / kg) are administered and INR test should be done before surgery.
Administration:
Acenocoumarol is usually taken once a day, at the same time each day.

Contraindications

Known hypersensitivity to coumarin derivatives or to any component of the drug.
Vitamin C deficiency, bacterial endocarditis, blood dyscrasias, or any blood disorders increasing risk of bleeding.
High blood pressure (severe).
Severe liver failure, especially when prothrombin time has been prolonged.
Risk of bleeding, recent surgery on the central nervous system or possibility for re-operation.
Stroke (except for cases of embolism elsewhere).
Severe renal impairment (Clcr <20 ml / min).
Esophageal varices.
Active gastric and duodenal ulcers.
Acenocoumarol should not be combined with high doses of aspirin, non-steroidal anti-inflammatory drugs having a pyrazole structure, systemic or vaginal miconazole; phenylbutazole, chloramphenicol, diflunisal.
Do not take acenocoumarol within 48 hours after delivery.

Warnings and precautions for use

– Attention should be paid to the patient's awareness during the treatment (risk of error in drug use). Patients should be carefully instructed to adhere to the indications correctly, understand the risk and attitude to treatment, especially the elderly.
– Taking acenocoumarol daily at the same time must be emphasized.
– International Standardized Ratio (INR) must be performed periodically and at the same place.
– If surgical intervention is required, individual case should be considered to adjust or temporarily discontinued anticoagulants, based on patient’s risk of thrombosis and risk of bleeding related to each type of surgery.
– Dosage should be carefully monitored and adjusted to be appropriate to patients with moderate to mild renal failure or hypoproteinemia.
– Bleeding events easily occur during initial months of treatment, therefore patients should be monitored closely, especially, after they have been discharged from hospital to home.
– Acenocoumarol should not be stopped abruptly.
– AZENMAROL contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion should not take this medicine.

Recommendation for pregnancy and breastfeeding

Pregnancy:
It is estimated that fetal anomalies account for 4% when pregnant women were given acenocoumarol during the first trimester of pregnancy. The risk is still found during the second and third trimester (including miscarriage). Therefore, Azenmarol is contra-indicated for use in pregnant women, especially during the first and the trimester of pregnancy. This medicine is only used when heparin cannot be indicated.
Lactation:
Avoid breastfeeding during the treatment with acenocoumarol. The infant should be given 1mg vitamin K1 per week as a prophylactic measure if he/she is breastfed.

Effects on ability to drive and use machines

Acenocoumarol has no influence on ability to drive and use machines.

Interactions, incompatibilities of medicine

A lot of drugs can interact with vitamin K antagonists, so it is necessary to monitor the patients for 3-4 days after increasing or reducing combined drugs.
Combination is contraindicated:
– Aspirin (especially used at doses over 3 g / day) increases the anti-coagulant effect and risk of bleeding by inhibiting platelet aggregation and translocating anticoagulant drug from plasma protein binding.
– Miconazole: Sudden hemorrhage can be severe due to elevated free forms of acenocoumarol anticoagulant in the blood and inhibition of metabolism of vitamin K antagonistic drug.
– Phenylbutazone increases anticoagulant effect in combination with irritation of gastrointestinal mucosa.
– Pyrazole nonsteroidal anti-inflammatory drugs: Increased risk of bleeding due to suppressing platelet aggregation and irritation of the gastrointestinal mucosa.
Concomitant use not being recommended:
– Aspirin used at doses less than 3g /day.
– Nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors.
– Chloramphenicol: Increases the effect of oral anticoagulants due to reducing the metabolism of anticoagulant drug in the liver. If coadministration can not be avoided, INR should be checked more frequently, doses should be adjusted during the treatment and after stopping chloramphenicol for 8 days.
– Diflunisal: Increases the effect of anticoagulant due to competition for plasma protein binding sites. Other pain killers, such as paracetamol, should be used.
Caution for combination:
Alopurinol, aminoglutethimide, amiodarone, androgen, selective serotonin re-uptake inhibitors, benzbromaron, bosentan, carbamazepine, cephalosporin, cimetidine (over 800 mg/day), cisapride, cholestyramine, corticoid (Except for hydrocortisone used as a substitute in Addison's disease), cycline, cytotoxic drugs, fibrates, antifungal azoles, fluoroquinolone, types of heparin, Thyroid hormone, enzyme inducers, statins, macrolides (except spiramycin), neviparin, efavirenz, imidazoles, orlistat, pentoxifylline, phenytoin, propafenone, ritonavir, lopinavir, some sulfonamides (sulfamethoxazole, sulfafurazole, sulfamethizol), sucralfate, cancer medication (tamoxifen, raloxifen), tibolone, vitamin E over 500 mg / day, alcohol, antiplatelet agents, thrombolytic agents etc. also change the anticoagulant effect.

Undesirable effects (ADRs)

Bleeding manifestations are the most common complications occurring throughout the body: Central nervous system, limbs, viscera, inside of abdomen, eyeballs, etc.
Occasionally diarrhea occurs (possibly accompanied with fatty feces), separate joint pain.
Rarely occur: Hair loss; localized skin necrosis, possibly due to inherited protein C or S deficiency; allergic skin rash.
Rarely seen: Vasculitis and liver damage.
Guidelines for ADR management:
See overdose and management sections.

Overdose and management

Symptoms:
Haemorrhage is the prominent feature of an overdose and may occur within 1 to 5 days after ingestion. Nose-bleeds, haematemesis, haemoptysis, gastro-intestinal haemorrhage, vaginal bleeding, haematuria (with renal colic), cutaneous haemorrhages, gingival bleeding, haematomata, and bleeding into the joints or menorrhagia may be experienced.
Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains.
Management:
Management of overdose is usually based on INR and signs of bleeding; corrective measures must be sequential to avoid risk of forming blood clots. If anticoagulant has been used but vitamin K is not given, re-test INR 2 – 3 days later to ensure that the INR is decreased.
– If INR <5, at treatment level, the patient has no signs of bleeding or rapid adjustment of blood clotting prior to surgery is not required: Skip one dose, then continue the treatment with lower dose when desired INR value is achieved. INR desires. If INR is very close to the desired INR, reduce the dose without skipping the dose.
– If 5 <INR <8, there are no bleeding manifestations other than bleeding gums or nose bleeds: Skip 1 or 2 doses of anticoagulants, INR value is measured more frequently. When desired INR is achieved lower doses, the drug is resumed at lower dosage.
– If 5 <INR <8, with slight bleeding: Stopping the drug, 1-3 mg intravenous vitamin K may be given by slow infusion. Acenocoumarol should only be resumed when INR is 8, without bleeding: Discontinue acenocoumarol, administer 1 – 5 mg phytomenadione (vitamin K1) (injection is used instead of oral form). After 24 hours if INR remains high, repeat the treatment with vitamin K. Acenocoumarol should only be resumed when INR is 8, with light bleeding: Discontinue the drug, 1-3 mg intravenous vitamin K may be given by slow infusion. After 24 hours if INR remains high, repeat vitamin K dose. Acenocoumarol should only be resumed when INR is 20): Discontinue the drug, 5 mg of vitamin K is given by slow IV infusion, administer lyophilized prothrombin mixture (factors II, VII, IX and X) 25 – 50 units / kg (if lyophilized prothrombin mixture is not available fresh frozen plasma 15 ml / kg is used as a substitute but less effective). Factor VIIa is not concomitantly used to give fist aid to reversal of anticoagulant effects.
In case of accidental poisoning, the conditions should be assessed based on INR values and manifestations of bleeding complications. INR should be measured several days later (2-5 days), taking into account the extended half life of anticoagulants. Administer vitamin K to adjust the effect of anticoagulants.

Pharmacodynamic properties

Acenocoumarol is a coumarin derivative and functions as vitamin K antagonist. It inhibits the vitamin K epoxide reductase enzyme, resulting in preventing the conversion of glutamic acid to gamma-carboxyglutamic acid in vitamin K dependent proteins which are precursors of coagulation factors II, VII, IX, X.
Thus, coumarin derivatives with vitamin K antagonistic effects have an indirect anticoagulant effect by inhibiting the synthesis of active forms of coagulation factors (II, VII, IX, X).
After oral administration of acenocoumarol, maximum effect of rise in prothrombin time is seen between 24-48 hours, depending on the dose. After withdrawal of acenocoumarol for 48 hours, the prothrombin time usually reverts to normal.
In general, vitamin K antagonistic coumarin derivatives cause hypoprothrombinemia within 36 to 72 hours. It takes several days to balance the treatment with vitamin K antagonistic medicines. After stopping the drugs, anticoagulant effect can last 2-3 days. These agents may limit extension of existing thrombi and prevent secondary thromboembolic complications although they have no direct thrombolytic effect because do not reverse ischemic tissue damage.
Compared with warfarin and phenprocoumon, acenocoumarol has the advantage of shorter duration of action.

Pharmacokinetic properties

Acenocoumarol is rapidly absorbed from the gastrointestinal tract. Oral bioavailability is approximately 60%. A significant portion of S (-) – acenocoumarol enantiomer undergoes first-pass hepatic metabolism, whereas the bioavailability of R (+) – acenocoumarol enantiomer is 100%. The drug is strongly bound to plasma protein (99%). Peak plasma concentrations are achieved within 1 to 3 hours. The volume of distribution is 0.16 – 0.34 liter / kg. Acenocoumarol crosses the placenta and a small fraction is found in breast milk.
Acenocoumarol is metabolized in the liver by cytochrome P450 enzymes (Metabolism of the S-isomer is mediated mainly by the cytochrome P450 isoenzyme CYP2C9, other isoenzymes as well are involved in the metabolism of the R-isomer) inactive amine and acetamide metabolites. Some other metabolites, such as diastereoisometric alcohol and hydroxyl metabolite, may be active. Clinicians need to know the possibility that some patients are highly susceptible to acenocoumarol because of polymorphism of hepatic mitochondria, and the dose may be reduced in these patients.
The elimination half-life of acenocoumarol from the plasma is 8 to 11 hours.
Acenocoumarol is excreted mainly in the urine (60% in about 1 week) as metabolites and partly in the faeces (29% in about 1 week).

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.