Azenmarol: A drug for the treatment and prevention of thrombosis

2021-06-11 05:59 PM

Azenmarol to prevent thromboembolic complications caused by atrial fibrillation, mitral valve disease, prosthetic valve. Prophylaxis of thromboembolic complications in myocardial infarction with complications such as thrombosis on the heart wall, severe left ventricular dysfunction.

Azenmarol: A drug for the treatment and prevention of thrombosis

Azenmarol: A drug for the treatment and prevention of thrombosis




Azenmarol 1 Each tablet: Acenocoumarol 1mg.

Azenmarol 4 Each tablet: Acenocoumarol 4mg.


Azenmarol 1: Round white tablet, one side smooth, one side dashed, 6.5mm diameter.

Azenmarol 4: Oval tablets, white color, one side smooth, one side crossed, size 7.5mm x 10.5mm.


Acenocoumarol is a vitamin K antagonist coumarin derivative. These drugs inhibit the enzyme vitamin K epoxid reductase, which prevents the conversion of glutamic acid to gamma-carboxyglutamic acid of precursor proteins of coagulation factors II, VII, IX, X.

Thus, vitamin K antagonist coumarin derivatives have an indirect anticoagulant effect by preventing the synthesis of active forms of the above coagulation factors (II, VII, IX, X).
Following oral administration of acenocoumarol, the effect on prolongation of prothrombin time is usually maximal within 24 to 48 hours, depending on the dose administered. 48 hours after drug discontinuation, prothrombin time returns to pre-dosing levels.

After oral administration, in general, vitamin K antagonist coumarin derivatives cause hypoprothrombinemia within 36 to 72 hours. Balancing vitamin K antagonist therapy requires several days. After discontinuation of the drug, the anticoagulant effect may persist for another 2-3 days. The drug can limit the development of pre-existing blood clots and prevent secondary thromboembolic symptoms, although it does not have a direct thrombolytic effect because it does not reverse tissue damage. local ischemia.

Compared with warfarin and phenprocoumon, acenocoumarol has the advantage of a shorter duration of action.


Acenocoumarol is rapidly absorbed from the gastrointestinal tract. Oral bioavailability is 60%. A significant portion of the S(-)-acenocoumarol isomer undergoes first-pass metabolism in the liver, while the bioavailability of the R(+)-acenocoumarol isomer is 100%. The drug is strongly bound to plasma proteins (99%). Peak plasma concentrations are reached within 1-3 hours. Volume of distribution 0.16-0.34 liters/kg. Acenocoumarol crosses the placenta and is detected to a small extent in breast milk.

Acenocoumarol is metabolized in the liver by the cytochrome P450 enzyme system (CYP2C9 isoenzyme metabolizes the S-isomer, the R-isomer is metabolized by several other isoenzymes) to inactive amine and acetamide metabolites. Several other metabolites such as diastereoisomeric alcohol and the hydroxyl metabolite may be active. Clinicians should be aware of the possibility that some patients are highly susceptible to acenocoumarol due to hepatic mitochondrial polymorphism, and dose reduction may be required in such patients.

The elimination half-life of acenocoumarol is approximately 8-11 hours.
The drug is eliminated mainly in the urine (60% in about 1 week) as metabolites and partly in the feces (29% in about 1 week).

Indications and uses

Cardiovascular disease: Prophylaxis of thromboembolic complications caused by atrial fibrillation, mitral valve disease, prosthetic valve.

Myocardial infarction: Prophylaxis of thromboembolic complications in myocardial infarction with complications such as thrombosis on the heart wall, severe left ventricular dysfunction, embolism-induced left ventricular dysrhythmias when continued therapy as an alternative to heparin. Prevention of recurrent myocardial infarction when aspirin cannot be used.

Treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrence on continued replacement of heparin.

Prophylaxis of venous thrombosis and pulmonary embolism in hip surgery.

Prophylaxis of intracatheter thrombosis.

Dosage and Administration


The dosage must be adjusted to achieve the goal of inhibiting the coagulation mechanism to the point where thrombosis does not occur but spontaneous bleeding is avoided. The dosage depends on individual response to treatment.

Usual oral dose

The first day is 4 mg/day, the second day is 4-8 mg/day. The maintenance dose is 1-8 mg/day depending on biological response. Adjustments are usually made in increments of 1 mg.

Biological monitoring and dose adjustment

A suitable biological test is the measurement of prothrombin time (PT) expressed as the International Normalized Ratio (INR). The prothrombin time allows the detection of factors II, VII, and X, which are reduced by vitamin K antagonists. Factor IX is also decreased by vitamin K antagonists, but is not detected by prothrombin time.

The INR is an expression of Quick time that takes into account the sensitivity of the reagent (thromboplastin) used in the test, thus reducing erratic changes between laboratories.

When vitamin K antagonists are not used, the normal human INR is 1. When taking drugs in the following situations, in most cases the target INR should be 2.5, ranging between 2 and 3. INR below 2 reflects inadequate anticoagulation. An INR above 3 is an overdose. An INR above 5 is at risk of bleeding.

Biological test pacing

The first test was conducted 48 h ± 12 h after the first intake of a vitamin K antagonist to detect individual increased susceptibility. If the INR is above 2, it indicates an overdosage at equilibrium, so the dose must be reduced. The following tests were performed daily or every other day until the INR was stable, then gradually spaced out depending on the response, for a maximum of 12 weeks. Treatment equilibrium is sometimes reached only after several weeks. After each dose change, the INR should be checked 1-2 days later and repeated until stable.

In general, an INR of 2 to 3 is recommended for the prevention or treatment of venous thromboembolism, including pulmonary embolism, atrial fibrillation, valvular heart disease, or biological valves. An INR of 2.5 to 3.5 is recommended after myocardial infarction, in patients with mechanical heart valves, or in certain patients with thrombosis or antiphospholipid syndrome. A higher INR may be recommended for recurrent embolism.

Dosage in the elderly

The starting dose must be lower than the adult dose. The average therapeutic dose is usually ½ to ¾ of the adult dose.

Serial heparin-therapy

Because of the slow anticoagulant effect of vitamin K antagonists, heparin must be maintained at a constant dose for the required time, that is, until the INR is within the desired value for 2 consecutive days. In the case of heparin-induced thrombocytopenia, vitamin K antagonists should not be given soon after stopping heparin because of the risk of increased coagulation due to premature reduction of protein S (anticoagulant). Administer vitamin K antagonists only after antithrombin agents (danaparoid or hirudin) have been given.

Anticoagulants should be stopped 5 days before surgery. If the day before surgery INR ≥1.5, vitamin K injection 1-5 mg should be given. If hemostasis is good, the drug (acenocoumarol) can be reintroduced at the usual maintenance dose on the evening of the day of surgery or the next morning.

Patients who stop the medication before surgery are considered to be at high risk for thrombosis and may need support with a low-molecular-weight (therapeutic) heparin. Low molecular weight heparin should be stopped at least 24 hours before surgery. If the surgery involves a high risk of bleeding, low molecular weight heparin should not be reintroduced for at least 48 hours after surgery.

Patients on medication (acenocoumarol) requiring urgent surgery that can be delayed by about 6-12 hours may be given 5 mg of vitamin K intravenously to reverse the anticoagulation effect. If the delay is not possible, both parenteral vitamin K and dry prothrombin mixture (eg, 25 units/kg) should be given and the INR should be tested prior to surgery.


Acenocoumarol is usually taken once at the same time each day.



The most prominent manifestation of overdose is bleeding, which can occur within 1-5 days of taking the drug. Hemorrhagic manifestations may be observed: nosebleed, vomiting blood, hemoptysis, gastrointestinal bleeding, vaginal bleeding, hematuria (with renal colic), subcutaneous hemorrhage, bleeding gums, hematomas, and bleeding in joints or menorrhagia.

Symptoms of tachycardia, hypotension, peripheral circulatory disturbance due to blood loss, nausea, vomiting, diarrhea and abdominal pain may be observed.

To solve

Management of overdose is usually based on INR and signs of bleeding, and corrective measures must be sequential to avoid thrombotic risk. If anticoagulation has been taken but not vitamin K, the INR should be retested 2-3 days later to ensure that the INR has dropped.

If INR < 5, at the therapeutic level, the patient does not show any bleeding or does not require rapid correction of coagulation before surgery: Skip 1 dose, then resume treatment with a lower dose when INR is reached. desire. If the INR is very close to the desired INR, reduce the dose without skipping a dose.

If 5 < INR < 8, no bleeding symptoms other than gingival or epistaxis: Skip 1 or 2 anticoagulants, measure INR more often, then when the desired INR is reached, restart medication with lower doses.

If 5 < INR < 8, mild bleeding: Discontinue the drug, give vitamin K 1-3 mg by slow intravenous infusion. Only restart acenocoumarol when INR < 5.0.

If INR > 8, no bleeding: Stop acenocoumarol, administer 1-5 mg phytomenadiol (vitamin K1) (use an injectable form instead of oral). If the INR is still high after 24 hours, repeat the vitamin K treatment. Only resume acenocoumarol when the INR is < 5.0.

If INR > 8, minor bleeding: Discontinue the drug, give vitamin K 1-3 mg by slow intravenous route. If the INR is still high after 24 hours, repeat the dose of vitamin K. Repeat acenocoumarol only when INR < 5.0.

In case of significant bleeding or severe overdose (eg, INR > 20): Discontinue drug, administer 5 mg vitamin K slowly intravenously, administer dry prothrombin mixture (factors II, VII, IX, and X). 25-50 units/kg (if dry prothrombin mixture is not available, replace with fresh frozen plasma 15 mL/kg but less effective). Factor VIIa should not be used in emergency situations where anticoagulation is reversed.

In the case of accidental poisoning, the INR and bleeding complications should also be assessed. The INR should be measured several days later (2-5 days), taking into account the prolonged half-life of the anticoagulant. Use vitamin K to correct the effect of anticoagulants.


Known hypersensitivity to coumarin derivatives or to any of the excipients.

Vitamin C deficiency, bacterial endocarditis, blood dysplasia or any blood disorder increase the risk of bleeding.

Hypertension (severe).

Severe liver failure, especially when prothrombin time has been prolonged.

Risk of bleeding, recent neurosurgery, and ocular surgery or possibility of re-operation.

Cerebrovascular accident (except in cases of embolism elsewhere).

Severe renal failure (ClCr < 20 mL/min).

Esophageal varices.

A peptic ulcer is progressing.

Do not combine with high-dose aspirin, non-steroidal anti-inflammatory drugs with pyrazol, miconazole for systemic and vaginal administration; phenylbutazol, chloramphenicol, diflunisal.

Do not take acenocoumarol within 48 hours of giving birth.

Use in pregnant and lactating women

Pregnancy period

There has been an estimated 4% of fetal malformations when the mother takes this drug during the first trimester of pregnancy. In later quarters, there is still a risk (including miscarriage). Therefore, avoid use in pregnant women, especially in the first and third trimesters of pregnancy. Use the drug only when it is not possible to give heparin.

Breastfeeding period

Avoid breastfeeding. If breastfeeding is required, vitamin K should be given to the infant.


Many drugs can interact with vitamin K antagonists, so it is necessary to monitor the patient for 3-4 days after adding or removing the combination drug.

Contraindications to combination

Aspirin (especially at high doses above 3 g/day) increases the anticoagulant effect and bleeding risk by inhibiting platelet aggregation and shifting the oral anticoagulant out of plasma protein binding.

Miconazole: Unexpected bleeding may be severe due to increased blood free-form and inhibited metabolism of vitamin K antagonists.

Phenylbutazone potentiates the anticoagulant effect associated with irritation of the gastrointestinal mucosa.

Non-steroidal anti-inflammatory drugs of the pyrazol group: Increased risk of bleeding due to inhibition of platelets and irritation of the gastrointestinal mucosa.

Should not coordinate

Aspirin in doses less than 3 g/day.

Nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors.

Chloramphenicol: Increases the effect of oral anticoagulants by reducing their metabolism in the liver. If the combination cannot be avoided, the INR should be checked more frequently and the dose adjusted during and 8 days after stopping chloramphenicol.

Diflunisal: Increased effect of oral anticoagulants due to competition for binding to plasma proteins. Another pain reliever, eg paracetamol, should be used.

Use caution when coordinating

Allopurinol, aminoglutethimide, amiodarone, androgens, serotonin-enhancing antidepressants, benzbromarone, bosentan, carbamazepine, cephalosporins, cimetidine (more than 800 mg/day), cisapride, colestyramine, corticosteroids (except hydrocortisone used to treat Addison's disease), cyclin, cytotoxic drugs, fibrates, antifungal azoles, fluoroquinolones, heparins, thyroid hormones, enzyme inducers, statins, macrolides (except spiramycin), neviparin, efavirenz, imidazole group, orlistat, pentoxifyllin, phenytoin, propafenon, ritonavir, lopinavir, certain sulphonamides (sulfametoxazol, sulfafurazol, sulfamethizol), sucralfate, cancer drugs (tamoxifen, raloxifen), tibolon, vitamin E more than 500 mg/day, alcohol, anti-aggregation platelets, thrombolytic drugs, etc. also change the anticoagulant effect.

Adverse Effects (ADRs)

Bleeding manifestations are the most common complication, which can occur throughout the body: Central nervous system, extremities, viscera, intra-abdominal, intra-ocular,...

Occasionally diarrhea (may be accompanied by fatty stools), isolated joint pain.

Rarely: Hair loss; localized skin necrosis, which may be caused by hereditary protein C deficiency or protein S cofactor; allergic skin rash.

Very rarely, vasculitis, liver damage.

Instructions on how to handle ADR

See overdose.


Conditions of caution

Attention must be paid to the patient's cognitive ability during treatment (the risk of taking the wrong drug). Carefully guide them to follow the exact indications, understand the risks and handle attitudes, especially with the elderly.

Emphasis must be placed on taking the medication at the same time every day.

International Normalized Ratio (INR) tests must be performed periodically and in the same place.

In the case of surgical intervention, a case-by-case basis must be considered to adjust or discontinue anticoagulants, based on the patient's thromboembolic risk and the bleeding risk associated with each type of surgery.

Carefully monitor and adjust the dose accordingly in patients with moderate to mild renal impairment or hypoproteinaemia.

Hemorrhagic complications are likely to occur in the first months of treatment, so close monitoring is required, especially when the patient is discharged from the hospital and returns home.

The medicine should not be stopped suddenly.

The excipients of this medicine contain lactose and therefore should not be used in patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Effects of the drug on the ability to drive and use machines

The drug does not affect the ability to drive or use machines.


Store at a temperature below 30oC, away from moisture and light.

Presentation and packaging

Tablets: box of 3 blisters x 10 tablets, box of 10 blisters x 10 tablets.