Exanta (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

ATC Code

B01AE05 (Ximelagatran)

Active Substance

Ximelagatran (Rec.INN registered by WHO)

Dosage Form

Exanta

Coated tablets, 24 mg: 14 pcs.

Dosage Form, Packaging, and Composition

Coated tablets light yellow in color, oval in shape, biconvex, with the engraving AZ/E on one side and 24 on the other.

Excipients: microcrystalline cellulose, mannitol, povidone, sodium starch glycolate, sodium stearyl fumarate.

Shell composition: hypromellose, yellow iron oxide, macrogol 6000, titanium dioxide.

14 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Anticoagulant. Direct thrombin inhibitor

Pharmacotherapeutic Group

Direct thrombin inhibitor

Pharmacological Action

Melagatran is a potent, competitive, and reversible direct inhibitor of alpha-thrombin with a small molecular size. Alpha-thrombin is a serine protease that converts fibrinogen to fibrin in the coagulation cascade. Thus, inhibition of thrombin prevents thrombus development.

Melagatran inhibits both free and fibrin-bound thrombin, as well as thrombin-induced platelet aggregation.

Ximelagatran is a prodrug of melagatran; after oral administration, it undergoes biotransformation to form the active melagatran. When the recommended prophylactic dose of the drug is used, standard coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (APTT) have relatively low sensitivity for assessing melagatran activity, so they are not suitable for assessing coagulation status.

Experiments have established a direct relationship between the plasma concentration of melagatran and the ecarin clotting time, but the plasma concentration did not reliably predict the individual risk of bleeding.

The efficacy and safety of melagatran/ximelagatran were studied in comparison with enoxaparin for the prevention of thromboembolic events (the METHRO III study), namely proximal and distal deep vein thrombosis, as well as pulmonary embolism after major elective orthopedic surgery (hip or knee replacement). The study included 2874 patients over 18 years of age (1439 in the melagatran/Ximelagatran group; 1435 in the enoxaparin group).

Administration of melagatran at a dose of 3 mg/0.3 ml as subcutaneous injections was started no earlier than 4 hours after the end of surgery and continued for 1-2 days twice a day; then they were switched to Ximelagatran (24 mg twice a day) as soon as the patient was able to take the drug orally. Enoxaparin was used at a dose of 40 mg once a day as a subcutaneous injection, with the first dose administered the day before the scheduled surgery.

Treatment with both drugs continued for 8-10 days without dose adjustment based on coagulation monitoring data.

When the first dose of melagatran was administered no earlier than 4 hours after the end of surgery (median time of first dose administration from the end of surgery 8 hours), the risk of proximal thromboembolism with melagatran/ximelagatran was 5.7% (95% CI 4.3-7.1%) compared to 6.2% with enoxaparin (95% CI 4.3-7.7%). This proves the comparable efficacy of melagatran/ximelagatran compared to enoxaparin.

The overall risk of thromboembolism in the melagatran/ximelagatran group was 31% (95% CI 28.3-33.7%) compared to 27.3% in the enoxaparin group (95% CI 24.6-29.9%), the difference was not statistically significant (p=0.052).

The incidence of symptomatic thromboembolism throughout the study was similar in the two groups (1.8% and 2.2%, respectively).

A higher incidence of distal deep vein thrombosis (4.1%; 95% CI 0.8-7.5%) was observed with melagatran/ximelagatran compared to enoxaparin, but the clinical significance of this observation is unknown.

The incidence of major bleeding with melagatran/ximelagatran was 1.4% (95% CI 0.88-2.2%), compared to 1.7% with enoxaparin (95% CI 1.05-2.47%). The percentage of heterologous transfusions was significantly lower (p=0.001) in the melagatran/Ximelagatran group (33.3%; 95% CI 30.8-35.8%) than in the enoxaparin group (39.3%; 95% CI 36.7-41.9%).

When the first dose of melagatran was administered in the interval from 4 to 8 hours after the completion of surgery, the risk of developing proximal deep vein thrombosis and/or pulmonary embolism was 5.6% (611 patients, 95% CI 3.88-7.69%), the overall risk of thromboembolism was 27.2% (613 patients, 95% CI 23.8-31%). This proves the comparable efficacy of melagatran/ximelagatran compared to enoxaparin. In patients who received the first dose of melagatran in the interval from 4 to 8 hours after the completion of surgery, the incidence of major bleeding was higher (1.6%; 95% CI 0.83-2.78%) compared to patients who received the first dose of melagatran later than 8 hours after the end of surgery (1.23%; 95% CI 0.53-2.41%).

This slight increase in the incidence of major bleeding did not cause an increase in the need for heterologous transfusions, the number of which was lower when the first dose was administered 4-8 hours after the completion of surgery (31.8%; 95% CI 28.5-35.2) than when the first dose was administered later than 8 hours after surgery (35%; 95% CI 31.4-38.8). Regardless of the time of the first dose administration, melagatran/Ximelagatran caused a number of major bleedings comparable to enoxaparin, while requiring significantly fewer heterologous transfusions than in the enoxaparin group.

Pharmacokinetics

Ximelagatran is a prodrug of melagatran; after oral administration, it undergoes biotransformation to form the active substance melagatran.

Absorption

After oral administration, Ximelagatran is rapidly absorbed and biotransformed into melagatran by de-esterification by esterases and reduction. The enzyme involved in the reduction of ximelagatran to melagatran has not been identified; however, it has been established that the CYP450 isoenzyme is not involved in the reduction.

C_max of melagatran in plasma is reached approximately 2 hours after administration.

The bioavailability of melagatran after oral administration is 23% and does not depend on food intake. Food intake delays the absorption of ximelagatran by approximately 1 hour. The equilibrium concentration of melagatran in plasma is reached within 24 hours.

Distribution

T_1/2 of melagatran after oral administration of ximelagatran is longer than after subcutaneous injection of melagatran due to a larger (approximately 2 times) volume of distribution of melagatran (about 30-40 L).

It is assumed that the more lipophilic Ximelagatran distributes into tissues inaccessible to melagatran, where bioconversion of ximelagatran to melagatran occurs, leading to a larger volume of distribution of melagatran. The binding of melagatran to plasma proteins is low (less than 15%), so interactions with other drugs by displacement from protein binding are unlikely.

Metabolism and excretion

Ximelagatran is rapidly biotransformed into melagatran, the main active form of the drug in plasma. Two intermediate metabolites are also formed, one of which has thrombin-inhibitory activity similar to melagatran, the other metabolite is inactive. The plasma concentrations of the metabolites are low; they are rapidly converted to melagatran. Ximelagatran is metabolized in the liver, lungs, intestine, and kidneys. Melagatran does not undergo further biotransformation and is mainly excreted unchanged in the urine at a rate proportional to the glomerular filtration rate. The exposure of melagatran after oral administration of ximelagatran is reproducible and correlates with renal function.

Alcohol intake does not affect the pharmacokinetic properties of ximelagatran. In vitro studies have shown no inhibition of CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4. The likelihood of interaction with CYP2B6 and CYP2C8 has not been studied.

Special patient groups

The bioavailability of melagatran after oral administration of ximelagatran is higher in patients with renal impairment (21.5%) than in patients with normal renal function (15.8%).

There is a direct relationship between renal function and the clearance of melagatran. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), the exposure (AUC) of ximelagatran after oral administration increases almost 6-fold (4-fold after subcutaneous injection of melagatran), and the T_1/2 of the drug increases 3-fold compared to patients with normal renal function.

Pharmacokinetic studies in elderly patients (24 patients aged 56 to 71 years) showed an increase in AUC values by 50%-60% and an increase in C_max of melagatran in plasma by more than 20% after a single dose of melagatran or ximelagatran compared to young volunteers.

The kinetics of melagatran after multiple doses of the drug were assessed in population studies in elderly patients (up to 90 years) with a creatinine clearance of more than 30 ml/min. The decrease in melagatran clearance correlated with the decrease in creatinine clearance.

Minor changes in melagatran exposure after oral administration of ximelagatran were identified in 12 patients with moderate hepatic impairment compared to 12 patients in the control group after correction for creatinine clearance.

No significant differences in the pharmacokinetics of melagatran after oral administration of ximelagatran were noted in overweight patients (body mass index from 32 to 39 kg/m²) compared to patients with normal body weight, except for a decrease in AUC associated with an increase in creatinine clearance.

After adjustment for weight, no dependence of melagatran pharmacokinetics on gender was observed.

No dependence of melagatran pharmacokinetics on ethnicity was observed.

Indications

• Prevention of venous thromboembolic complications in patients after elective hip or knee replacement surgery.

ICD codes

Dosage Regimen

Treatment should be started only after the completion of surgery. First, the subcutaneous injection solution – Exanta SC at a dose of 3 mg/0.3 ml (melagatran) is administered, then Exanta tablets at 24 mg (Ximelagatran) are prescribed.

Solution for subcutaneous injection

The first injection of Exanta SC at a dose of 3 mg/0.3 ml should be administered subcutaneously no earlier than 4 hours and no later than 8 hours after the completion of surgery, provided that adequate hemostasis was achieved during the surgery. The specified time of the first dose administration must be strictly observed. The dose should be administered twice a day for 1-2 days, until the patient is able to take tablets orally.

Tablets

Taking Exanta at a dose of 24 mg, 1 tablet twice a day, can replace melagatran injections as early as the next day after surgery. The tablets can be taken with food or on an empty stomach.

The recommended total duration of treatment is 8-11 days. Due to the current lack of data on the efficacy and safety of the drug for prophylaxis for more than 11 days, the duration of treatment with Exanta SC followed by Exanta tablets at a dose of 24 mg should not exceed 11 days.

Due to the current lack of data on the efficacy and safety of the drug for prophylaxis for more than 11 days, the duration of treatment with Exanta SC followed by Exanta tablets at a dose of 24 mg should not exceed 11 days. If long-term anticoagulant therapy is necessary, patients should be switched to drugs for which there is experience with long-term prophylaxis.

Special patient groups

Exanta is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

There is currently limited clinical experience with the use of Exanta at recommended doses in patients with moderate renal impairment (creatinine clearance greater than 30 but less than 50 ml/min). Caution should be exercised when using the drug in this group of patients.

Experience with the use of Exanta at the recommended dose in patients over 75 years of age is currently limited. Based on available kinetic data, this group of patients should take Exanta with caution and under the supervision of specialists.

Exanta is contraindicated in patients with hepatic impairment and/or patients in whom the ALT level before the start of treatment exceeded the upper limit of normal by more than 2 times. ALT must be determined before surgery.

Experience with the use of the drug in patients with a body weight of less than 50 kg is currently limited.

Available clinical data on the use of Exanta in patients with a body mass index greater than 35 kg/m² are limited and do not exclude the possibility of reduced treatment efficacy.

The efficacy and safety of the drug in patients under 18 years of age have not been studied, therefore the drug is not recommended for children and adolescents.

Recommendations for switching between Exanta and other anticoagulants heparin/low molecular weight heparin (LMWH)

Patients receiving heparin/LMWH before prescribing melagatran/ximelagatran

Treatment with Exanta SC as subcutaneous injections and subsequent intake of Exanta tablets can be started 12 hours after the administration of the last dose of heparin/LMWH. If it is necessary to continue prophylactic treatment and switch to heparin/LMWH, the first injection of heparin or LMWH should be given 12 hours after the last dose of Exanta.

Vitamin K antagonists (VKA)

• Patients with indications for long-term use of vitamin K antagonists before prescribing melagatran/ximelagatran: given the probable risk of bleeding and the lack of clinical experience, these patients should be switched to other antagonists if it is important to ensure continuity of anticoagulant therapy before surgery.
• Switching a patient to vitamin K antagonists after a course of melagatran/ximelagatran: due to the lack of data on the combined use of vitamin K antagonists after using Exanta SC, patients should first be switched to heparin/LMWH before starting therapy with vitamin K antagonists and continue the combined administration of heparin/LMWH and vitamin K antagonists until stable maintenance of the INR (International Normalized Ratio) in the appropriate range is achieved with vitamin K antagonists.

Adverse Reactions

Adverse events observed in patients treated with melagatran/Ximelagatran in the METHRO III study (1406 participants), with a frequency of more than 2% for cases not related to bleeding, and regardless of a causal relationship with the drug, are presented in the table.

Most of the observed adverse events can be attributed to the surgical intervention and the mechanism of action of the drug.

The safety of melagatran followed by ximelagatran, at a dosage equivalent to the recommended one, was studied in 4208 patients after major elective orthopedic surgery on the lower extremities with a treatment duration of up to 11 days. In this case, when the drug was started before surgery, the incidence of bleeding was higher than when treatment was started after surgery. The incidence of other adverse events not related to bleeding was comparable.

With long-term use of ximelagatran (more than 2 months), an increase in the level of liver enzymes (mainly transaminases) was more often observed; in most patients, the increase was reversible within approximately 2 months after discontinuation of the drug.

Contraindications

• Severe renal impairment (creatinine clearance less than 30 ml/min);
• Clinically significant bleeding;
• Bleeding or tendency to bleed due to congenital or acquired coagulation disorders;
• Organic diseases with a high risk of bleeding;
• Hepatic impairment, as well as ALT exceeding the upper limit of normal by more than 2 times (ALT must be determined before surgery);
• Age under 18 years (due to lack of clinical use data);
• Hypersensitivity to melagatran, ximelagatran or any other component of the drug.

Use in Pregnancy and Lactation

There are no clinical data on the safety of ximelagatran use in pregnant women. Animal studies have shown reproductive toxicity at doses causing maternal bleeding. The potential risk to humans is unknown.

Exanta should not be used during pregnancy, except in cases where the potential benefit of using the drug justifies the possible risk to the fetus.

Melagatran, the active form of ximelagatran, is excreted in breast milk in small amounts. It is recommended to discontinue breastfeeding while using Exanta.

Use in Hepatic Impairment

Exanta is contraindicated in patients with hepatic insufficiency and/or in patients whose ALT level before the start of treatment exceeded the upper limit of normal by more than 2 times. ALT must be determined before the start of surgery.

Use in Renal Impairment

The drug is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Currently, there is limited clinical experience with the use of Exanta at recommended doses in patients with moderate renal impairment (creatinine clearance greater than 30 but less than 50 ml/min). Caution should be exercised when using the drug in this group of patients.

Pediatric Use

The efficacy and safety of the drug in patients under 18 years of age have not been studied, therefore the drug is not recommended for children and adolescents.

Geriatric Use

Currently, experience with the use of Exanta at the recommended dose in patients over 75 years of age is limited. According to available kinetic data, this group of patients should take Exanta with caution and under the supervision of specialists.

Special Precautions

Patients should be warned about the need to strictly adhere to the recommended dosage regimen and duration of treatment. When the first dose was taken 8-12 hours after surgery completion, a higher frequency of distal deep vein thrombosis was observed with melagatran/ximelagatran compared with enoxaparin.

A negative trend towards an increased frequency of distal deep vein thrombosis was also observed when the first dose of melagatran was taken 4-8 hours after surgery completion. However, the clinical significance of these data is unknown.

The efficacy and safety of melagatran/ximelagatran for hip fracture surgery have not been studied.

ALT level must be determined before the start of surgery.

Due to the risk of bleeding, the following drugs should not be taken concomitantly with subcutaneous Exanta

• VKA;
• Unfractionated heparin and its derivatives;
• LMWH;
• Fondaparinux;
• Desirudin;
• Thrombolytics;
• GPIIb/IIIa receptor antagonists;
• Clopidogrel;
• Ticlopidine;
• ASA at a dose of more than 500 mg/day;
• Dipyridamole;
• Sulfinpyrazone.

Careful clinical monitoring (checking for signs of bleeding and/or anemia) and measurement of hemoglobin level during surgery, after surgery, and throughout the entire treatment period is necessary, especially in the following situations that lead to an increased risk of bleeding

• Diseases associated with an increased risk of bleeding: such as congenital or acquired coagulation disorders, thrombocytopenia or functional platelet defects, active peptic ulcer disease, as well as performing a biopsy, recent major trauma or intracranial bleeding, recent surgery on the brain or spinal cord, and ophthalmic surgery;
• ASA as an antiplatelet agent (at a dose of less than 500 mg/day), NSAIDs and dextran should be taken with caution. If it is necessary to use these drugs concomitantly, their use should be under strict control;
• An increased risk of bleeding may occur with the concomitant use of ximelagatran and erythromycin;
• Bacterial endocarditis.

Renal impairment

Melagatran is primarily excreted by the kidneys. Patients with impaired renal function are at an increased risk of bleeding when using melagatran.

Exanta is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

There is limited experience with the use of the drug at the recommended dose in patients with moderate renal impairment (creatinine clearance greater than 30 but less than 50 ml/min). Such patients should use Exanta with caution, with careful monitoring for signs of bleeding and/or anemia and monitoring of renal function throughout the entire treatment period.

Elderly patients

There are limited clinical data on the use of the recommended dosage regimen of Exanta in elderly patients. In elderly patients, delayed elimination and increased exposure to melagatran are possible, especially in the postoperative period. Based on available pharmacokinetic data, Exanta should be prescribed to patients over 75 years of age with caution.

Careful clinical monitoring for signs of bleeding and/or anemia and monitoring of renal function are recommended throughout the entire treatment, especially in the presence of an additional risk factor for bleeding in the medical history.

Low body weight

Data on the use of Exanta in patients with a body weight of less than 50 kg are limited. Caution should be exercised when prescribing the drug to this group of patients due to an increased risk of bleeding.

Epidural or spinal anesthesia/lumbar puncture

When using subcutaneous Exanta followed by oral Exanta tablets at a dose of 24 mg concomitantly with epidural/spinal anesthesia or lumbar puncture, the possibility of an epidural or spinal hematoma cannot be excluded, which may lead to prolonged or permanent paralysis.

Such a course of events is rare, but its risk may be higher with the use of an indwelling epidural catheter in the postoperative period, or with the concomitant use of other drugs affecting hemostasis.

The risk may also increase with traumatic or repeated puncture.

If indwelling catheters have been inserted, they should not be removed earlier than 8 hours after the last dose of Exanta was administered.

The next dose of Exanta should be applied no earlier than 1-2 hours after the removal of the indwelling catheter.

Patients should be frequently assessed neurologically to detect signs or symptoms of neurological impairment.

Effect on ability to drive and operate machinery

Studies on the effect of Exanta on the ability to drive a car or operate machinery have not been conducted.

Overdose

An antidote for Exanta is unknown.

It is assumed that the use of drug doses higher than recommended may lead to an increased risk of bleeding.

In case of overdose and associated hemorrhagic complications, it is necessary to immediately stop treatment and determine the cause of bleeding. Since melagatran is excreted by the kidneys, adequate diuresis must be maintained. The T_1/2 of melagatran after oral administration is short (4-5 hours). Residual anticoagulant effect is indicated by an increase in aPTT. Dialysis is effective.

In case of a high risk of developing life-threatening bleeding, appropriate treatment may be required: surgical hemostasis or transfusion of blood and/or its components.

Drug Interactions

When Exanta is used concomitantly with drugs affecting hemostasis or coagulation, the risk of bleeding is significantly increased.

The following drugs must not be prescribed concomitantly with Exanta: VKA, unfractionated heparin and its derivatives, LMWH, fondaparinux, desirudin, thrombolytics, GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, ASA (at a dose of more than 500 mg/day), dipyridamole, sulfinpyrazone.

Aspirin (as an antiplatelet agent at a dose of less than 500 mg/day), NSAIDs and dextran should be taken with caution due to the potential increase in the risk of bleeding when used concomitantly with Exanta. If it is necessary to use these drugs concomitantly, their use should be under careful observation.

In vitro interaction studies did not reveal inhibition of the major cytochrome P450 isoenzymes responsible for the metabolism of many drugs. These results were confirmed in in vivo studies conducted on healthy volunteers, which showed no interaction between ximelagatran and the following drugs: nifedipine (CYP3A4), diazepam (CYP2C19 and CYP3A4), diclofenac (CYP2C9).

When oral ximelagatran and erythromycin are taken concomitantly, an increased risk of hemorrhagic complications is possible. The mechanism of such interaction may involve inhibition of transport proteins, possibly P-glycoprotein (P-gp).

Therefore, there is a possibility of pharmacokinetic interactions with P-glycoprotein (P-gp) inhibitors (e.g., erythromycin, azithromycin, clarithromycin, cyclosporine), which may lead to increased exposure to melagatran.

Storage Conditions

Store the drug at a temperature not exceeding 30°C (86°F). Keep out of reach of children.

Shelf Life

The shelf life is 4 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.