Dabixom (Capsules) Instructions for Use

Marketing Authorization Holder

Krka-Rus, LLC (Russia)

ATC Code

B01AE07 (Dabigatran etexilate)

Active Substance

Dabigatran etexilate (Rec.INN registered by WHO)

Dosage Forms

	Dabixom	Capsules 75 mg: 30, 60, or 90 pcs.
		Capsules 110 mg: 30, 60, 90, or 180 pcs.
		Capsules 150 mg: 30, 60, 90, or 180 pcs.

Dosage Form, Packaging, and Composition

Capsules No. 2; capsule cap and body are white or almost white; the inscription “75” is printed on the capsule body in black ink; capsule contents: pellets from yellowish-white to light yellow.

Excipients: tartaric acid, hypromellose, hyprolose, talc.

Capsule compositionCap and body titanium dioxide (E171), carrageenan, potassium chloride, hypromellose, purified water.
Ink composition shellac, anhydrous ethyl alcohol¹, isopropanol¹, butanol¹, propylene glycol¹, concentrated ammonia solution¹, black iron oxide (E172), potassium hydroxide, purified water¹.

¹ Anhydrous ethyl alcohol, isopropanol, butanol, propylene glycol, concentrated ammonia solution, purified water are not present in the capsule, they evaporate during application.

10 pcs. – blisters (3 or 9) – cardboard packs.
60 pcs. – bottles (1) – cardboard packs.

Capsules No. 1; capsule cap and body are blue; the inscription “110” is printed on the capsule body in black ink; capsule contents: pellets from yellowish-white to light yellow.

Capsule compositionCap and body titanium dioxide (E171), carrageenan, potassium chloride, hypromellose, purified water.
Ink composition shellac, anhydrous ethyl alcohol¹, isopropanol¹, butanol¹, propylene glycol¹, concentrated ammonia solution¹, black iron oxide (E172), potassium hydroxide, purified water¹.

¹ Anhydrous ethyl alcohol, isopropanol, butanol, propylene glycol, concentrated ammonia solution, purified water are not present in the capsule, they evaporate during application.

10 pcs. – blisters (3, 6, or 9) – cardboard packs.
60 pcs. – bottles (1) – cardboard packs.
10 pcs. – blisters (18) – cardboard packs (multipack).

Capsules No. 0; capsule cap and body are blue, capsule body is white or almost white; the inscription “150” is printed on the capsule body in black ink; capsule contents: pellets from yellowish-white to light yellow.

Excipients: tartaric acid, hypromellose, hyprolose, talc.

Capsule compositionCap titanium dioxide (E171), indigo carmine (E132), carrageenan, potassium chloride, hypromellose, purified water.
Body titanium dioxide (E171), carrageenan, potassium chloride, hypromellose, purified water¹.
Ink composition shellac, anhydrous ethyl alcohol¹, isopropanol¹, butanol¹, propylene glycol¹, concentrated ammonia solution¹, black iron oxide (E172), potassium hydroxide, purified water¹.

¹ Anhydrous ethyl alcohol, isopropanol, butanol, propylene glycol, concentrated ammonia solution, purified water are not present in the capsule, they evaporate during application.

10 pcs. – blisters (3, 6, or 9) – cardboard packs.
60 pcs. – bottles (1) – cardboard packs.
10 pcs. – blisters (18) – cardboard packs (multipack).

Clinical-Pharmacological Group

Anticoagulant. Direct thrombin inhibitor

Pharmacotherapeutic Group

Antithrombotic agents; direct thrombin inhibitors

Pharmacological Action

Anticoagulant. Direct thrombin inhibitor. Dabigatran etexilate is a low molecular weight, pharmacologically inactive prodrug of the active form, dabigatran. After oral administration, Dabigatran etexilate is rapidly absorbed in the gastrointestinal tract and, by hydrolysis catalyzed by esterases in the liver and plasma, is converted to dabigatran. Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor and the main active substance in plasma.

Since thrombin (a serine protease) converts fibrinogen to fibrin in the coagulation cascade, inhibiting its activity prevents thrombus formation. Dabigatran inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.

Antithrombotic effects and anticoagulant activity of dabigatran after intravenous administration and dabigatran etexilate after oral administration have been confirmed in experimental studies on various models of thrombosis in vivo and ex vivo.

A direct correlation has been established between the plasma concentration of dabigatran and the degree of anticoagulant effect. Dabigatran prolongs aPTT, ecarin clotting time (ECT), and thrombin time (TT).

Pharmacokinetics

After oral administration of dabigatran etexilate, a rapid dose-dependent increase in its plasma concentration and AUC is observed. C_max of dabigatran etexilate is reached within 0.5-2 hours.

After reaching C_max, plasma concentrations of dabigatran decrease biexponentially, with a mean terminal T_1/2 of about 11 hours (in elderly individuals). The terminal T_1/2 after multiple administration was about 12-14 hours. T_1/2 is dose-independent. However, in cases of renal impairment, T_1/2 is prolonged.

Food intake does not affect the bioavailability of dabigatran etexilate, but the time to reach C_max increases by 2 hours.

When dabigatran etexilate is administered 1-3 hours postoperatively, a reduction in the absorption rate of the active substance is observed compared to healthy volunteers. The AUC is characterized by a gradual increase in amplitude without high C_max values. C_max in plasma is observed 6 hours after administration of dabigatran etexilate or 7-9 hours after surgery.

It should be noted that factors such as anesthesia, gastrointestinal paresis, and surgery may contribute to the delayed absorption, regardless of the dosage form. The reduced absorption rate of dabigatran is usually observed only on the day of surgery. On subsequent days, absorption of dabigatran occurs rapidly, with C_max reached 2 hours after oral administration.

The V_d of dabigatran is 60-70 L, which exceeds the total body water volume, indicating moderate distribution of dabigatran in tissues.

After oral administration, Dabigatran etexilate is rapidly and completely converted to dabigatran via hydrolysis by esterases; dabigatran is the main active metabolite in plasma. Conjugation of dabigatran yields 4 isomers of pharmacologically active acylglucuronides: 1-O, 2-O, 3-O, 4-O, each accounting for less than 10% of the total dabigatran in plasma. Traces of other metabolites are detected only when using highly sensitive analytical methods.

Dabigatran is excreted unchanged, primarily by the kidneys (85%), and only 6% via the gastrointestinal tract. It has been established that 88-94% of the dose of radiolabeled dabigatran etexilate is excreted from the body within 168 hours after administration.

Dabigatran has low plasma protein binding capacity (34-35%), which is independent of its concentration.

In elderly individuals, the AUC value is 1.4-1.6 times higher (40-60%) than in young individuals, and C_max is more than 1.25 times higher (25%). The observed changes correlated with the age-related decrease in CrCl.

In elderly women (over 65 years), AUC_t,ss and C_max,ss values were approximately 1.9 times and 1.6 times higher, respectively, than in young women (18-40 years), and in elderly men, they were 2.2 and 2.0 times higher than in young men. In a study of patients with atrial fibrillation, the influence of age on dabigatran exposure was confirmed: baseline concentrations of dabigatran in patients aged >75 years were approximately 1.3 times (31%) higher, and in patients aged <65 years, they were approximately 22% lower than in patients aged 65-75 years.

In volunteers with moderate renal impairment (CrCl 30-50 ml/min), the AUC value of dabigatran after oral administration was approximately 3 times greater than in individuals with normal renal function.

In patients with severe renal impairment (CrCl 10-30 ml/min), the AUC values of dabigatran etexilate and T_1/2 increased by 6 and 2 times, respectively, compared to similar indicators in individuals without renal impairment.

In patients with atrial fibrillation and moderate renal failure (CrCl 30-50 ml/min), trough and peak concentrations of dabigatran were on average 2.29 and 1.81 times higher, respectively, than in patients without renal impairment.

When using hemodialysis in patients without atrial fibrillation, it was found that the amount of active substance removed was proportional to the blood flow rate. The duration of dialysis, with a dialysate flow rate of 700 ml/min, was 4 hours, and the blood flow rate was 200 ml/min or 350-390 ml/min. This led to the removal of 50% and 60% of the concentrations of free and total dabigatran, respectively. The anticoagulant activity of dabigatran decreased as plasma concentrations decreased; the relationship between pharmacokinetics and pharmacodynamic effect did not change.

Indications

Prevention of venous thromboembolism in patients after orthopedic surgery; prevention of stroke, systemic thromboembolism, and reduction of cardiovascular mortality in patients with atrial fibrillation.

ICD codes

Dosage Regimen

The daily dose is 110-300 mg, depending on the indication. Frequency of administration is 1-2 times/day. The treatment regimen and duration of use depend on the indication and clinical situation.

Dosage adjustment is required when dabigatran etexilate is used concomitantly with active P-glycoprotein inhibitors (amiodarone, quinidine, verapamil), as well as in patients aged 75 years and older, with moderate renal impairment (CrCl 30-50 ml/min), or with a history of gastrointestinal bleeding.

Transition from dabigatran to parenteral anticoagulants and vice versa, as well as from dabigatran etexilate to vitamin K antagonists and vice versa, is carried out according to a specific scheme, depending on the indication and clinical situation.

Adverse Reactions

From the hematopoietic and lymphatic systems: anemia, thrombocytopenia.

From the immune system: hypersensitivity reactions, including urticaria, rash and pruritus, bronchospasm.

From the nervous system: intracranial bleeding.

From the vascular system: hematoma, hemorrhage, surgical site bleeding.

From the respiratory system: epistaxis, hemoptysis.

From the digestive system: gastrointestinal bleeding, rectal bleeding, hemorrhoidal bleeding, abdominal pain, diarrhea, dyspepsia, nausea, ulceration of the gastrointestinal mucosa, gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia, increased activity of liver transaminases, impaired liver function, hyperbilirubinemia.

From the skin and subcutaneous tissues: skin hemorrhagic syndrome.

From the musculoskeletal system: hemarthrosis.

From the renal and urinary tract: urogenital bleeding, hematuria.

General disorders and administration site conditions: injection site bleeding, catheter site bleeding.

Injuries, poisonings and procedural complications: post-traumatic hematoma, access site bleeding; wound hematoma, wound bleeding, postoperative anemia, wound discharge after procedures, wound secretion; wound drainage, wound treatment drainage.

Contraindications

Severe renal failure (CrCl less than 30 ml/min); clinically significant active bleeding, hemorrhagic diathesis, spontaneous or pharmacologically induced impairment of hemostasis; organ damage due to clinically significant bleeding, including hemorrhagic stroke within the previous 6 months before initiation of therapy; concomitant use of systemic ketoconazole; liver function impairment and liver disease that may affect survival; children and adolescents under 18 years of age; hypersensitivity to dabigatran or dabigatran etexilate.

Use in Pregnancy and Lactation

There are no data on the use of dabigatran etexilate during pregnancy. The potential risk to humans is unknown.

Experimental studies have not revealed adverse effects on fertility or postnatal development of newborns.

Women of reproductive age should use reliable methods of contraception to exclude the possibility of pregnancy during treatment with dabigatran etexilate. If pregnancy occurs, the use of dabigatran etexilate is not recommended, except in cases where the expected benefit of treatment outweighs the possible risk.

If it is necessary to use dabigatran etexilate during breastfeeding, due to the lack of clinical data, breastfeeding is recommended to be discontinued (as a precautionary measure).

Special Precautions

Use with caution in conditions characterized by an increased risk of bleeding. During therapy with dabigatran etexilate, bleeding of various locations may develop. A decrease in blood hemoglobin and/or hematocrit, accompanied by a decrease in blood pressure, is a reason to search for a source of bleeding.

Tests for determining TT or ECT should be used to detect excessive anticoagulant activity of dabigatran. If these tests are not available, the aPTT test should be used.

In case of acute renal failure development, Dabigatran etexilate should be discontinued.

The following factors can lead to an increase in the plasma concentration of dabigatran: decreased renal function (CrCl 30-50 ml/min), age ≥75 years, concomitant use of a P-glycoprotein inhibitor. The presence of one or more such factors may increase the risk of bleeding.

Concomitant use of dabigatran etexilate with the following drugs has not been studied but may increase the risk of bleeding: unfractionated heparin (except for doses required to maintain the patency of a venous or arterial catheter) and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux sodium, thrombolytic drugs, glycoprotein GP IIb/IIIa platelet receptor blockers, ticlopidine, dextran, rivaroxaban, ticagrelor, vitamin K antagonists and P-glycoprotein inhibitors (itraconazole, tacrolimus, cyclosporine, ritonavir, nelfinavir and saquinavir). The risk of bleeding is increased in patients concomitantly taking selective serotonin reuptake inhibitors. The risk of bleeding may also increase with the concomitant use of antiplatelet agents and other anticoagulants.

Concomitant use of dronedarone and dabigatran is not recommended.

In case of increased risk of bleeding (e.g., recently performed biopsy or extensive trauma, bacterial endocarditis), monitoring of the patient’s condition is required for timely detection of signs of bleeding.

Concomitant use of dabigatran etexilate, antiplatelet agents (including acetylsalicylic acid and clopidogrel) and NSAIDs increases the risk of bleeding.

Use of fibrinolytic drugs can only be considered if the patient’s TT, ECT, or aPTT values do not exceed the upper limit of the local reference range.

In patients receiving Dabigatran etexilate, the risk of bleeding is increased during surgical operations or invasive procedures. Therefore, Dabigatran etexilate should be discontinued prior to surgery.

Before performing invasive procedures or surgical operations, Dabigatran etexilate should be discontinued at least 24 hours before their performance. In patients with an increased risk of bleeding or before extensive surgery requiring complete hemostasis, Dabigatran etexilate should be discontinued 2-4 days before surgery.

In patients with renal failure, the clearance of dabigatran may be prolonged.

Dabigatran etexilate is contraindicated in patients with severe renal impairment (CrCl <30 ml/min), but if it is still used, discontinuation should be performed at least 5 days before surgery.

If emergency surgical intervention is necessary, administration of dabigatran etexilate must be temporarily stopped. Surgery, if possible, should be performed no earlier than 12 hours after the last dose. If surgery cannot be postponed, the risk of bleeding may increase. In such a case, the risk-benefit ratio of the urgent intervention should be assessed.

Procedures such as spinal anesthesia may require complete restoration of hemostasis. In the case of traumatic or repeated spinal puncture and prolonged use of an epidural catheter, the risk of developing spinal bleeding or an epidural hematoma may increase. The first dose of dabigatran should be taken no earlier than 2 hours after catheter removal.

Monitoring of patients’ condition is necessary to rule out neurological symptoms that may be caused by spinal bleeding or an epidural hematoma.

Effect on the ability to drive vehicles and operate machinery

Considering that the use of dabigatran etexilate may be accompanied by an increased risk of bleeding, caution should be exercised when engaging in such activities.

Drug Interactions

Concomitant use with medicinal products affecting hemostasis or coagulation processes, including vitamin K antagonists, may significantly increase the risk of bleeding.

Dabigatran etexilate is a substrate for the transport molecule P-glycoprotein. Concomitant use of P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, systemic ketoconazole, or clarithromycin) leads to an increase in the plasma concentration of dabigatran.

When dabigatran etexilate was used concomitantly with a single oral dose of amiodarone (600 mg), the extent and rate of absorption of amiodarone and its active metabolite, desethylamiodarone, did not change. The AUC and C_max values of dabigatran increased approximately 1.6-fold and 1.5-fold (by 60% and 50%), respectively. In a study in patients with atrial fibrillation, the concentration of dabigatran increased by no more than 14%, and no increase in the risk of bleeding was recorded.

After simultaneous use of dabigatran etexilate and a single dose of dronedarone 400 mg, the AUC_0-∞ and C_max of dabigatran increased 2.1-fold and 1.9-fold (by 114% and 87%), respectively, and after multiple doses of dronedarone 400 mg/day – 2.4-fold and 2.3-fold (by 136% and 125%), respectively. After single and multiple doses of dronedarone taken 2 hours after dabigatran etexilate intake, AUC_0-∞ increased 1.3-fold and 1.6-fold, respectively. Dronedarone did not affect the terminal T_1/2 and renal clearance of dabigatran.

When dabigatran etexilate was used concomitantly with orally administered verapamil, the C_max and AUC values of dabigatran increased depending on the time of administration and the dosage form of verapamil. The greatest increase in the effect of dabigatran was observed when using the first dose of verapamil in an immediate-release formulation taken 1 hour before dabigatran etexilate (C_max increased by 180%, and AUC by 150%). When using a sustained-release formulation of verapamil, this effect progressively decreased (C_max increased by 90%, and AUC by 70%), as well as when using multiple doses of verapamil (C_max increased by 60%, and AUC by 50%), which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with long-term use of verapamil. When verapamil was used 2 hours after dabigatran etexilate intake, no clinically significant interaction was observed (C_max increased by 10%, and AUC by 20%), since dabigatran is completely absorbed after 2 hours. In a study in patients with atrial fibrillation, the concentration of dabigatran increased by no more than 21%, and no increase in the risk of bleeding was recorded.

Systemic ketoconazole after a single 400 mg dose increases the AUC_0-∞ and C_max of dabigatran approximately 2.4-fold (by 138% and 135%) respectively, and after multiple doses of ketoconazole 400 mg/day – approximately 2.5-fold (by 153% and 149%) respectively. Ketoconazole did not affect T_max and terminal T_1/2. The combination of dabigatran etexilate and systemic ketoconazole is contraindicated.

When clarithromycin 500 mg twice daily was used concomitantly with dabigatran etexilate, no clinically significant pharmacokinetic interaction was observed (C_max increased by 15%, and AUC by 19%).

The AUC_t,ss and C_max,ss values of dabigatran when used twice daily in case of concomitant administration with quinidine 200 mg every 2 hours until a total dose of 1000 mg was reached increased on average by 53% and 56%, respectively.

Concomitant use of dabigatran etexilate and P-glycoprotein inducers should be avoided, as concomitant use leads to a reduction in dabigatran exposure.

Prior use of the test inducer rifampicin at a dose of 600 mg/day for 7 days led to a reduction in dabigatran exposure. After discontinuation of rifampicin, this inductive effect decreased, and on day 7, the effect of dabigatran was close to the baseline level. Over the next 7 days, no further increase in the bioavailability of dabigatran was observed.

It is assumed that other P-glycoprotein inducers, such as St. John’s wort or carbamazepine, can also reduce the plasma concentration of dabigatran; such combinations should be used with caution.

In a study of the simultaneous use of dabigatran etexilate 150 mg twice daily and acetylsalicylic acid in patients with atrial fibrillation, it was found that the risk of bleeding may increase from 12% to 18% (with an acetylsalicylic acid dose of 81 mg) and to 24% (when using acetylsalicylic acid at a dose of 325 mg). It has been shown that acetylsalicylic acid or clopidogrel used concomitantly with dabigatran etexilate at a dose of 110 mg or 150 mg twice daily may increase the risk of major bleeding. Bleeding is also observed more frequently with the concomitant use of warfarin with acetylsalicylic acid or clopidogrel.

It has been established that the simultaneous use of dabigatran etexilate and clopidogrel does not lead to an additional increase in capillary bleeding time compared with clopidogrel monotherapy. Furthermore, it has been shown that the AUC_t,ss and C_max,ss values of dabigatran, as well as blood coagulation parameters monitored to assess the effect of dabigatran (aPTT, ecarin clotting time or thrombin time (anti-FIIa), and the degree of platelet aggregation inhibition (the main indicator of the effect of clopidogrel) during combination therapy did not change compared to the corresponding indicators in monotherapy. When using a “loading” dose of clopidogrel (300 or 600 mg), the AUC_t,ss and C_max,ss values of dabigatran increased by 30-40%.

When dabigatran etexilate and pantoprazole were used together, a 30% decrease in the AUC of dabigatran was observed. Pantoprazole and other proton pump inhibitors were used concomitantly with dabigatran etexilate in clinical studies, with no observed effect on the risk of bleeding or efficacy.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.