Pradaxa, capsules 110mg, 60pcs

Composition

Active ingredient:

dabigatran etexylate mesylate;

Auxiliary substances:

acacia gum;

tartaric acid,

coarse-grained;

tartaric acid powder;

tartaric acid crystal;

hypromellose;

dimethicone;

talc;

hyprolose (hydroxypropylcellulose);

Shell:

hypromellose capsule (HPMC) with black ink overprint (Colorcon S-1-27797);

HPMC capsules:  carrageenan; potassium chloride; titanium dioxide; indigo carmine (E 132); sunset yellow dye (E 110); hypromellose (hydroxypropylmethylcellulose), purified water;

Composition of black ink Colorcon S-1-27797, (wt%):  shellac 52.500%, butanol 6.550%, purified water 1.940%, denatured ethanol (methylated alcohol) 0.650%, iron oxide black dye (E 172) 33.770%, isopropanol 3.340%, propylene glycol 1.250%

Pharmacological action

Pradaxa has an anticoagulant effect.

Pharmacodynamics

Dabigatran etexylate is a low-molecular-weight, non-pharmacologically active precursor to the active form of dabigatran. After oral use of dabigatran, etexylate is rapidly absorbed in the gastrointestinal tract (GIT) and, by hydrolysis catalyzed by esterases, is converted to dabigatran in the liver and blood plasma. Dabigatran is a powerful competitive reversible direct thrombin inhibitor and the main Active ingredient in blood plasma.

Since thrombin (serine protease) converts fibrinogen to fibrin during coagulation, inhibition of thrombin activity prevents the formation of a blood clot. Dabigatran has an inhibitory effect on free thrombin, fibrin clot-bound thrombin, and thrombin-induced platelet aggregation.

Experimental studies on various models of thrombosis in vivo and ex vivo confirmed the antithrombotic effect and anticoagulant activity of dabigatran after intravenous use and dabigatran etexilate after oral use.

A direct correlation was established between the concentration of dabigatran in blood plasma and the severity of the anticoagulant effect. Dabigatran extends activated partial thromboplastin time (APTT), ecarin clotting time (EMU), and thrombin time (TV).

Prevention of venous thromboembolism (VTE) after large joint replacement

The results of clinical studies in patients who underwent orthopedic operations – knee and hip replacement – confirmed the preservation of hemostasis parameters and the equivalence of using 75 mg or 110 mg of dabigatran etexilate 1-4 hours after surgery and a subsequent maintenance dose of 150 or 220 mg once a day for 6-10 days (for knee surgery) and 28-35 days (for hip surgery) compared with enoxaparin at a dose of 40 mg once a day, which was used.

The equivalence of the antithrombotic effect of dabigatran etexilate at 150 mg or 220 mg compared with enoxaparin at a dose of 40 mg per day was shown in the assessment of the main endpoint, which includes all cases of venous thromboembolism and mortality from any cause.

Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

With prolonged use, on average about 20 months, in patients with atrial fibrillation and with a moderate or high risk of stroke or systemic thromboembolism, dabigatran etexilate 110 mg administered twice daily was shown to be as effective as warfarin in preventing stroke and systemic thromboembolism in patients with atrial fibrillation; also, in the dabigatran group, there was a decrease in the risk of intracranial bleeding and the overall frequency of bleeding. The use of a higher dose of the drug (150 mg twice daily) significantly reduced the risk of ischemic and hemorrhagic strokes, cardiovascular death, intracranial bleeding, and the overall frequency of bleeding, compared with warfarin. The lower dose of dabigatran was characterized by a significantly lower risk of major bleeding compared to warfarin.

The net clinical effect was evaluated by determining a combined endpoint that included the incidence of stroke, systemic thromboembolism, pulmonary thromboembolism, acute myocardial infarction, cardiovascular mortality, and major bleeding events.

The annual incidence of these events in patients treated with dabigatran etexilate was lower than in patients treated with warfarin.

Changes in laboratory parameters of liver function in patients treated with dabigatran etexilate were observed with a comparable or lower frequency compared to patients treated with warfarin.

Pharmacokinetics

After oral use of dabigatran etexilate, there is a rapid dose-dependent increase in its plasma concentration and area under the concentration-time curve (AUC). The maximum concentration of dabigatran etexylate (Cmax) is reached within 0.5-2 hours.

After reaching Cmax, plasma concentrations of dabigatran decrease biexponentially, the final half-life (T 1/2) is on average about 11 hours (in the elderly). The final T 1/2 after repeated use of the drug was about 12-14 hours. T 1/2 does not depend on the dose. However, in the case of impaired renal function, T 1/2 is lengthened.

The absolute bioavailability of dabigatran after oral use of dabigatran etexylate in hypromellose-coated capsules is about 6.5%.

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

When using dabigatran etexylate without a special capsule shell made of hypromellose, oral bioavailability can increase approximately 1.8 times (by 75%) compared to the dosage form in capsules. Therefore, the integrity of capsules made from hypromellose should be preserved, taking into account the risk of increasing the bioavailability of dabigatran etexylate, and it is not recommended to open the capsules and use their contents in pure form (for example, by adding them to food or beverages) (see the section “Dosage and use”).

When using dabigatran etexilate in 1-3 hours, patients after surgical treatment showed a decrease in the rate of absorption of the drug compared to healthy volunteers. AUC is characterized by a gradual increase in the amplitude without the appearance of a high peak in plasma concentration. Cmax in blood plasma is observed 6 hours after the use of dabigatran etexilate or 7-9 hours after surgery. It should be noted that factors such as anesthesia, gastrointestinal paresis, and surgery may play a role in slowing absorption, regardless of the dosage form of the drug. A decrease in the rate of absorption of the drug is usually noted only on the day of surgery. In the following days, the absorption of dabigatran occurs rapidly, with the Cmax reaching 2 hours after ingestion.

Metabolism

After oral use, during hydrolysis under the influence of dabigatran esterase, etexylate is rapidly and completely converted to dabigatran, which is the main active metabolite in blood plasma. During conjugation of dabigatran,4 isomers of pharmacologically active acylglucuronides are formed: 1-O,2-O,3-O,4-O, each of which is less than 10% of the total dabigatran content in blood plasma. Traces of other metabolites are detected only when highly sensitive analytical methods are used.

Distribution

The volume of distribution of dabigatran is 60-70 liters and exceeds the volume of total water content in the body, which indicates a moderate distribution of dabigatran in tissues.

Deduction

Dabigatran is excreted unchanged, mainly by the kidneys (85%), and only 6% – through the gastrointestinal tract. It was found that in 168 hours after use of the labeled radioactive drug,88-94% of its dose is eliminated from the body.

Dabigatran has a low binding capacity to plasma proteins (34-35%), it does not depend on the concentration of the drug.

Special patient groups

Elderly patients

In the elderly, the AUC value is 1.4-1.6 times higher than in young people (by 40-60%), and Cmax is more than 1.25 times (by 25%).

The observed changes correlated with an age-related decrease in creatinine clearance (CC).

In elderly women (older than 65 years), AUCt, ss and Cmax, ss values were approximately 1.9 and 1.6 times higher than in young women (18-40 years), and in elderly men – 2.2 and 2.0 times higher than in young men. In a study in patients with atrial fibrillation, the effect of age on dabigatran exposure was confirmed: initial dabigatran concentrations in patients aged ≥75 years were approximately 1.3 times (31%) higher, and in patients aged

Impaired renal function

In volunteers with moderate renal impairment (creatinine clearance 30-50 ml/min), the AUC value of dabigatran after oral use was approximately 3 times higher than in individuals with unchanged renal function.

In patients with severe renal impairment (creatinine clearance – 10-30 ml/min), the AUC values of dabigatran etexilate and T 1/2 increased by 6 and 2 times, respectively, compared with similar indicators in individuals without impaired renal function.

In patients with atrial fibrillation and moderate renal insufficiency (creatinine clearance 30-50 ml/min), the concentrations of dabigatran before and after use of the drug were on average 2.29 and 1.81 times higher than in patients without impaired renal function.

When using hemodialysis in patients without atrial fibrillation, it was found that the amount of drug excreted is 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 resulted in the removal of 50% and 60% of the free and total dabigatran concentrations, respectively. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations, the relationship between FC and PD did not change.

Impaired liver function

In patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale), there were no changes in the concentration of dabigatran in blood plasma compared with patients without impaired liver function.

Body weight

In studies, basal concentrations of dabigatran in patients with a body weight >100 kg were approximately 20% lower than in patients with a body weight of 50-100 kg. Body weight in most (80.8%) patients was ≥50 – Data on patients with a body weight of < 50 kg are limited.

Gender

In the main studies on the prevention of VTE, it was found that the effect of the drug in female patients was approximately 1.4-1.5 times (40-50%) higher. In patients with atrial fibrillation, basal and post-drug concentrations were on average 1.3 times (30%) higher. These differences were not clinically significant.

Ethnic groups

In a comparative study of the pharmacokinetics of dabigatran in Europeans and Japanese after a single and repeated use of the drug in the studied ethnic groups, no clinically significant differences were found. Pharmacokinetic studies in black patients are limited, but the available data indicate that there are no significant differences.

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.

Contraindications

• Known hypersensitivity to dabigatran, dabigatran etexylate or any of the excipients;
• Severe renal failure (creatinine clearance less than 30 ml / min);
• Active clinically significant bleeding, hemorrhagic diathesis, spontaneous or pharmacologically induced hemostasis disorder;
• Organ damage resulting from clinically significant bleeding, including hemorrhagic stroke, within 6 months prior to the start of therapy;
• Simultaneous use of ketoconazole for systemic use;
• Liver function disorders and liver diseases that may affect survival;
• Age up to 18 years (no clinical data available).

Side effects

Disorders of the hematopoietic and lymphatic system: anemia, thrombocytopenia.

Immune system disorders: hypersensitivity reactions, including urticaria, rash and pruritus, bronchospasm.

Nervous system disorders: intracranial bleeding.

Vascular disorders: hematoma, bleeding.

Respiratory, thoracic and mediastinal disorders: nosebleeds, hemoptysis.

Gastrointestinal disorders: gastrointestinal bleeding, rectal bleeding, hemorrhoidal bleeding, abdominal pain, diarrhea, dyspepsia, nausea, ulceration of the gastrointestinal mucosa, gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia.

Disorders of the hepatobiliary system: increased activity of “hepatic” transaminases, impaired liver function, hyperbilirubinemia.

Changes in the skin and subcutaneous tissues: cutaneous hemorrhagic syndrome.

Musculoskeletal disorders, connective tissue and bone disorders: hemarthrosis.

Changes in the kidneys and urinary tract: urogenital bleeding, hematuria.

General disorders and changes in the injection site: bleeding from the injection site, bleeding from the catheter insertion site.

Damage, toxicity, and complications from the procedures: post-traumatic hematoma, bleeding from the surgical access site.

Vascular disorders: bleeding from an operating wound.

General disorders and disorders at the injection site: spotty discharge.

Postoperative damage, toxicity, and complications: hematoma after wound treatment, bleeding after wound treatment, anemia in the postoperative period, discharge from the wound after procedures, secretion from the wound.

Surgical and therapeutic procedures: wound drainage, drainage after wound treatment.

Interaction

Concomitant use of PRADAXA with medications that affect hemostasis or the coagulation system, including vitamin K antagonists, may significantly increase the risk of bleeding.

Pharmacokinetic interactions

No inducing or inhibitory effect of dabigatran on cytochrome P450 has been established in in vitro studies. In vivo studies in healthy volunteers showed no interaction between dabigatran etexilate and atorvastatin (a CYP3A4 substrate) and diclofenac (a CYP2C9 substrate).

Interactions with P-glycoprotein inhibitors/inducers:

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

Concomitant use with P-glycoprotein inhibitors:

Dose adjustment for the use of the listed P-glycoprotein inhibitors for the prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation is not required.

If used for the prevention of venous thromboembolism in patients after orthopedic surgery, see the sections “Dosage and use” and “Interaction with other medications”.

Amiodarone. Concomitant use of dabigatran etexilate with a single dose of amiodarone (600 mg) taken orally did not change the degree and rate of absorption of amiodarone and its active metabolite, desethylamiodarone. Dabigatran AUC and Cmax values increased approximately 1.6 and 1.5 times (by 60% and 50%), respectively.

In the study, in patients with atrial fibrillation, the concentration of dabigatran increased by no more than 14%, and there was no increase in the risk of bleeding.

Dronedaron. After simultaneous application of dabigatran etexilate and dronedarone at a dose of 400 mg as a single dose,

AUC0-∞ and Cmax of dabigatran increased by 2.1 and 1.9 times (114% and 87%, respectively), and after repeated use of dronedarone at a dose of 400 mg per day – in 2.4 and 2.3 (136% and 125%, respectively). After a single and repeated use of dronedarone 2 hours after taking dabigatran etexylate, AUC0 – ∞ increased by 1.3 and 1.6 times, respectively. Dronedarone did not affect the final T 1/2 and renal clearance of dabigatran.

Verapamil. When dabigatran etexilate was co-administered with oral verapamil, the Cmax and AUC values of dabigatran increased depending on the time of use 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 dosage form, which was applied 1 hour before taking dabigatran etexilate (Cmax increased by 180%, and AUC-by 150%). When using the delayed-release verapamil dosage form, this effect was progressively reduced (Cmax increased by 90%, and AUC-by 70%), as well as when using multiple doses of verapamil (Cmax increased by 60%, and AUC – by 50%), which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with prolonged use of verapamil.

When using verapamil 2 hours after taking dabigatran etexilate, no clinically significant interactions were observed (Cmax increased by 10%, and AUC-by 20%), since after 2 hours dabigatran is completely absorbed (see the section “Dosage and use”).

In the study, in patients with atrial fibrillation, the concentration of dabigatran increased by no more than 21%, and there was no increase in the risk of bleeding.

There are no data on the interaction of dabigatran etexilate with parenterally administered verapamil; no clinically significant interaction is expected.

Ketoconazole. Systemic ketoconazole increases dabigatran AUC0-∞ and Cmax approximately 2.4 – fold (by 138% and 135%), respectively, after a single 400 mg dose, and approximately 2.5-fold (by 153% and 149%), respectively, after repeated 400 mg ketoconazole use. Ketoconazole had no effect on Tmax and final T 1/2. Concomitant use of PRADAXA and ketoconazole for systemic use is contraindicated.

Clarithromycin. No clinically significant pharmacokinetic interaction was observed when clarithromycin was co-administered at a dose of 500 mg twice daily with dabigatran etexilate (Cmax increased by 15%, and AUC-by 19%).

Quinidine. The values of AUCt, ss and Cmax, ss of dabigatran when used 2 times a day in the case of simultaneous use with quinidine at a dose of 200 mg every 2 hours until the total dose of 1000 mg was reached increased on average by 53% and 56%, respectively.

Simultaneous use with P-glycoprotein substrates:

Digoxin. No pharmacokinetic interaction was observed when dabigatran etexylate was co-administered with digoxin, a P-glycoprotein substrate. Neither dabigatran nor the prodrug dabigatran etexylate are clinically significant inhibitors of P-glycoprotein.

Concomitant use with P-glycoprotein inducers:

Concomitant use of PRADAXA and P-glycoprotein inducers should be avoided, as concomitant use reduces the effect of dabigatran (see section “Special instructions”).

Rifampicin. Preliminary use of the test inducer rifampicin at a dose of 600 mg per day for 7 days resulted in reduced exposure to dabigatran. After discontinuation of rifampicin, this inductive effect decreased, and on day 7, the effect of dabigatran was close to the initial level. During the next 7 days, there was no further increase in the bioavailability of dabigatran.

It is suggested that other inducers of P-glycoprotein, such as St. John’s wort or carbamazepine, may also reduce the concentration of dabigatran in blood plasma and should be used with caution.

Simultaneous use with antiplatelet

agents Acetylsalicylic acid (ASA). When studying the simultaneous use of dabigatran etexilate at a dose of 150 mg 2 times a day and acetylsalicylic acid (ASA) in patients with atrial fibrillation, it was found that the risk of bleeding can increase from 12% to 18% (when using ASA at a dose of 81 mg) and up to 24% (when using ASA at a dose of 325 mg). It has been shown that ASA or clopidogrel, used simultaneously with dabigatran etexilate at a dose of 110 mg or 150 mg 2 times a day, may increase the risk of major bleeding. Bleeding is also more common when warfarin is co-administered with ASA or clopidogrel.

NSAIDs. NSAIDs (nonsteroidal anti-inflammatory drugs) used for short-term analgesia after surgery did not increase the risk of bleeding when used concomitantly with dabigatran etexilate. The experience of long-term use of NSAIDs, T 1/2 of which is less than 12 hours, with dabigatran etexilate is limited, there are no data on an additional increase in the risk of bleeding.

Clopidogrel. Concomitant use of dabigatran etexylate and clopidogrel did not result in an additional increase in capillary bleeding time compared to clopidogrel monotherapy. In addition, it was shown that the values of AUCt, ss and Cmax, ss of dabigatran, as well as blood clotting parameters that were monitored to assess the effect of dabigatran (APTT, ecarin clotting time or thrombin time (anti-FIIa), as well as the degree of inhibition of platelet aggregation (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 AUCt, ss and Cmax values of dabigatran increased by 30-40%.

Simultaneous use with drugs that increase the pH of the stomach contents

Pantoprazole. When dabigatran etexylate and pantoprazole were co-administered, a 30% decrease in dabigatran AUC was observed. Pantoprazole and other proton pump inhibitors have been co-administered with dabigatran etexilate in clinical trials, but no effect on bleeding risk or efficacy has been observed.

Ranitidine. Ranitidine, when administered concomitantly with dabigatran etexylate, did not significantly affect the degree of absorption of dabigatran.

The changes in the pharmacokinetic parameters of dabigatran detected during the population analysis under the influence of proton pump inhibitors and antacids were clinically insignificant, since the severity of these changes was small (the decrease in bioavailability was not significant for antacids, and for proton pump inhibitors was 14.6%). It was found that the simultaneous use of proton pump inhibitors is not accompanied by a decrease in the concentration of dabigatran and, on average, only slightly reduces the concentration of the drug in blood plasma (by 11%). Therefore, concomitant use of proton pump inhibitors does not appear to increase the incidence of stroke or systemic thromboembolism, especially when compared with warfarin, and therefore the reduced bioavailability of dabigatran caused by concomitant use of pantoprazole is probably not clinically significant.

How to take, course of use and dosage

Capsules should be taken orally,1 or 2 times a day, regardless of the meal time, with water. Do not open the capsule.

Overdose

Overdose when using the drug PRADAXA may be accompanied by hemorrhagic complications, which is due to the pharmacodynamic characteristics of the drug. If bleeding occurs, the drug is discontinued. Symptomatic treatment is indicated. There is no specific antidote.

Given the main route of elimination of dabigatran (by the kidneys), it is recommended to provide adequate diuresis. Surgical hemostasis and replacement of the circulating blood volume (BCC) are performed. It is possible to use fresh whole blood or transfusion of fresh frozen plasma. Since dabigatran has a low ability to bind to plasma proteins, the drug can be eliminated during hemodialysis, but clinical experience with the use of dialysis in these situations is limited (see the section “Pharmacokinetics”).

In case of overdose of PRADAXA, it is possible to use concentrates of activated prothrombin complex or recombinant factor VIIa or concentrates of clotting factors II, IX or X. There are experimental data confirming the effectiveness of these drugs in countering the anticoagulant effect of dabigatran, but no special clinical studies have been conducted.

In the case of thrombocytopenia, or when using long-acting antiplatelet agents, the use of platelet mass may be considered.

Form of production

Capsules

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

3 years

Active ingredient

Dabigatran etexylate

Conditions of release from pharmacies

By prescription

Dosage form

Capsules

Purpose

For adults as directed by your doctor

Indications

Prevention of heart attacks and strokes, Prevention of thrombosis, Myocardial infarction