Pradaxa, 150mg capsules, 180pcs

Composition

of 1 capsule. : – dabigatran etexylate mesylate 172.95 mg, acc. the content of dabigatran etexylate is 150 mgcompliant substances: acacia gum – 8.86 mg, tartaric acid (coarse) – 44.28 mg, tartaric acid (powder) – 59.05 mg, tartaric acid (crystalline) – 73.81 mg, hypromellose-4.46 mg, dimethicone-0.08 mg, talc-34.31 mg, hyprolose (hydroxypropylcellulose) – 34.59 mg. Capsule shell composition: carrageenan (E407) – 0.285 mg, potassium chloride-0.4 mg, titanium dioxide (E171) – 5.4 mg, indigo carmine (E132) – 0.054 mg, sunset yellow dye (E110) – 0.004 mg, hypromellose (hydroxypropylmethylcellulose) – 79.35 mg, purified water-4.5 mg. The composition of black ink Colorcon S-1-27797: shellac 52.5%, butanol 6.55%, denatured ethanol (methylated alcohol) 0.65%, iron oxide black dye (E172) 33.77%, isopropanol 3.34%, propylene glycol 1.25%, purified water 1.94%.

Pharmacological action

PRADAXA-dabigatran etexylate is a low-molecular-weight prodrug with no pharmacological activity. After oral use, it is rapidly absorbed and converted to dabigatran by hydrolysis catalyzed by esterases. Dabigatran is an active, competitive, reversible direct inhibitor of thrombin and has an effect mainly in plasma. Since thrombin (serine protease) converts fibrinogen into fibrin during the coagulation cascade, inhibition of its activity prevents the formation of a blood clot. Dabigatran inhibits free thrombin, fibrin-binding thrombin, and thrombin-induced platelet aggregation. In vivo and ex vivo animal studies using different models of thrombosis have demonstrated the antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous use and dabigatran etexilate after oral use. A close correlation was found between the concentration of dabigatran in plasma and the severity of the anticoagulant effect. Dabigatran extends activated partial thromboplastin time (APTT).

Indications

Prevention of venous thromboembolism in patients after orthopedic surgery.

Contraindications

Known hypersensitivity to dabigatran or dabigatran etexylate or to one of the excipients. Patients with severe renal insufficiency ( creatinine clearance less than 30 ml / min). Hemorrhagic disorders, patients with hemorrhagic diathesis, patients with spontaneous or pharmacologically induced hemostasis disorders. Active clinically significant bleeding. Liver function disorders and liver diseases that may affect survival. Simultaneous use of quinidine. Organ damage resulting from clinically significant bleeding, including hemorrhagic stroke, during the previous 6 months prior to initiation of therapy. Patients are less than 18 years old.

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 dose,

the AUC_0-∞ and C_max 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, the AUC_{0 – ∞} 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 formulations of verapamil sustained release this effect progressively decreased (C_max increased by 90% and AUC by 70%), as well as by using multiple doses of verapamil (C_max increased by 60% and AUC by 50%), which may be due to induction of P-glycoprotein in the intestine with long-term 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 AUC_0-∞ 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 multiple 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 500 mg twice daily was co-administered with dabigatran etexilate (_cmax increased by 15% and AUC increased by 19%).

Quinidine. Values of AUC_{τ, ss} and_{cmax, ss} dabigatran when used twice 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, on average, increased 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. Furthermore, it is shown that the values of AUC_{τ, ss} and C_{max, ss} dabigatran, and the parameters of blood coagulation, which were controlled to assess the effect of dabigatran (APTT, abarinova the coagulation time, or thrombin time (anti-FIIa) and the degree of inhibition of platelet aggregation (the main indicator of the effect of clopidogrel) during combination therapy has not changed in comparison with those in monotherapy. When using a” loading ” dose of clopidogrel (300 or 600 mg), the values of AUC_{t, ss} and_{cmax, ss} 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

Inside. During meals or on an empty stomach, washed down with water. Special instructions when removing capsules from the blister, remove the capsules from the blister by peeling off the foil. Do not squeeze the capsules through the foil. Remove the foil so that it is convenient to remove the capsules. Adult prevention of venous thromboembolism (VT) in patients after orthopedic surgeries, the recommended dose is 220 mg once daily (2 capsules of 110 mg).

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.

Special instructions

Risk of hemorrhage: Unfractionated heparin can be used to maintain the functioning of the central venous or arterial catheter. Do not use at the same time as PRADAXA:unfractionated heparins or its derivatives, low molecular weight heparins, fondaparinux sodium, desirudin, thrombolytics, GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists. The combined use of PRADAX® in the recommended doses for the treatment of deep vein thrombosis and acetylsalicylic acid in doses of 75-320 mg increases the risk of bleeding. There are no data indicating an increased risk of bleeding associated with dabigatran when taking PRADAXA® at the recommended dose in patients receiving small doses of acetylsalicylic acid in order to prevent cardiovascular diseases. However, the available information is limited, so when using low-dose acetylsalicylic acid and PRADAXA together, it is necessary to monitor the condition of patients in order to diagnose bleeding in a timely manner. Careful monitoring (for symptoms of bleeding or anemia) should be carried out in cases where there may be an increased risk of hemorrhagic complications. :- A recent biopsy or injury. – Use of drugs that increase the risk of hemorrhagic complications. Combination of PRADAXA with drugs that affect hemostasis or coagulation processes. – Bacterial endocarditis: Short-term use of NSAIDs in combination with PRADAXA® for postoperative analgesia does not increase the risk of bleeding. There are limited data on the systematic use of NSAIDs with a half-life of less than 12 hours in combination with PRADAXA, and there is no evidence of an increased risk of bleeding. Renal insufficiency: pharmacokinetic studies have shown that patients with reduced renal function, including those associated with age, showed an increase in the effectiveness of the drug. In patients with moderately reduced renal function (creatinine clearance 50-30 ml/min), it is recommended to reduce the daily dose to 150 mg per day. PRADAXA® is contraindicated in patients with severe renal impairment (creatinine clearance Spinal anesthesia/Epidural anesthesia / Lumbar puncture: Traumatic or repeated spinal puncture and prolonged use of an epidural catheter may increase the risk of developing spinal bleeding or an epidural hematoma. The first dose of PRADAXA should be taken no earlier than 2 hours after catheter removal. These patients should be monitored for possible neurological symptoms. The effect of dabigatran etexylate on the ability to drive vehicles and manage mechanisms on the ability to drive mechanisms has not been studied.

Storage conditions

Store in a dry place, at a temperature not exceeding 25 ° C.

Shelf

life is 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

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