Pradaxa, 150 mg capsules 180 pcs

PRADAXA – dabigatran etexilate is a low molecular weight prodrug that has no pharmacological activity. After oral administration, it is rapidly absorbed and is converted to dabigatran by esterase-catalyzed hydrolysis. Dabigatran is an active, competitive, reversible direct thrombin inhibitor and acts mainly in plasma.

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

In vivo and ex vivo animal studies using various models of thrombosis have demonstrated the antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and dabigatran etexilate after oral administration.

A close correlation between the concentration of dabigatran in plasma and the severity of anticoagulant effect was revealed. Dabigatran prolongs activated partial thromboplastin time (ATTB).

Indications

Active ingredient

How to take, the dosage

Interaction

The co-administration of PRADAXA with drugs affecting hemostasis or the coagulation system, including vitamin K antagonists, may significantly increase the risk of bleeding.

Pharmacokinetic interactions

In in vitro studies, no inducing or inhibitory effect of dabigatran on cytochrome P450 was found. In in vivo studies in healthy volunteers, no interaction was observed between dabigatran etexilate and atorvastatin (CYP3A4 substrate) and diclofenac (CYP2C9 substrate).

Interactions with P-glycoprotein inhibitors/inducers:

The substrate for the transport molecule of P-glycoprotein is dabigatran etexilate. Concomitant use of P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, ketoconazole for systemic use or clarithromycin) leads to increased plasma concentrations of dabigatran.

Concomitant use with P-glycoprotein inhibitors:

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

When used for prophylaxis of venous thromboembolism in patients after orthopedic surgery, see sections “Administration and Dose” and “Interaction with Other Medications”.

Amiodarone. When dabigatran etexilate was used concomitantly with a single dose of amiodarone (600 mg) taken orally, the degree and rate of absorption of amiodarone and its active metabolite, desethylamiodarone, did not change. The AUC and Cmax values of dabigatran increased approximately 1.6 and 1.5-fold (60% and 50%), respectively.

In the study in patients with atrial fibrillation, dabigatran concentrations were increased by no more than 14% and no increase in bleeding risk was reported.

Dronedarone. After concomitant administration of dabigatran etexilate and dronedarone at a dose of 400 mg once,

The AUC0-∞ and Cmax of dabigatran increased 2.1 and 19 times (by 114% and 87%), respectively, and 2.4 and 2.3 times (by 136% and 125%), respectively, after multiple dronedarone doses of 400 mg per day. The AUC0-∞ increased 1.3 and 1.6-fold, respectively, after single and multiple dronedarone administration 2 hours after dabigatran etexilate administration. Dronedarone had no effect on the final T1/2 and renal clearance of dabigatran.

Verapamil. When dabigatran etexilate was used concomitantly with orally administered verapamil, the Cmax and AUC values of dabigatran were increased depending on the time of administration and the dosage form of verapamil.

The greatest increase in the effect of dabigatran was observed with the first dose of verapamil in immediate-release dosage form administered 1 h before dabigatran etexilate (Cmax increased by 180% and AUC increased by 150%). This effect was progressively reduced with the delayed-release dosage form verapamil (Cmax increased by 90% and AUC increased by 70%), as well as with multiple doses of verapamil (Cmax increased by 60% and AUC increased by 50%), which may be due to induction of P-glycoprotein in the GI tract with long-term verapamil administration.

When using verapamil 2 h after dabigatran etexilate administration, no clinically significant interactions were observed (Cmax increased by 10% and AUC increased by 20%) because dabigatran is fully absorbed after 2 h (see section “Dosage and administration”).

In the study in patients with atrial fibrillation the concentration of dabigatran did not increase by more than 21%, no increased risk of bleeding was registered.

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

Ketoconazole. Ketoconazole for systemic use increases the AUC0-∞ and Cmax of dabigatran by approximately 2.4-fold (by 138% and 135%), respectively, and by approximately 2.5-fold (by 153% and 149%) after a single 400-mg daily dose of ketoconazole, respectively. Ketoconazole had no effect on Tmax and final T1/2. Simultaneous use of PRADAXA and ketoconazole for systemic use is contraindicated.

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

Hinidine. The AUCτ,ss and Cmax,ss values of dabigatran when administered 2 times daily when concomitantly with quinidine at a dose of 200 mg every 2 hours until the total dose of 1000 mg was increased by 53% and 56% on average, respectively.

Concomitant use with substrates for P-glycoprotein:

Digoxin. No pharmacokinetic interaction has been observed when dabigatran etexilate is used concomitantly with digoxin, which is a P-glycoprotein substrate. Neither dabigatran nor the prodrug dabigatran etexilate are clinically significant inhibitors of P-glycoprotein.

Simultaneous use with P-glycoprotein inducers:

The simultaneous administration of PRADAXA and P-glycoprotein inducers should be avoided because co-administration results in reduced effects of dabigatran (see section “Special Precautions”).

Rifampicin. Pre-administration of the test inducer rifampicin at a dose of 600 mg daily for 7 days resulted in decreased exposure to dabigatran. After withdrawal of rifampicin, this inductive effect decreased, with the dabigatran effect close to baseline on day 7. No further increase in dabigatran bioavailability was observed over the next 7 days.

It has been suggested that other P-glycoprotein inducers, such as St. John’s wort or carbamazepine, may also decrease plasma concentrations of dabigatran and should be used with caution.

Simultaneous use with antiaggregants

Acetylsalicylic acid (ASA). In a study of concomitant use of dabigatran etexilate at a dose of 150 mg twice daily and acetylsalicylic acid (ASA) in patients with atrial fibrillation, it was found that the risk of bleeding may 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 concomitantly with dabigatran etexilate at a dose of 110 mg or 150 mg twice daily may increase the risk of major bleeding. Bleeding is observed more often also when concomitant use of warfarin 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. There is limited experience with long-term use of NSAIDs with a T1/2 of less than 12 hours with dabigatran etexilate and no evidence of an additional increased risk of bleeding.

Clopidogrel. Concomitant use of dabigatran etexilate and clopidogrel has not been shown to result in an additional increase in capillary bleeding time compared with clopidogrel monotherapy. In addition, the AUCτ,ss and Cmax,ss values have been shown dabigatran, as well as clotting parameters that were monitored to assess the effect of dabigatran (aChTV, ecarinic clotting time or thrombin time (anti FIIa), as well as the degree of inhibition of platelet aggregation (the main indicator of clopidogrel effect) during combination therapy were not changed compared with the corresponding values in monotherapy. When using a “loading” dose of clopidogrel (300 or 600 mg), the AUCt,ss and Cmax,ss values of dabigatran were increased by 30-40%.

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

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

Ranitidine. When used concomitantly with dabigatran etexilate, ranitidine had no significant effect on the degree of absorption of dabigatran.

The changes in pharmacokinetic parameters of dabigatran under the influence of proton pump inhibitors and antacid drugs revealed in the population analysis were clinically insignificant, because the degree of severity of these changes was small (the decrease in bioavailability was not significant for antacids, and for proton pump inhibitors it was 14.6%). It was found that concomitant use of proton pump inhibitors is not accompanied by a decrease in dabigatran concentration 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 in comparison with warfarin, and, therefore, the decrease in dabigatran bioavailability caused by concomitant use of pantoprazole is probably not clinically significant.

Special Instructions

Contraindications

Side effects

Hematopoietic and lymphatic system disorders: anemia, thrombocytopenia.

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

Nervous system disorders: intracranial bleeding.

vascular disorders: hematoma, bleeding.

Respiratory, chest and mediastinal disorders: nasal bleeding, hemoptysis.

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

Hepatobiliary system disorders: increased “liver” transaminases activity, liver dysfunction, hyperbilirubinemia.

Skin and subcutaneous tissue changes: skin hemorrhagic syndrome.

Skeletal and muscular disorders, connective tissue and bone disorders: hemarthrosis.

Kidney and urinary tract changes: urogenital bleeding, hematuria.

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

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

Vascular disorders: bleeding from the surgical wound.

General disorders and disorders at the site of administration: bloody discharge.

Damage, toxicity and complications of postoperative treatment: hematoma after wound care, bleeding after wound care, anemia in the postoperative period, discharge from the wound after procedures, wound secretions.

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

Overdose

Overdose when using PRADAXA may be accompanied by hemorrhagic complications due to the pharmacodynamic characteristics of the drug. In case of bleeding discontinue the use of the drug. Symptomatic treatment is indicated. There is no specific antidote.

Given the main route of dabigatran excretion (by the kidneys), it is recommended to ensure adequate diuresis. Surgical hemostasis and replenishment of circulating blood volume (RBC) are performed. Fresh whole blood or fresh frozen plasma transfusion is possible. Since dabigatran has low plasma protein binding capacity, the drug may be excreted by hemodialysis, but clinical experience with the use of dialysis in these situations is limited (see section “Pharmacokinetics”).

In case of an overdose of PRADAXA, activated prothrombin complex or recombinant factor VIIa concentrates or concentrates of II, IX or X clotting factors may be used. There is experimental evidence to support the effectiveness of these agents in counteracting the anticoagulant effect of dabigatran, but no specific clinical studies have been conducted.

If thrombocytopenia develops, or if long-acting antiaggregants are used, platelet mass may be considered.