PRADAKSA

Active material: Dabigatran эteksilat
When ATH: B01AE07
CCF: Anticoagulants. The direct thrombin inhibitor
ICD-10 codes (testimony): I74, I82
When CSF: 20.02.01.05
Manufacturer: BOEHRINGER INGELHEIM INTERNATIONAL GmbH (Germany)

Pharmaceutical form, composition and packaging

Capsules oblong, opaque, body cream-colored printed dosage “R 75” cap and light blue with a printed symbol Boehringer Ingelheim, color overprint – black; contents of capsules – yellowish pellets.

Excipients: acacia gum, tartaric acid (coarse-grained, powder, Crystal), gipromelloza, Dimethicone, talc, giproloza (hydroksypropyltsellyuloza).

Ingredients of the capsule shell: karraginan (E407), potassium chloride, Titanium dioxide (E171), indigokarmin (E132), colorant sunset yellow (E110), gipromelloza (hydroxypropyl), Purified water.
The composition of black ink Colorcon S-1-27797: shellac, Butanol, denatured ethanol (methylated spirit), dye iron oxide black (E172), isopropanol, propylene glycol, Purified water.

10 PC. – blisters (1) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (6) – packs cardboard.
60 PC. – vials made of polypropylene (1) – packs cardboard.

Capsules oblong, opaque, body cream-colored printed dosage “R 110” cap and light blue with a printed symbol Boehringer Ingelheim, color overprint – black; contents of capsules – yellowish pellets.

Excipients: acacia gum, tartaric acid (coarse-grained, powder, Crystal), gipromelloza, Dimethicone, talc, giproloza (hydroksypropyltsellyuloza).

Ingredients of the capsule shell: karraginan (E407), potassium chloride, Titanium dioxide (E171), indigokarmin (E132), colorant sunset yellow (E110), gipromelloza (hydroxypropyl), Purified water.
The composition of black ink Colorcon S-1-27797: shellac, Butanol, denatured ethanol (methylated spirit), dye iron oxide black (E172), isopropanol, propylene glycol, Purified water.

10 PC. – blisters (1) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (6) – packs cardboard.
60 PC. – vials made of polypropylene (1) – packs cardboard.

Pharmacological action

Anticoagulants. The direct thrombin inhibitor. Dabigatran etexilate is a small molecule prodrug, do not possess pharmacological activity. After intake of rapidly absorbed and by hydrolysis, catalysed by esterases, converted into dabigatran.

Dabigatran is an active, competitive, reversible direct thrombin inhibitor and has an effect mainly in plasma.

Tak how thrombin (serinovaya protease) It turns in the coagulation cascade, fibrinogen into fibrin, the inhibition of its activity prevents the formation of a blood clot. Dabigatran ingibiruet svobodnыy thrombin, fibrinsvyazыvayushtiy thrombin and vыznannuyu trombinom agregatsiyu trombotsitov.

In vivo and ex vivo in animal studies using a variety of thrombosis demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after the I / O applications and of dabigatran etexilate after oral administration.

The close correlation between the concentration of dabigatran in plasma and the severity of the anticoagulant effect. Dabigatran udlinyaet aktivirovannoe partiality tromboplastinovoe Vremya (ACHTV).

Pharmacokinetics

Absorption

After taking the drug pharmacokinetic profile of dabigatran in blood plasma of healthy volunteers is characterized by a rapid increase in the plasma concentration attainment C_max within 0.5-2 no.

After reaching C_max Plasma concentrations of dabigatran reduced biexponential manner, final T_1/2 averages around 14-17 h in young people and 12-14 hours in the elderly. T_1/2 not dose. FROM_max and AUC values ​​vary in proportion to the dose. Food does not affect the bioavailability of dabigatran etexilate, but T_max slows to 2 no.

The absolute bioavailability of dabigatran is about 6.5%.

The research for the study of absorption of dabigatran etexilate over 1-3 hours after surgery demonstrated depot compared with healthy volunteers. AUC revealed smooth increase without the appearance of C_max plasma. FROM_max We watched to 6 hours after administration or 7-9 hours after surgery. It should be noted, Such factors, as anesthesia, gastrointestinal paresis, and surgical operation, may have a value in the depot, regardless of dosage forms of the drug. In another study, it was shown, that slow the absorption or delay absorption is usually observed only in the day of surgery. In subsequent days absorption of dabigatran is rapid with the achievement With_max through 2 h after administration.

Distribution

Slow capacity (34-35%) binding of dabigatran to human plasma proteins, regardless of the concentration of the drug. V_d Dabigatran sostavlyaet 60-70 L and greater than the volume of total body water, indicating moderate tissue distribution of dabigatran.

Metabolism and excretion

After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, It is the active form in plasma. The main route of metabolism of dabigatran etexilate is the hydrolysis, catalysed by esterases, this is accompanied by its conversion to the active metabolite of dabigatran.

When dabigatran conjugation forms 4 isomers pharmacologically aktivnыh atsilglyukuronidov: 1-ABOUT, 2-ABOUT, 3-ABOUT, 4-ABOUT, each of which is less than 10% the total content of dabigatran plasma. Traces of other metabolites were found only by using highly sensitive analytical methods.

Metabolism and excretion of dabigatran were studied in healthy volunteers (men) After odnokpatnogo / in the radioactively-labeled dabigatran. Withdrawal occurred mainly through the kidneys (85%) in unchanged form. Excretion in the feces was about 6% From the administered dose. During 168 h after administration of the drug excretion of total radioactivity was 88-94% the magnitude of the applied dose.

Pharmacokinetics in special clinical situations

In volunteers with mild renal impairment (CC 30-50 ml / min) the AUC of dabigatran after the oral administration was 2.7 fold increase compared with the test with normal renal function. In renal failure, severe (CC 10-30 ml / min) meaning dabigatran AUC and T_1/2 increased respectively 6 and 2 times compared with patients without renal failure.

Compared with young people, elderly patients the AUC and C_max increased respectively 40-60% and 25%. In the population pharmacokinetic studies with elderly patients to 88 s found, that the repeated receptions dabigatran increased its content and body. The observed changes were correlated with age-related decrease in creatinine clearance.

In 12 patients with moderate liver function violation (Class B for Child-Pugh) There were no changes in the content of dabigatran compared to control.

In the population pharmacokinetic studies, pharmacokinetic parameters were evaluated in patients with a body weight of 48 to 120 kg. Body weight has little effect on the plasma clearance of dabigatran. Its content in the body was higher in patients with low body weight. In patients weighing more than 120 kg decreased efficacy about 20%, and body weight 48 kg increase approximately 25% compared to patients with a mean body weight.

In clinical studies, 3 phase there was no difference in the effectiveness and safety Pradaksa^® men and women. In women, the impact of the drug was on the 40-50% higher, than men, however, dose modification is not required.

A comparative study of the pharmacokinetics of dabigatran in Europeans and the Japanese after single and repeated administration of the drug in the studied ethnic groups showed no clinically significant changes. Pharmacokinetic studies in patients blacks were not carried out.

Testimony

- Prevention of venous thromboembolism in patients undergoing orthopedic surgery.

Dosage regimen

The drug is prescribed inside.

Adults to prevention of venous thromboembolism (VT) in patients undergoing orthopedic surgery The recommended dose is 220 mg / day one (2 caps. by 110 mg).

In Patients with moderate renal impairment increased risk of bleeding, the recommended dose is 150 mg / day one (2 caps. by 75 mg).

To BT prevention after knee replacement treatment should be started by 1-4 hours after dosing operations 110 mg followed by increasing doses up to 220 mg / once daily for the next 10 days. If hemostasis was not achieved, Treatment should be delayed. If treatment is not started on the day of surgery, therapy should be initiated with a dose 220 mg / day one.

To BT prevention after hip replacement treatment should be started by 1-4 hours after dosing operations 110 mg followed by increasing doses up to 220 mg / once daily for the next 28-35 days. If hemostasis was not achieved, Treatment should be delayed. If treatment is not started on the day of surgery, therapy should be initiated with a dose 220 mg / day one.

Patients with severe hepatic impairment (Class B and C Child-Pugh) or diseases liver, may have an impact on survival, or increase over 2 times ULN liver enzymes were excluded from clinical trials. Concerning, use Pradaksy^® in these patients is not recommended.

After the on / in the 85% dabigatran eliminated via the kidneys. In Patients with moderate renal impairment (CC 30-50 ml / min) there is a high risk of bleeding. In such patients, the dose should be reduced to 150 mg / day.

Creatinine clearance is determined by Cockcroft:

To Men

CC (ml / min)=(140-age) X weight (kg)/72 x serum creatinine (mg / dL)

To Women 0.85 QC's values ​​for men.

There are no data on the use of the drug in patients with severely impaired renal function (CC less than 30 ml / min). Use of the drug Pradaksa^® in these patients is not recommended.

Dabigatran at vыvoditsya dialysis. Clinical studies in these patients has not been.

Experience with elderly patients aged 75 years limited. The recommended dose is 150 mg / day one. When conducting pharmacokinetic studies in elderly patients, which with age there is a decrease in renal function, It was found elevated levels of drug in the body. The dose should be calculated as, as well as for patients with impaired renal function.

The transition from the treatment of dabigatran etexilate to a parenteral administration of anticoagulants should be carried out 24 hours after the last dose Pradaksy^®.

Transition from parenteral anticoagulants to Pradaksu^®: no data, it is not recommended to start treatment Pradaksoy^® to the planned introduction of the next dose of parenteral anticoagulant.

Terms of use of the drug

1.Remove the capsule from the blister, otslaivaya foil.

2.Do not squeeze the capsule through the foil.

3.Remove the foil so, it was convenient to remove the capsules.

The capsules should be taken with water, taken with food or on an empty stomach.

Side effect

In controlled trials of the drug for patients receiving 150-220 mg / day, part – less 150 mg / day, part – more 220 mg / day.

There are bleeding of any localization. Extensive bleeding is rare. The development of adverse reactions was similar to the reaction in the case of enoxaparin sodium.

From the hematopoietic system: anemia, thrombocytopenia.

From the blood coagulation: hematoma, bleeding wounds, nosebleed, Gastrointestinal bleeding, bleeding from the rectum, hemorrhoidal bleeding, cutaneous hemorrhagic syndrome, gemartroz, hematuria.

From the digestive system: abnormal liver function, increase in liver transaminases, giperʙiliruʙinemija.

From the laboratory parameters: reduction of hemoglobin and hematocrit

Local reactions: bleeding from the injection site, bleeding from the catheter site.

Complications, related to the procedures and surgeries: bloody discharge from the wounds, bruising after the procedure, bleeding after the procedure, posleoperatsionnaya anemia, post-traumatic hematoma, bloody discharge after the procedure, bleeding from the incision site, drainage after the procedure, wound drainage.

The frequency of observed adverse reactions when taking dabigatran etexilate did not exceed the range of the frequency of adverse reactions, Developing using sodium enoksiparina.

Contraindications

- Severe renal insufficiency (CC less than 30 ml / min);

- Hemorrhagic disorders, gyemorragichyeskii diatyez, spontaneous or pharmacologically induced hemostasis disorders;

- Active clinically significant bleeding;

- Abnormal liver function and liver disease, which may affect survival;

- Concomitant use of quinidine;

- Organ failure as a result of clinically significant bleeding, including hemorrhagic stroke within the previous 6 months before treatment;

- Age less than 18 years;

- Known hypersensitivity to dabigatran or dabigatran etexilate or any of the excipients.

Pregnancy and lactation

IN experimental studies Animal reproductive toxicity was identified. Clinical data on the use of dabigatran etexilate in pregnancy is not available. The potential risk for humans is not known.

Women of reproductive age pregnancy should be avoided in the treatment of Pradaksoy^®. In pregnancy, the use of dabigatran etexilate is not recommended, except, when the expected benefits outweigh the potential risks.

In the case of dabigatran etexilate breast-feeding should be discontinued. Clinical data on the use of the drug during breast-feeding is not available.

Cautions

Unfractionated heparin may be employed to maintain the functioning central venous or arterial catheter.

It should not be used simultaneously with the preparation Pradaksa^® unfractionated heparins or its derivatives, nizkokomolekulyarnye heparins, fondaparinux sodium, desirudin, thrombolytic agents, receptor antagonists, GPIIb / IIIa, Clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists.

The combined use of Pradaksy^® a recommended treatment for deep venous thrombosis and doses of aspirin at doses 75-320 mg increases the risk of bleeding. Data, evidence of an increased risk of bleeding, associated with dabigatran at reception Pradaksy^® at the recommended dose, sick, get a small dose of aspirin to prevent cardiovascular disease, no. But, Available information is limited, so the joint application of acetylsalicylic acid at a low dose and Pradaksy^® Patients must be monitored with a view to timely diagnosis of bleeding.

Careful observation (for signs of bleeding or anemia) should be performed in cases, where possible increased risk of bleeding complications:

- Recent biopsy or trauma;

- The use of drugs, increase the risk of bleeding complications;

- Combination Pradaksы^® medicine, that affect hemostasis or coagulation processes;

- Bacterial endocarditis.

Appointment for a short time NSAIDs when combined with Pradaksoy^® chain analgesia after surgery does not increase the risk of bleeding. There are limited data on the systemic administration of NSAIDs with T_1/2 less than 12 hours in combination with Pradaksoy^®, confirm an increased risk of bleeding are absent.

When conducting pharmacokinetic studies have shown, In patients with reduced renal function, incl. age-related, It noted an increase in drug efficacy. In patients with moderately decreased kidney function (CC 30-50 ml / min) it is recommended to reduce the daily dose 150 mg / day. Pradaksa^® contraindicated in patients with severe renal impairment (CC <30 ml / min). With the development of acute renal failure the drug should be discontinued.

In the case of traumatic or repeated lumbar puncture and prolonged use of epidural catheter may increase the risk of spinal or epidural hematoma bleeding. The first dose Pradaksy^® should be taken no earlier than 2 hours after removal of the catheter. Such patients should be monitored for possible detection of neurological symptoms.

Effects on ability to drive vehicles and management mechanisms

The effects of dabigatran etexilate on the ability to drive and use machines has not been studied.

Overdose

There is no antidote to dabigatran etexilate or dabigatran.

Using doses, than recommended, It leads to an increased risk of bleeding. In case of bleeding, treatment should be stopped to ascertain the causes of bleeding. Given the primary route of elimination of dabigatran through the kidneys, It is recommended to ensure adequate urine output. If necessary, possible surgical hemostasis or transfusion of fresh frozen plasma.

Dabigatran udalyaetsya Dialysis, However, clinical experience with this method, there is no.

Drug Interactions

The combined use of drugs, affecting hemostasis or coagulation processes, vitamin K antagonists including, can significantly increase the risk of bleeding.

Dabigatran эteksilat and dabigatran are not metaboliziruyutsya with uchastiem sistemы cytochrome P450 and vliyayut of in vitro cytochrome P450 in fermentы per person. Therefore, when combined with Pradaksoy^® drug interactions are expected.

When combined with atorvastatin interaction is not observed.

In a joint application pharmacokinetics of dabigatran etexilate and diclofenac did not change, indicating little interaction. Application over a short time NSAIDs for pain relief after surgery did not increase the risk of bleeding.

There is limited experience with Pradaksy^® in combination with systematic prolonged NSAID, and therefore it requires careful monitoring of patients.

Pharmacokinetic interaction with digoxin is not revealed.

In clinical studies did not reveal the effect of the combination of pantoprazole or other proton pump inhibitors and Pradaksy^® on the development of bleeding or pharmacological effects.

In a joint application with ranitidine extent of absorption of dabigatran is not changed.

In a joint application Pradaksy^® amiodarone, and the rate and extent of absorption of the latter and formation of its active metabolite dezetilamiodarona unchanged. AUC and C_max increases by 60% and 50% respectively. In a joint application of dabigatran etexilate and amiodarone dose should be reduced Pradaksy^® to 150 mg / day. Due to the long T_1/2 amiodarone the potential drug interactions may persist for several weeks after discontinuation of amiodarone.

Caution must be exercised in a joint application Pradaksy^® to active inhibitors of p-glycoprotein (verapamil, clarithromycin).

Repeated administration of verapamil for several days led to an increase in the concentration of dabigatran 50-60%. This effect can be reduced by assigning at least dabigatran 2 hours before drug verapamil.

Simultaneous reception Pradaksy^® with quinidine is contraindicated.

Potential inducers, such as rifampicin and hypericum extract of the herb, may reduce the effect of dabigatran. Caution should be exercised when used in conjunction with such drugs dabigatran.

In a joint application with antacids and dabigatran means, depressing gastric secretion, changing the dose of dabigatran is not required.

There were no interactions with dabigatran opioid analgesics, Diuretics, paracetamol, NSAIDs (incl. COX-2 inhibitors), inhibitors MMC-CoA reductase, preparations, lowering cholesterol / triglyceride (unrelated to statins), angiotensin II receptor blockers, ACE inhibitors, beta-blockers, calcium channel blockers, prokinetiki, benzodiazepines.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug vials should be stored out of reach of children, at a temperature no higher than 25 ° C.

The bottle should be kept tightly closed, for protection against moisture. After opening the bottle the drug should be used within 30 days.

The drug in the blister should be kept out of reach of children, dry place, at a temperature no higher than 25 ° C. Shelf life – 3 year.