Active ingredients: Dabigatran (dabigatran etexilate)
Pradaxa 75 mg hard capsules
Pradaxa package inserts are available for pack sizes:- Pradaxa 75 mg hard capsules
- Pradaxa 110 mg hard capsules
- Pradaxa 150 mg hard capsules
Why is Pradaxa used? What is it for?
Pradaxa is a medicine that contains the active substance dabigatran etexilate. It blocks the action of a substance in the body that is involved in the formation of blood clots.
Pradaxa is used to prevent blood clots from forming in the veins following knee or hip replacement surgery in adults.
Contraindications When Pradaxa should not be used
Do not take Pradaxa
- if you are allergic to dabigatran etexilate or any of the other ingredients of this medicine (listed in section 6).
- if your kidney function is severely reduced
- if you have ongoing bleeding.
- if you have injury to an organ which increases the risk of severe bleeding.
- if you have an increased bleeding tendency. This may be congenital, due to an unknown cause or due to other medicines.
- if you have severely reduced liver function or liver disease which can in some way cause death.
- if you are taking ketoconazole or itraconazole by mouth, medicines to treat fungal infections.
- if you are taking cyclosporine a medicine to prevent rejection episodes after organ transplantation.
- if you are taking dronedarone, a medicine used to prevent the problem of an irregular heartbeat from returning.
- if you are taking medicines to prevent blood clots (e.g. warfarin, rivaroxaban, apixaban or heparin), except when you are switching from one anticoagulant treatment to another or when an arterial venous catheter is placed and take heparin through it to keep it open.
- if you have been implanted with an artificial heart valve.
Precautions for use What you need to know before taking Pradaxa
Talk to your doctor before taking Pradaxa. You may also need to see your doctor during treatment with Pradaxa if you experience symptoms or if you need to have surgery. Tell your doctor if you have or have suffered from any medical condition or disease, especially any of those included in the following list:
- if you suffer from liver disease associated with abnormal blood tests, the use of Pradaxa is not recommended.
- if you have an increased risk of bleeding as it could be in the following situations:
- if you have had recent bleeding.
- if you have had a biopsy (surgical removal of tissue) in the previous month.
- if you have suffered serious injuries (e.g. bone fracture, head injury or any injury that required surgery).
- if you suffer from inflammation of the esophagus or stomach.
- if you have problems with reflux of gastric juice into the esophagus.
- if you have taken medicines that may increase the risk of bleeding such as aspirin (acetylsalicylic acid), clopidogrel, ticagrelor.
- if you are taking anti-inflammatory medicines such as diclofenac, ibuprofen, piroxicam.
- if you suffer from a "heart infection (bacterial endocarditis).
- if you know that your kidney function is impaired or you suffer from dehydration (symptoms include feeling thirsty and urinating in reduced amounts of dark (concentrated) urine).
- if you are over 75 years old.
- if it weighs 50kg or less.
- if you have had a heart attack or have been diagnosed with conditions that increase your risk of developing a heart attack.
- if you are undergoing a planned surgery. Pradaxa will need to be stopped temporarily due to the increased risk of bleeding during and shortly after the operation. If possible Pradaxa should be stopped at least 24 hours before the operation. In patients with an increased risk of bleeding, the doctor may decide to stop treatment earlier.
- if you are undergoing unscheduled surgery. If possible, surgery should be postponed to 12 hours after the last dose of Pradaxa. If surgery cannot be postponed, there may be an increased risk of bleeding. Your doctor will assess the risk of bleeding and the urgency of surgery.
- if you have a tube (catheter) inserted in your back: a tube can be inserted in your back, eg. to administer anesthetics or pain relieving medicines, during or after surgery. If you are given Pradaxa after removing a catheter, your doctor will check you regularly.
- if you fall or are injured during treatment, especially if you get a blow to the head, call your doctor right away. Your doctor may find it necessary to see you because you may be at a high risk of bleeding.
Children and adolescents
Pradaxa should not be used in children and adolescents under the age of 18.
Interactions Which drugs or foods may change the effect of Pradaxa
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Eg:
- Medicines that reduce blood clotting (e.g. warfarin, phenprocoumon, heparin, clopidogrel, prasugrel, ticagrelor, rivaroxaban)
- Anti-inflammatory and pain-relieving medicines (e.g. aspirin)
- St. John's wort, a herbal medicine to treat depression
- Antidepressant medicines called selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors
- Rifampicin or clarithromycin, two antibiotics
- Medicines to treat altered heart beat (e.g. amiodarone, dronedarone, quinidine, verapamil). If you are taking medicines containing amiodarone, quinidine or verapamil, you should take a reduced dose of Pradaxa of 150mg taken once daily as 2 capsules of 75mg, as the risk of bleeding may increase. Pradaxa and these medicines must be taken together.If you are taking medicines containing verapamil and your kidney function has decreased by more than half, you should take a reduced dose of Pradaxa equal to 75mg as the risk of bleeding may increase.
- Medicines to treat fungal infections (e.g. ketoconazole, itraconazole, posaconazole) unless only applied to the skin
- Medicines to prevent direct episodes after organ transplantation (eg tacrolimus, cyclosporine)
- Viral medicines for AIDS (eg ritonavir)
- Medicines to treat epilepsy (eg carbamazepine, phenytoin)
Warnings It is important to know that:
Pregnancy and breastfeeding
The effects of Pradaxa on pregnancy and the fetus are not known. You should not take Pradaxa if you are pregnant unless your doctor tells you it is safe to do so. If you are a woman of childbearing potential, you must avoid becoming pregnant while being treated with Pradaxa.
You should not breastfeed while being treated with Pradaxa.
Driving and using machines
Pradaxa has no known effects on the ability to drive or use machines.
Pradaxa contains sunset yellow (E110)
This medicine contains a dye called sunset yellow (E110) which can cause allergic reactions
Dose, Method and Time of Administration How to use Pradaxa: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor.
The recommended dose is 220mg once daily (taken as 2 capsules of 110mg).
If your kidney function is reduced by more than half or if you are 75 or older, the recommended dose is 150mg once a day (taken as 2 capsules of 75mg).
If you are taking medicines containing amiodarone, quinidine or verapamil, the recommended dose is 150mg once daily (taken as 2 capsules of 75mg).
If you are taking verapamil-containing medicines and your kidney function has decreased by more than half, you should take a reduced dose of Pradaxa of 75mg as the risk of bleeding may increase.
After knee replacement surgery
You must start treatment with Pradaxa within 1-4 hours of completing the surgery, taking a single capsule. Thereafter two capsules, once a day, for a total of 10 days.
After hip replacement surgery
You must start treatment with Pradaxa within 1-4 hours of completing the surgery, taking a single capsule. Thereafter two capsules, once a day, for a total of 28-35 days.
For both surgeries, treatment should not be initiated in case of bleeding at the operation site. If treatment cannot be started until the day after surgery, dosing should begin with a dose of 2 capsules once daily. .
Pradaxa can be taken with or without food. The capsule should be swallowed whole with a glass of water, to ensure gastric release. Do not break, chew or remove the granules from the capsule as this may increase the risk of bleeding.
When using blister packed Pradaxa, please observe the following instructions
- remove the capsules from the blister by lifting the aluminum foil on the back.
- do not push the capsules through the blister.
- the aluminum foil from the blister should only be lifted when a capsule is to be removed.
When using Pradaxa packaged in bottle, please observe the following instructions
- the bottle is opened by pressing and turning the cap.
Change in anticoagulant treatment
- Switching from Pradaxa treatment to treatment with anticoagulants given by injection: Do not start treatment with injectable anticoagulant medicines (eg heparin) before 24 hours have passed since the last Pradaxa administration.
- Switching from treatment with anticoagulants given by injection to treatment with Pradaxa: Start taking Pradaxa 0-2 hours before your next injection was due.
Overdose What to do if you have taken too much Pradaxa
If you take more Pradaxa than you should
If you take more Pradaxa than recommended, you may be at an increased risk of bleeding. Your doctor may do a blood test to assess the risk of bleeding.
Tell your doctor immediately if you take more Pradaxa than prescribed. If a bleeding episode occurs, surgery or treatment with blood transfusions may be required.
If you forget to take Pradaxa
Continue with the remaining daily doses of Pradaxa at the usual time the next day.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Pradaxa
Take Pradaxa exactly as prescribed. Do not stop taking Pradaxa without first checking with your doctor. Stopping Pradaxa may increase the risk of developing a blood clot in patients treated after hip or knee replacement surgery.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Pradaxa
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Pradaxa acts on the blood clotting system, so most side effects are related to signs such as hematoma or bleeding.
Major or severe bleeding events can occur, these are the most serious side effects, which regardless of location, can be disabling, life-threatening or even lead to death. In some cases, these bleeding may not be evident.
If you experience any bleeding that does not resolve spontaneously or if you experience symptoms of excessive bleeding (exceptional weakness, tired feeling, pale skin, dizziness, headache or unexplained swelling), see your doctor immediately.
Your doctor may decide to have you checked carefully or to change your treatment.
Tell your doctor immediately if you experience a severe allergic reaction which causes difficulty in breathing or dizziness.
Side effects are listed below, grouped by how often they occur.
Common (may affect up to 1 in 10 people):
- Reduction in the amount of hemoglobin present in the blood (the substance contained in red blood cells)
- Abnormal liver function test results
Uncommon (may affect up to 1 in 100 people):
- Bleeding which can occur from the nose, stomach or intestines, penis / vagina or urinary tract (including blood in the urine that makes it pink or red), from hemorrhoids, into the rectum, under the skin, in a joint, from a wound or subsequently to it, after surgery
- Formation of hematoma or hematoma that occurs after an "operation
- Presence of blood in the stool, detected by laboratory examination
- Reduction in the number of red blood cells
- Reduction in the proportion of red blood cells in the blood
- Allergic reaction
- He retched
- Diarrhea with poorly formed or liquid stools
- Feeling unwell
- Exudation of a small amount of liquid from the incision made for surgical purposes
- Wound discharge (exudation of fluid from the surgical wound)
Rare (may affect up to 1 in 1,000 people):
- Bleeding
- Bleeding that can occur in the brain, from a "surgical incision, injection site, or catheter insertion site into a vein
- Blood-stained discharge from the catheter insertion site into a vein
- Expectoration of blood or blood-stained sputum
- Reduction in the number of platelets in the blood
- Reduction in the number of red blood cells in the blood after an "operation
- Severe allergic reaction causing difficulty in breathing or dizziness
- Severe allergic reaction which causes swelling of the face or throat
- Noticeable skin rash with dark red, swollen, itchy lumps caused by an allergic reaction
- Sudden alteration of the skin that changes its color and appearance
- Itching
- Gastrointestinal ulcer (including ulcer of the esophagus)
- Inflammation of the esophagus and stomach
- Reflux of gastric juices into the esophagus
- Pain in the abdomen or stomach
- Indigestion
- Difficulty swallowing
- Fluid from a wound
- Fluid coming from a wound after an operation
Not known (frequency cannot be estimated from the available data):
- Difficulty in breathing or wheezing
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton, blister or bottle after EXP. The expiry date refers to the last day of that month.
Blisters: Store in the original package to protect from moisture.
Bottle: Once opened, the medicine should be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect the medicine from moisture.
Do not throw any medicines into wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Pradaxa contains
- The active substance is dabigatran, which is administered in the form of dabigatran etexilate as dabigatran etexilate mesylate, at a dosage of 75mg.
- The other ingredients are tartaric acid, gum arabic, hypromellose, dimethicone 350, talc and hydroxypropylcellulose.
- The capsule shell contains carrageenan, potassium chloride, titanium dioxide, indigo carmine, sunset yellow (E110), hypromellose and purified water.
- Black printing ink contains shellac, N-butyl alcohol, isopropyl alcohol, industrial denatured ethanol, black iron oxide, purified water and propylene glycol.
Description of what Pradaxa looks like and contents of the pack
Pradaxa is a hard capsule.
Pradaxa 75mg hard capsules have an opaque light blue cap and opaque cream body. The Boehringer Ingelheim logo is printed on the cap and the code "R75" on the body of the capsule.
Pradaxa 75mg hard capsules are available in packs containing 10x1, 30x1 or 60x1 capsules in perforated aluminum unit dose blisters.
Pradaxa 75mg hard capsules are also available in packs containing 60x1 hard capsules in white perforated unit dose aluminum blisters.
Pradaxa 75mg hard capsules are also available in polypropylene (plastic) bottles containing 60 hard capsules.
Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
PRADAXA 75 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 75 mg of dabigatran etexilate (as mesylate).
Excipients with known effects:
Each hard capsule contains 2 mcg of sunset yellow (E110).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsule.
Capsules with opaque light blue cap and size 2 opaque cream body filled with yellowish pellets. The Boehringer Ingelheim logo is printed on the head, "R75" on the body.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Primary prevention of thromboembolic episodes in adult patients undergoing elective total hip or knee replacement surgery.
04.2 Posology and method of administration
Dosage
Primary prevention of venous thromboembolism episodes in orthopedic surgery
Patients undergoing elective knee replacement surgery
The recommended dose of Pradaxa is 220 mg once a day, taken as 2 capsules of 110 mg. Treatment should commence orally within 1-4 hours after completion of surgery with one 110 mg capsule and continue from the next day with 2 capsules once daily for a total of 10 days.
Patients undergoing elective hip replacement surgery
The recommended dose of Pradaxa is 220 mg once a day, taken as 2 capsules of 110 mg. Treatment should commence orally within 1-4 hours after completion of surgery with a 110 mg capsule and continue from the next day with 2 capsules once daily for a total of 28-35 days.
For the following groups the recommended daily dose of Pradaxa is 150 mg once a day, taken as 2 capsules of 75 mg.
Treatment should commence orally within 1-4 hours after completion of surgery with one 75 mg capsule and continue from the next day with 2 capsules once daily for a total of 10 days (knee replacement surgery) or 28 days. -35 days (hip replacement surgery):
• Patients with moderate renal impairment (creatinine clearance, CrCL 30-50 ml / min [see Renal impairment (primary prevention of venous thromboembolism episodes in orthopedic surgery)]
• Patients concurrently receiving verapamil, amiodarone, quinidine [see Concomitant use of Pradaxa with weak to moderate P-glycoprotein (P-gp) inhibitors, such as amiodarone, quinidine or verapamil (primary prevention of venous thromboembolism in orthopedic surgery) ]
• Patients aged 75 years and older [see Elderly patients (primary prevention of venous thromboembolism episodes in orthopedic surgery)]
For both interventions, if haemostasis is not normal, the start of treatment should be postponed. If treatment is not started on the day of surgery, it should be started with 2 capsules once a day.
Evaluation of renal function (primary prevention of venous thromboembolism episodes in orthopedic surgery):
In all patients:
• Renal function should be assessed by calculating creatinine clearance (CrCL) prior to initiation of Pradaxa treatment to exclude patients with severe renal impairment (ie CrCL
• Renal function should also be evaluated when decreased renal function is suspected during treatment (eg hypovolaemia, dehydration and in the case of concomitant use of certain medicinal products).
The method used to estimate renal function (CrCL in mL / min) during the clinical development of Pradaxa was that of Cockgroft-Gault. The formula is as follows:
• For creatinine expressed in mcmol / l:
• For creatinine expressed in mg / dl:
This method is recommended for evaluating patients' CrCL before and during treatment with Pradaxa.
Special populations
Renal impairment (primary prevention of venous thromboembolism episodes in orthopedic surgery)
Treatment with Pradaxa in patients with severe renal impairment (CrCLr
Clinical experience in patients with moderate renal impairment (CrCL 30-50 ml / min) is limited. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 75 mg capsules (see sections 4.4 and 5.1).
Concomitant use of Pradaxa with weak to moderate P-glycoprotein (P-gp) inhibitors, such as amiodarone, quinidine or verapamil (primary prevention of venous thromboembolism in orthopedic surgery)
Pradaxa dose should be reduced to 150 mg, taken once daily as two 75 mg capsules, in patients receiving dabigatran etexilate and amiodarone, quinidine or verapamil concurrently (see sections 4.4 and 4.5). In this case Pradaxa and these medicines must be taken together.
In patients with moderate renal impairment who are concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg per day should be considered (see sections 4.4 and 4.5).
Elderly (primary prevention of venous thromboembolism episodes in orthopedic surgery)
Clinical experience is limited in elderly patients (> 75 years). These patients should be treated with caution. The recommended dose is 150 mg taken once daily as two 75 mg capsules (see sections 4.4 and 5.1).
Since renal impairment may be common in the elderly (age> 75 years), renal function should be assessed by calculating the CrCL prior to the initiation of Pradaxa treatment to exclude patients with severe renal impairment (i.e.
Hepatic impairment (primary prevention of venous thromboembolism episodes in orthopedic surgery)
Patients with liver enzymes elevated above twice the upper limit of normal (ULN) were excluded from clinical trials evaluating the prevention of VTE following elective total hip or knee replacement surgery. .There is no treatment experience in this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2). It is contraindicated in the case of hepatic impairment or liver disease which may have any impact on survival (see section 4.3).
Weight (primary prevention of venous thromboembolism episodes in orthopedic surgery)
Clinical experience with the recommended dose in patients weighing 110 kg is very limited. No dose adjustment is necessary based on clinical and kinetic data (see section 5.2), but close clinical monitoring is recommended (see paragraph 4.4).
Gender (primary prevention of venous thromboembolism episodes in orthopedic surgery)
Based on available clinical and kinetic data, no dose adjustment is required (see section 5.2).
Switching (primary prevention of venous thromboembolism episodes in orthopedic surgery)
From treatment with Pradaxa to a parenteral anticoagulant
It is recommended to wait 24 hours after the last dose before switching from Pradaxa to a parenteral anticoagulant (see section 4.5).
From parenteral anticoagulants to Pradaxa
Withhold parenteral anticoagulant and initiate dabigatran etexilate 0-2 hours prior to the scheduled next dose of the original therapy or upon discontinuation in case of continuous treatment (eg intravenous unfractionated heparin (ENF)) (see section 4.5).
Pediatric population (primary prevention of venous thromboembolism episodes in orthopedic surgery)
There is no relevant use of Pradaxa in the pediatric population in the indication: primary prevention of venous thromboembolism episodes in patients undergoing elective total hip replacement surgery or elective total knee replacement surgery.
Missed dose (primary prevention of venous thromboembolism episodes in orthopedic surgery)
It is recommended that the remaining daily doses of dabigatran etexilate be continued at the same time the next day.
Do not double doses to make up for a forgotten dose.
Method of administration (primary prevention of venous thromboembolism episodes in orthopedic surgery)
Pradaxa can be taken with or without food. Pradaxa should be swallowed whole with a glass of water to facilitate gastric release.
Patients should be instructed not to open the capsules as this may lead to an increased risk of bleeding (see sections 5.2 and 6.6).
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Patients with severe renal impairment (CrCL
• Clinically significant active bleeding
• Injuries or conditions, if considered a significant risk factor for major bleeding. They may include current or recent gastrointestinal ulcer, presence of neoplasms with high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities
• Concomitant treatment with any other anticoagulant such as unfractionated heparin (ENF), low molecular weight heparin (enoxaparin, dalteparin etc.), heparin derivatives (fondaparinux etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban etc.) made except for specific circumstances of changing anticoagulant therapy (see section 4.2) or when ENF is administered at the doses necessary to maintain a central venous or arterial catheter patent (see section 4.5)
• Hepatic impairment or liver disease that may have any impact on survival
• Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and dronedarone (see section 4.5)
• Heart valve prostheses requiring anticoagulant treatment (see section 5.1).
04.4 Special warnings and appropriate precautions for use
Hepatic impairment
Patients with elevated liver enzymes above twice the upper limit of normal were excluded from controlled clinical trials evaluating the prevention of VTE following elective total hip or knee replacement surgery. There is no treatment experience in this subpopulation of patients and therefore the use of Pradaxa is not recommended in this population.
Bleeding risk
Dabigatran etexilate should be used with caution in conditions of increased risk of bleeding and in situations involving concomitant use with substances that alter haemostasis by inhibiting platelet aggregation. Bleeding can occur at any body site during therapy. with dabigatran etexilate. An unexplained drop in hemoglobin and / or hematocrit or blood pressure should prompt a search for the bleeding site.
Factors such as decreased renal function (30-50 mL / min CrCL), age ≥ 75 years, low body weight plasma levels of dabigatran (see sections 4.2, 4.5 and 5.2).
Concomitant use of ticagrelor increases exposure to dabigatran and may lead to pharmacodynamic interactions, which may result in an increased risk of bleeding (see section 4.5).
The use of acetylsalicylic acid (ASA), clopidogrel or non-steroidal anti-inflammatory drugs (NSAIDs), as well as the presence of esophagitis, gastritis, or gastroesophageal reflux increase the risk of gastrointestinal bleeding. The administration of a PPI may be considered to prevent the gastrointestinal bleeding.
The risk of bleeding may be increased in patients concomitantly treated with selective serotonin reuptake inhibitors (SSRIs) or with selective serotonin and norepinephrine reuptake inhibitors (SNRIs) (see section 4.5).
Close clinical observation (looking for signs of bleeding or anemia) is recommended during treatment, especially if the risk factors are combined (see section 5.1).
Table 1 summarizes the factors that may increase the risk of bleeding. Refer also to the contraindications in section 4.3.
Table 1: Factors that may increase the risk of bleeding
The presence of lesions, conditions, procedures and / or treatment with drugs (such as NSAIDs, antiplatelet agents, SSRIs and SNRIs, see section 4.5), which significantly increase the risk of major bleeding requires a careful "benefit-risk assessment. Pradaxa must be given only if the benefit outweighs the risk of bleeding.
Pradaxa does not normally require routine monitoring of coagulation parameters. However, assessment of dabigatran-related anticoagulant effect may be useful to avoid excessively high exposure to dabigatran in the presence of additional risk factors. The INR test is not reliable in patients treated with Pradaxa and false positive INR elevation has been reported. Therefore the INR test should not be performed. Diluted plasma thrombin time (dTT), ecarin time (ECT ), activated partial thromboplastin time (aPTT) may provide useful information, but tests are not standardized and results should be interpreted with caution (see section 5.1).
Table 2 shows cut-offs at trough time of coagulation tests that may be associated with an increased risk of bleeding (see section 5.1).
Table 2: Threshold limit values at the trough time of coagulation tests that may be associated with an increased risk of bleeding
Patients who develop acute renal failure should stop taking Pradaxa (see section 4.3).
The data in weight patients
When severe bleeding occurs, treatment should be stopped and the source of the bleeding investigated (see section 4.9).
Medicinal products that may increase the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see section 4.5).
Use of fibrinolytic drugs for the treatment of acute ischemic stroke
The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient has a dTT, ECT, or aPTT below the upper limit of normal, according to the local reference range.
Interactions with P-gp inducers
With concomitant administration of P-gp inducers (such as rifampicin, St. John's wort (Hypericum perforatum), carbamazepine or phenytoin) a reduction in the plasma concentrations of dabigatran may be expected and should therefore be avoided (see sections 4.5 and 5.2).
Surgery and interventions
Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk of bleeding. Therefore, surgical interventions may require the temporary suspension of treatment.
Caution and monitoring of anticoagulant activity is recommended when treatment is temporarily suspended due to surgery. The clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be evaluated prior to each procedure. In such cases a coagulation test (see sections 4.4 and 5.1) can help determine whether haemostasis is still impaired.
Pre-operative phase
Table 3 summarizes the withdrawal rules prior to invasive or surgical procedures.
Table 3: Withdrawal rules before invasive or surgical procedures
If urgent action is required, dabigatran etexilate should be temporarily suspended. The operation / intervention, if possible, should be postponed at least until 12 hours after the last dose taken. If surgery cannot be postponed there may be an increased risk of bleeding. This bleeding risk must be weighed against the urgency of surgery.
Spinal anesthesia / epidural anesthesia / lumbar puncture
Procedures such as spinal anesthesia require normal hemostatic functions.
The risk of spinal or epidural hematoma may be increased in cases of traumatic or repeated puncture and by prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the first dose of dabigatran etexilate is administered. These patients require frequent observation of neurological signs and symptoms of spinal or epidural hematoma.
Post-operative phase
Administration of dabigatran etexilate should be resumed as soon as possible following the invasive procedure or surgery, provided it has been established that the clinical situation allows for adequate haemostasis.
Patients at high risk of bleeding or patients at risk of overexposure, particularly patients with moderate renal impairment (CrCL 30-50 mL / min), should be treated with caution (see sections 4.4 and 5.1).
Patients at high risk of mortality due to surgery and with intrinsic risk factors for thromboembolic events
There are limited efficacy and safety data available for dabigatran in these patients and therefore should be treated with caution.
Hip fracture surgery
There are no data on the use of Pradaxa in patients undergoing hip fracture surgery. Therefore treatment is not recommended.
Dyes
Pradaxa hard capsules contain sunset yellow dye (E110) which may cause allergic reactions.
04.5 Interactions with other medicinal products and other forms of interaction
Anticoagulants and antiplatelet agents
There is no or limited experience with the following treatments which may increase the risk of bleeding when used concomitantly with Pradaxa: anticoagulants such as unfractionated heparin (ENF), low molecular weight heparin (LMWH) and heparin derivatives (fondaparinux , desirudin), thrombolytic medicinal products and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see section 4.3) and antiplatelet agents such as GPIIb / IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran and sulfinpyrazone (see section 4.4).
ENF can be administered at doses necessary to keep a central venous or arterial catheter patent (see section 4.3).
Clopidogrel: In a phase I study in healthy, young male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel did not result in a further prolongation of capillary bleeding times compared to clopidogrel alone. Furthermore, the "AUC?, Ss and Cmax, ss and coagulation measures for the effect of dabigatran or the inhibition of platelet aggregation as a measure of the effect of clopidogrel" remained essentially unchanged when comparing the combined treatment and the respective mono- Treatments: With a loading dose of 300 mg or 600 mg of clopidogrel, dabigatran AUC, ss and Cmax, ss were increased by approximately 30-40% (see section 4.4).
ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeding was studied in patients with atrial fibrillation in a phase II study in which randomized co-administration of ASA was applied. Based on an analysis of ASA. logistic regression, co-administration of ASA and dabigatran etexilate 150 mg twice daily may increase the risk of any type of bleeding from 12% to 18% and 24% with 81 mg and 325 mg of ASA, respectively (see section 4.4).
NSAIDs: NSAIDs administered as short-acting analgesics in the perioperative period have been shown not to be associated with an increased risk of bleeding when combined with dabigatran etexilate. Chronic use of NSAIDs increased the risk of bleeding by approximately 50%. with both dabigatran etexilate and warfarin. Therefore, due to the risk of haemorrhage, especially with NSAIDs with an elimination half-life> 12 hours, close observation for signs of bleeding is recommended (see section 4.4).
LMWH: The concomitant use of LMWH such as enoxaparin and dabigatran etexilate has not been specifically evaluated. After switching from a 3-day treatment with enoxaparin 40 mg administered once a day by the sc route, 24 hours after the administration of the LMWH. last dose of enoxaparin, exposure to dabigatran was slightly lower than after administration of dabigatran etexilate alone (single dose of 220 mg). Greater anti-FXa / FIIa activity was observed after administration of dabigatran etexilate preceded by pre-treatment with enoxaparin versus treatment with dabigatran etexilate alone. This is believed to be due to a driving effect of enoxaparin treatment and is considered not clinically relevant. The results of other dabigatran-related anti-coagulant activity tests were not significantly modified by pre-treatment with enoxaparin.
Interactions related to the metabolic profile of dabigatran etexilate and dabigatran
Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no effect. in vitro on human cytochrome P450 enzymes. Therefore, interactions with related medicinal products and dabigatran are not expected.
Transporter interactions
Inhibitors of P-gp
Dabigatran etexilate is a substrate of the efflux transporter P-gp. Coadministration with P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole, dronedarone, clarithromycin and ticagrelor) is likely to result in increased plasma concentrations of dabigatran .
Unless specifically prescribed otherwise, close clinical monitoring (looking for signs of bleeding or anemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps identify patients with an increased risk of bleeding due to "increased exposure to dabigatran (see sections 4.2, 4.4 and 5.1).
The following potent P-gp inhibitors are contraindicated: systemically administered ketoconazole, cyclosporine, itraconazole and dronedarone (see section 4.3). Concomitant treatment with tacrolimus is not recommended. P-gp inhibitors from weak to moderate (eg.amiodarone, posaconazole, quinidine, verapamil and ticagrelor) should be used with caution (see sections 4.2 and 4.4).
Ketoconazole: Ketoconazole following a single oral dose of 400 mg increased the total AUC0-∞ and Cmax of dabigatran by 138% and 135%, respectively, and 153% and 149%, respectively, after multiple oral doses of 400. mg of ketoconazole once daily. Time to peak, terminal half-life and mean residence time were not altered by ketoconazole (see section 4.4). Concomitant use with systemic ketoconazole is contraindicated (see section 4.3).
Dronedarone: When dabigatran etexilate and dronedarone were co-administered, the total values of dabigatran AUC0-∞ and Cmax increased approximately 2.4-fold and 2.3-fold (+ 136% and 125%), respectively, after multiple doses of 400. mg dronedarone bid, and approximately 2.1-fold and 1.9-fold (+ 114% and 87%), respectively, after a single 400 mg dose The terminal half-life and renal clearance of dabigatran were not affected by dronedarone. When single and multiple doses of dronedarone were administered 2 hours after dabigatran etexilate, the increases in dabigatran AUC0-∞ were 1.3-fold and 1.6-fold, respectively. Concomitant treatment with dronedarone is contraindicated.
Amiodarone: When Pradaxa was co-administered with a single oral 600 mg dose of amiodarone, the amount and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The AUC and Cmax of dabigatran increased by approximately 60% and 50%, respectively. The mechanism of interaction is not fully elucidated. Considering the long half-life of amiodarone, the potential drug interaction may persist for weeks after amiodarone discontinuation (see sections 4.2 and 4.4).
In patients treated for the prevention of VTE after hip or knee replacement surgery, the dose of Pradaxa should be reduced to 150 mg taken once daily as 2 x 75 mg capsules when treated concomitantly with dabigatran etexilate and amiodarone (see section 4.2 ). Close clinical monitoring is recommended when dabigatran etexilate is combined with amiodarone, particularly when bleeding occurs and with extra caution in the case of patients with mild to moderate renal impairment.
Quinidine: Quinidine was administered in doses of 200 mg every 2 hours up to a total dose of 1,000 mg. Dabigatran etexilate was administered twice daily for 3 consecutive days, on the third day with or without quinidine. The dabigatran AUC, ss and Cmax, ss were increased on average by 53% and 56%, respectively, with concomitant administration of quinidine (see sections 4.2 and 4.4).
In patients treated for the prevention of VTE after hip or knee replacement surgery, the dose of Pradaxa should be reduced to 150 mg taken once daily as 2 x 75 mg capsules if treated concomitantly with dabigatran etexilate and quinidine (see section 4.2). Close clinical monitoring is recommended when dabigatran etexilate is combined with quinidine, particularly when bleeding occurs and with extra caution in the case of patients with mild to moderate renal impairment.
Verapamil: When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran increased, but the magnitude of this change varied with time of administration and the verapamil formulation (see sections 4.2 and 4.4).
The maximum increase in dabigatran exposure was observed with the first dose of an immediate-release formulation of verapamil, administered one hour prior to taking dabigatran etexilate (increase in Cmax by approximately 180% and in AUC by approximately 150%). The effect was progressively diminished with administration of a prolonged-release formulation (increase in Cmax by approximately 90% and AUC by approximately 70%) or with administration of multiple doses of verapamil (increase in Cmax by approximately 60% and increase in AUC of approximately 50%).
Therefore, close clinical monitoring (looking for signs of bleeding or anemia) is required when dabigatran is co-administered with verapamil. In patients with normal renal function after hip or knee replacement surgery treated with dabigatran etexilate and verapamil concurrently, the dose of Pradaxa should be reduced to 150 mg taken as 2 x 75 mg capsules once daily. In patients with moderate renal impairment, treated concomitantly with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.2 and 4.4). Close clinical monitoring is recommended when dabigatran etexilate is combined with verapamil, particularly when bleeding occurs and with extra caution in the case of patients with mild to moderate renal impairment.
No significant interaction was observed when verapamil was administered 2 hours after taking dabigatran etexilate (increase in Cmax by approximately 10% and increase in AUC by approximately 20%). This is explained by complete absorption. dabigatran after 2 hours (see section 4.4).
Clarithromycin: When clarithromycin (500 mg twice daily) was administered in combination with dabigatran etexilate in healthy volunteers, an increase in AUC of approximately 19% and Cmax of approximately 15% was observed with no effect on the clinical safety. However, in patients receiving dabigatran, a clinically significant interaction cannot be excluded when combined with clarithromycin. Therefore, careful monitoring should be made when dabigatran etexilate is combined with clarithromycin and particularly in the event of bleeding, especially in patients with mild to moderate renal impairment.
Ticagrelor: When a single 75 mg dose of dabigatran etexilate was co-administered with a 180 mg starting dose of ticagrelor, dabigatran AUC and Cmax increased by 1.73 and 1.95-fold, respectively (+73 % and 95%). After multiple dosing of 90 mg ticagrelor bid the increase in dabigatran exposure is 1.56 and 1.46 fold (+ 56% and 46%) for AUC and Cmax, respectively. .
Concomitant administration of an initial dose of 180 mg of ticagrelor and 110 mg of dabigatran etexilate (at steady state) increased the AUC?, Ss and Cmax, ss of dabigatran by 1.49-fold and 1.65-fold, respectively ( + 49% and 65%), compared to the administration of dabigatran etexilate alone. When an initial 180 mg dose of ticagrelor was administered 2 hours after administration of dabigatran etexilate 110 mg (steady state), the increase in dabigatran AUC?, Ss and Cmax, ss was reduced to 1.27-fold, respectively. and 1.23 times (+ 27% and 23%), compared to the administration of dabigatran etexilate alone.This staggered administration is the one recommended for starting ticagrelor with an initial dose.
Concomitant administration of 90 mg ticagrelor BID (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted AUC?, Ss and Cmax, ss of dabigatran by 1.26-fold and 1.29-fold, respectively, compared to administration. of dabigatran etexilate alone.
The following potent P-gp inhibitors have not been studied clinically, but based on the data in vitro an effect similar to that of ketoconazole is expected:
Itraconazole and cyclosporine, which are contraindicated (see section 4.3).
In vitro tacrolimus has been shown to have a similar inhibitory effect on P-gp to that observed for itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied in combination with tacrolimus. However, the limited clinical data available with another P-gp substrate (everolimus) suggests that the inhibition of P-gp with tacrolimus is weaker than that observed with potent P-gp inhibitors. Based on these data, treatment concomitant with tacrolimus is not recommended.
Posaconazole also partially inhibits P-gp, but has not been studied clinically. Co-administration of Pradaxa and posaconazole should be done with caution.
Inductors of P-gp
Concomitant administration of a P-gp inducer (such as rifampicin, St. John's wort (Hypericum perforatum), carbamazepine or phenytoin) may decrease dabigatran concentrations and should be avoided (see sections 4.4 and 5.2).
Rifampicin: Pre-administration of the inducer rifampicin at a dose of 600 mg once daily for 7 days reduced the total dabigatran peak and total exposure by 65.5% and 67%, respectively. The inducer effect was diminished resulting in dabigatran exposure close to the reference value within the seventh day following discontinuation of rifampicin treatment. No increases in bioavailability were observed after a further 7 days.
Other medicines affecting P-gp
Protease inhibitors such as ritonavir and its combinations with other protease inhibitors affect P-gp (both as inhibitors and as inducers). As they have not been studied they are not recommended for concomitant treatment with Pradaxa.
Substrate of P-gp
Digoxin: In a study involving 24 healthy patients, when Pradaxa was co-administered with digoxin, neither changes in digoxin nor significant clinical changes in dabigatran exposure were observed.
Concomitant use of selective serotonin reuptake inhibitors (SSRIs) or with selective serotonin and norepinephrine reuptake inhibitors (SNRIs)
SSRIs and SNRIs increased the risk of bleeding in all treatment groups of the RE-LY study.
gastric pH
Pantoprazole: When Pradaxa was administered in combination with pantoprazole, an approximately 30% reduction in the area under the plasma concentration-time curve of dabigatran was observed. Pantoprazole and other proton pump inhibitors (PPIs) were observed. administered with Pradaxa in clinical trials and concomitant treatment with PPI did not appear to reduce the efficacy of Pradaxa.
Ranitidine: Administration of ranitidine with Pradaxa has no clinically relevant effect on the absorption of dabigatran.
04.6 Pregnancy and lactation
Women of childbearing age / Male and female contraception
Women of childbearing potential should avoid becoming pregnant while being treated with dabigatran etexilate.
Pregnancy
There is a limited amount of data available from the use of dabigatran etexilate in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Pradaxa should not be used during pregnancy unless clearly needed.
Feeding time
There are no clinical data regarding the effects of dabigatran on nursing infants.
Breast-feeding should be discontinued during treatment with Pradaxa.
Fertility
No data are available in humans.
In animal studies an effect on female fertility in the form of decreased implantation and increased pre-implantation loss was observed at a dose of 70 mg / kg (plasma exposure 5 times that of patients). No other effects on female fertility were observed. No influence on male fertility was found. At maternally toxic doses (plasma exposure 5 to 10 times higher than that of patients), decreased fetal body weight and embryo-fetal viability with increased fetal changes were observed in rats and rabbits. In pre- and postnatal studies, an increase in fetal mortality was observed at doses that were toxic to the mothers (a dose corresponding to a plasma exposure 4 times higher than that of patients).
04.7 Effects on ability to drive and use machines
Pradaxa has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
A total of 10,795 patients were treated in 6 actively controlled VTE prevention studies with at least one strength of study drug. Of these 6,684 patients were treated with 150 mg or 220 mg of Pradaxa per day.
The most commonly reported adverse reactions are bleeding which occurred in a total of approximately 14% of patients; the frequency of major bleeding (including wound bleeding) is less than 2%.
Although rarely occurring in clinical trials, major or serious bleeding events can occur which, regardless of location, can be disabling, life-threatening, or even death.
Summary table of adverse reactions
Table 4 shows adverse reactions sorted by system organ class (SOC) and frequency using the following convention: very common (≥ 1/10); common (≥ 1/100,
Table 4: Adverse reactions
Bleeding
Table 5 reports the number (%) of patients experiencing adverse bleeding reactions during the VTE prevention treatment period in the two pivotal clinical trials, according to dose.
Table 5: Number (%) of patients experiencing adverse bleeding reactions
The definitions of adverse reactions of major bleeding in the RE-NOVATE and RE-MODEL studies were as follows:
• fatal bleeding
• clinically manifest bleeding associated with a drop in hemoglobin ≥ 20 g / l (corresponding to 1.24 mmol / l) both in excess of expected
• clinically manifest bleeding in excess of expected and requiring transfusion of ≥ 2 units of erythrocytes or whole blood in excess of expected
• symptomatic retroperitoneal, intracranial, intraocular or intraspinal bleeding
• bleeding that required discontinuation of treatment
• bleeding that has required a new surgery.
Objective testing was required for retroperitoneal bleeding (ultrasound scan or computed tomography (CT)) and intraspinal bleeding (CT or magnetic resonance imaging).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Doses of dabigatran etexilate higher than those recommended expose the patient to an increased risk of bleeding.
If overdose is suspected, coagulation tests can help determine the risk of bleeding (see sections 4.4 and 5.1). Quantitative calibrated dTT test or repeated dTT measurements allow predicting by when certain levels of dabigatran will be reached (see section 5.1) even if other measures have been taken eg. dialysis.
Excessive anticoagulant activity may require discontinuation of Pradaxa treatment. There is no specific antidote for dabigatran.In the event of bleeding complications, treatment should be suspended and the cause of the bleeding investigated. Since dabigatran is mainly excreted by the kidney, adequate diuresis should be maintained. Appropriate supportive treatment such as surgical haemostasis and blood volume restoration should be undertaken, at the physician's discretion.
Concentrates of the activated prothrombin complex (eg FEIBA) or recombinant factor VIIa or concentrates of coagulation factors II, IX and X may be considered. There is some experimental evidence supporting the role of these drugs in counteracting the anticoagulant effect of dabigatran, but data on their usefulness in the clinical setting and also on the possible risk of rebound thromboembolism are very limited. Coagulation tests may become unreliable. after the administration of the drugs contrasting the anticoagulant effect. Caution should be exercised when interpreting the results of these tests. Administration of platelet concentrates should also be considered if thrombocytopenia occurs or long-acting antiplatelet agents have been used. All symptomatic treatments should be administered in accordance with the physician's judgment.
Depending on local availability, in the event of major bleeding, the advisability of consulting a coagulation expert should be considered.
Since protein binding is low, dabigatran can be dialyzed; the clinical experience demonstrating the utility of this approach in clinical trials is limited (see section 5.2).
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antithrombotics, direct thrombin inhibitors.
ATC code: B01AE07.
Mechanism of action
Dabigatran etexilate is a small molecular prodrug that does not exert any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase catalyzed hydrolysis in plasma and liver. Dabigatran is a potent direct, competitive, reversible thrombin inhibitor and is the main active substance found in plasma.
Since thrombin (serine protease) allows the conversion of fibrinogen to fibrin in the coagulation cascade, its inhibition prevents thrombus formation. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
Pharmacodynamic effects
Studies carried out on animals in-vivo And ex vivo demonstrated the antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate after oral administration in various animal models of thrombosis.
There is a clear correlation between the plasma concentration of dabigatran and the magnitude of the anticoagulant effect, based on data from phase II studies. Dabigatran prolongs the thrombin time (TT), ECT and aPTT.
The Thrombin Time (dTT) calibrated assay for dabigatran on diluted plasma provides an estimate of the plasma concentration of dabigatran which can be compared with the expected plasma concentrations of dabigatran.
ECT can provide a direct measure of the activity of direct thrombin inhibitors.
The aPTT test is widely used and provides an approximate indication of the intensity of the anticoagulant effect achieved with dabigatran. However, the aPTT test is characterized by limited sensitivity and is not indicated for the exact quantification of the anticoagulant effect, especially at high plasma concentrations. by dabigatran. Elevated aPTT values should be interpreted with caution.
In general, it can be argued that these anticoagulant activity measurements reflect dabigatran levels and may provide guidance for assessing the risk of bleeding, i.e. exceeding the 90th percentile limit of dabigatran levels at trough time or measured aPTT. at trough time they are considered to be associated with an increased risk of bleeding.
At steady state (after 3 days) the geometric mean of dabigatran plasma concentration at peak time, measured approximately 2 hours after administration of 220 mg dabigatran etexilate, was 70.8 ng / ml, with a range of 35 , 2-162 ng / ml (25th -75th percentile).
The geometric mean of dabigatran concentration at trough time, measured at the end of the dosing period (i.e. 24 hours after a 220 mg dose of dabigatran), averaged 22.0 ng / mL, with a range of 13, 0-35.7 ng / mL (25th-75th percentile).
In patients treated for the prevention of VTE after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily,
• the 90th percentile of dabigatran plasma concentrations, measured at trough time (20-28 hours after the previous dose), was 67 ng / mL (see sections 4.4 and 4.9),
• the 90th percentile of aPTT at trough time (20-28 hours after the previous dose) was 51 seconds, or 1.3 times the upper limit of normal.
ECT was not measured in patients treated for the prevention of VTE after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily.
Clinical efficacy and safety
Ethnic origins
No relevant inter-ethnic differences were observed between Caucasian, African American, Hispanic, Japanese, or Chinese patients.
Clinical trials in venous thromboembolism (VTE) prophylaxis following major joint replacement surgery
In 2 large, randomized, parallel-group, double-blind, dose-confirmatory studies, patients scheduled for major orthopedic surgery (one for knee replacement surgery and one for hip replacement surgery) were treated with Pradaxa 75 mg or 110 mg within 1-4 hours after surgery and therefore with 150 or 220 mg per day, haemostasis having been evaluated normal or with 40 mg of enoxaparin the day before the surgery and therefore daily.
In the RE-MODEL study (knee replacement) the treatment duration was 6-10 days and in the RE-NOVATE study (hip replacement) it was 28-35 days. A total of 2,076 (hip replacement) were treated respectively. knee) and 3,494 (hip replacement) patients.
The combination of all episodes of VTE (which included PE, proximal and distal DVT, both symptomatic and asymptomatic detected with routine venography) and all-cause mortality were the primary endpoints of both studies.
The combination of all major episodes of VTE (which included PE, both symptomatic and asymptomatic proximal DVT detected with routine venography) and VTE-related mortality were a secondary endpoint considered to be of greater clinical relevance.
The results of both studies demonstrated that the antithrombotic effect of Pradaxa 220 mg and 150 mg was statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The estimated incidence of major episodes of VTE is VTE-related mortality for the 150 mg dose was slightly worse than for enoxaparin (Table 6). Better results were seen with the 220 mg dose where the estimated incidence of major VTE episodes was slightly better than for with enoxaparin (table 6).
Clinical studies were conducted in a patient population with a mean age of> 65 years.
No differences in efficacy and safety were found between men and women in the Phase 3 clinical trials.
Of the patient population participating in the RE-MODEL and RE-NOVATE studies (5,539 treated patients), 51% suffered from concomitant hypertension, 9% from concomitant diabetes, 9% from coronary artery disease, and 20% had a history of venous insufficiency. None of these conditions have been shown to interfere with the effects of dabigatran on the prevention of VTE or the frequency of bleeding.
Data for the major VTE and VTE-related mortality endpoint were homogeneous with respect to the primary efficacy endpoint and are shown in Table 6.
Endpoint data for total VTE and all cause mortality are shown in Table 7.
Data for the endpoints of bleeding judged to be major are listed in Table 8 below.
Table 6: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and RE-NOVATE orthopedic surgery studies
Table 7: Analysis of total VTE and all-cause mortality during the treatment period of the RE-NOVATE and RE-MODEL orthopedic surgery studies
Table 8: Major Bleeding Episodes (ESM) Following Treatment in the Individual RE-MODEL and RE-NOVATE Studies
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Pradaxa in all subsets of the pediatric population for the prevention of thromboembolic episodes in the authorized indication (see section 4.2 for information on pediatric use).
Clinical studies for the prevention of thromboembolism in patients with heart valve prostheses
A phase II study evaluated dabigatran etexilate and warfarin in a total of 252 patients who underwent partly recent mechanical valve surgery (i.e. enrolled during hospitalization) and partly mechanical heart valve surgical implantation. for more than three months. More thromboembolic events (mainly stroke and symptomatic / asymptomatic valve thrombosis) and more bleeding events were observed with dabigatran etexilate than with warfarin. In immediate postoperative patients, major bleeding manifested mainly as haemorrhagic pericardial effusions, particularly in patients who started dabigatran etexilate shortly (ie on day 3) after cardiac valve prosthesis surgery (see paragraph 4.3).
05.2 Pharmacokinetic properties
After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. Cleavage of the prodrug dabigatran etexilate by esterase-catalyzed hydrolysis to the active substance dabigatran is the predominant metabolic reaction. The absolute bioavailability of dabigatran following oral administration of Pradaxa is approximately 6.5%.
After oral administration of Pradaxa to healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax reached 0.5 - 2.0 hours after dosing.
Absorption
A study evaluating the post-operative absorption of dabigatran etexilate, 1-3 hours after surgery, demonstrated a relatively slow absorption compared to that seen in healthy volunteers, demonstrating a plasma concentration-time profile without high peak plasma concentrations. . Peak plasma concentrations are reached 6 hours after administration in a post-operative period due to factors such as anesthesia, intestinal paresis and surgical effects, regardless of the oral formulation of the medicinal product. In a further study it was shown that slow and delayed absorption usually occurs only on the day of surgery. In the days following the absorption of dabigatran is rapid with peak plasma concentrations reached 2 hours after drug administration.
Food does not alter the bioavailability of dabigatran etexilate, but delays the time to peak plasma concentration by 2 hours.
When the pellets are taken without the (hydroxypropylmethylcellulose) HPMC capsule, the oral bioavailability may increase by 75% compared to the reference formulation with the capsule. Therefore, the integrity of HPMC capsules must always be preserved during clinical use to avoid an unintended increase in the bioavailability of dabigatran etexilate. Therefore patients should be advised not to open the capsules and not to take their contents alone (e.g. sprinkled on food or poured into a drink) (see section 4.2).
Distribution
A low concentration-independent binding (34-35%) of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran of 60-70 l exceeds the volume of total body fluids indicating moderate tissue distribution of dabigatran.
Cmax and area under the plasma concentration-time curve were dose proportional. Plasma concentrations of dabigatran showed a bi-exponential decline with a mean terminal half-life of 11 hours in healthy, elderly subjects. After multiple doses, a "terminal half-life of approximately 12 - 14 hours" was observed. The half-life was independent of dose. The half-life is prolonged if renal function is impaired as shown in table 9.
Biotransformation
Metabolism and excretion of dabigatran were studied following administration of a single intravenous dose of radioactive dabigatran to healthy male subjects. After an intravenous dose, dabigatran-derived radioactivity was eliminated primarily in the urine (85%). Faecal excretion was estimated to be 6% of the administered dose. Total radioactivity recovery ranged from 88 to 94% of the administered dose within 168 hours of administration.
Dabigatran is subject to conjugation with the formation of pharmacologically active acylglucuronides. There are four positional isomers 1-O, 2-O, 3-O, 4-O of the acylglucuronides each estimated to be less than 10% of the total dabigatran in plasma. Traces of other metabolites are only detectable by highly sensitive analytical methods. Dabigatran is eliminated mainly unchanged in the urine at a rate of approximately 100 ml / min corresponding to the glomerular filtration rate.
Special populations
Kidney failure
In phase I studies, exposure (AUC) to dabigatran following oral administration of Pradaxa is approximately 2.7-fold higher in volunteers with moderate renal impairment (CrCL between 30 and 50 mL / min) than in those without renal impairment.
In a small number of volunteers with severe renal insufficiency (CrCL 10 - 30 ml / min), dabigatran exposure (AUC) was approximately 6 times higher and half-life approximately 2 times longer than that observed in a population without renal insufficiency. (see sections 4.2, 4.3 and 4.4).
Table 9: Half-life of total dabigatran in healthy subjects and subjects with impaired renal function.
The clearance of dabigatran by hemodialysis was examined in 7 patients with end-stage chronic renal failure (ESRD) without atrial fibrillation. Dialysis was conducted at a dialysate flow rate of 700 mL / min, for a duration of four hours, and at a blood flow rate of both 200 mL / min and 350-390 mL / min. This resulted in a removal of 50% to 60% of dabigatran concentrations, respectively. The amount of substance removed by dialysis is proportional to the blood flow rate up to 300 ml / min. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the pharmacokinetic / pharmacodynamic relationship was not altered by the procedure.
Elderly patients
Specific phase I pharmacokinetic studies conducted in elderly subjects showed a 40 to 60% increase in AUC and more than 25% in C compared to young subjects.
The effect of age on dabigatran exposure was confirmed in the RE-LY study with a higher trough concentration of approximately 31% in subjects ≥ 75 years of age and with a lower trough concentration of approximately 22% in subjects of age
Hepatic impairment
No alteration of dabigatran exposure was found in 12 subjects with moderate hepatic impairment (Child Pugh B) compared to 12 control subjects (see sections 4.2 and 4.4).
Body weight
Dabigatran concentrations at trough time were approximately 20% lower in patients with body weight> 100 kg compared to patients with body weight between 50 and 100 kg. Most patients (80.8%) had body weight ≥ 50 kg and
Type
Active substance exposure in primary VTE prevention studies was approximately 40% to 50% higher in female patients and no dose adjustment is recommended.
ethnic background
No relevant inter-ethnic differences were observed between Caucasians, African Americans, Hispanics, Japanese or Chinese regarding the pharmacokinetics and pharmacodynamics of dabigatran.
Pharmacokinetic interactions
The pro-drug dabigatran etexilate is a substrate of the efflux transporter P-gp, but not dabigatran.For this reason, concomitant use with inhibitors of the P-gp transporter (amiodarone, verapamil, clarithromycin, quinidine, dronedarone, ticagrelor and ketoconazole) and with inducers (rifampicin) has been studied (see sections 4.2, 4.4 and 4.5).
The interaction studies in vitro showed no inhibition or induction of the major cytochrome P450 isoenzymes. This was confirmed by in vivo studies performed on healthy volunteers, in which no interaction was shown between this treatment and the following active substances: atorvastatin (CYP3A4), digoxin (interaction with the P-gp transporter) and diclofenac (CYP2C9) .
05.3 Preclinical safety data
Data from non-clinical studies reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Effects observed in repeat dose toxicity studies were due to the amplified pharmacodynamic effect of dabigatran.
An effect on female fertility in the form of decreased implantation and increased pre-implantation loss was observed at doses of 70 mg / kg (5 times the plasma exposure level in patients). At maternally toxic doses (5 to 10 times the plasma exposure level in patients), a decrease in fetal body weight and viability with an increase in fetal changes was observed in rats and rabbits. In a pre- and postnatal study, an increase in fetal mortality was observed at maternally toxic doses (dose corresponding to a plasma exposure level 4 times higher than that observed in patients).
In lifelong toxicity studies in rats and mice, there was no evidence of a tumorigenic potential of dabigatran up to a maximum dose of 200 mg / kg.
Dabigatran, the active molecule of dabigatran etexilate mesylate, is persistent in the environment.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule contents
• Tartaric acid
• Arabic gum
• Hypromellose
• Dimethicone 350
• Talc
• Hydroxypropylcellulose
Capsule
• Carrageenan
• Potassium chloride
• Titanium dioxide
• Indigo carmine (E132)
• Sunset yellow (E110)
• Hypromellose
Black ink for printing
• Shellac
• Black iron oxide (E172)
• Potassium hydroxide
06.2 Incompatibility
Not relevant.
06.3 Period of validity
Blister and bottle: 3 years.
Once the bottle is opened, the medicinal product should be used within 4 months.
06.4 Special precautions for storage
Blister
Store in the original package to protect the medicine from moisture.
Bottle
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
06.5 Nature of the immediate packaging and contents of the package
Packs containing 10 x 1, 30 x 1 or 60 x 1 hard capsules in perforated unit dose blisters. In addition, packs containing 6 white aluminum blister strips, divisible by unit dose (60 x 1). The blister consists of an upper layer of aluminum coated with polyvinyl chloride-polyvinyl acetate copolymers (PVCAC acrylates) in contact with the product and a lower layer of aluminum coated with polyvinyl chloride (PVC) in contact with the product.
Polypropylene bottle with screw cap containing 60 hard capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
When using Pradaxa packed in blister packs, the following instructions should be observed:
• The hard capsule must be removed from the blister by lifting the aluminum foil on the back.
• The hard capsule must not be pushed through the blister.
• The aluminum foil of the blister should only be lifted when a hard capsule is needed.
When using the bottle packed capsules, the following instructions should be observed:
• The bottle is opened by pressing and turning the cap.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/08/442/001
038451011
EU / 1/08/442/002
038451023
EU / 1/08/442/003
038451035
EU / 1/08/442/004
038451047
EU / 1/08/442/017
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 18 March 2008
Date of most recent renewal: January 17, 2013
10.0 DATE OF REVISION OF THE TEXT
December 18, 2014
