1. Name Of The Medicinal Product
2. Qualitative And Quantitative Composition
Each hard capsule contains 75 mg of dabigatran etexilate (as mesilate).
Excipients: Each hard capsule contains 2 micrograms sunset yellow (E110).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Hard capsule
Imprinted capsules with light blue, opaque cap and cream-coloured, opaque body of size 2 filled with yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with “R75”.
4. Clinical Particulars
4.1 Therapeutic Indications
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
4.2 Posology And Method Of Administration
Posology
Prevention of Venous Thromboembolism (VTE)
Patients following elective knee replacement surgery
The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1–4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
Patients following elective hip replacement surgery
The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1–4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.
For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.
Renal impairment
Treatment with Pradaxa in patients with severe renal impairment (creatinine clearance (CrCL) < 30 ml/min) is contraindicated (see section 4.3).
In patients with moderate renal impairment (CrCL 30-50 ml/min), there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1).
Concomitant use of Pradaxa with strong P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil
Dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa in patients who receive concomitantly dabigatran etexilate and amiodarone, quinidine or verapamil (see sections 4.4 and 4.5). In this situation Pradaxa and these medicinal products should be taken at the same time.
In patients with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.4 and 4.5).
Elderly
In elderly patients (> 75 years) there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1).
Hepatic impairment
Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2).
Weight
There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see section 5.2), but close clinical surveillance is recommended (see section 4.4).
Gender
Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2).
Switching
Pradaxa treatment to 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).
Parenteral anticoagulants to Pradaxa
Dabigatran etexilate should be given 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).
Paediatric population
There is no relevant use of Pradaxa in the paediatric population in the indication: primary prevention of venous thromboembolic events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
Pradaxa is not recommended for use in patients below 18 years due to lack of data on safety and efficacy.
Missed dose
It is recommended to continue with the remaining daily doses of dabigatran etexilate at the same time of the next day.
No double dose should be taken to make up for missed individual doses.
Method of administration
Pradaxa should be swallowed as a whole with water, with or without food.
Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see sections 5.2 and 6.6).
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients
• Patients with severe renal impairment (CrCL < 30 ml/min)
• Active clinically significant bleeding
• Organic lesion at risk of bleeding
• Spontaneous or pharmacological impairment of haemostasis
• Hepatic impairment or liver disease expected to have any impact on survival
• Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and tacrolimus (see section 4.5)
4.4 Special Warnings And Precautions For Use
Hepatic impairment
Patients with elevated liver enzymes > 2 ULN were excluded in controlled clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population.
Haemorrhagic risk
As with all anticoagulants, dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding. Bleeding can occur at any site during therapy with dabigatran. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.
Factors, such as decreased renal function (30-50 ml/min CrCL), age
Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux requiring proton pump inhibitors (PPI) or histamine 2 (H2)-blocker treatment increase the risk of GI bleeding. The administration of a PPI can be considered to prevent GI bleeding.
Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined (see section 5.1).
Table 1 summarises factors which may increase the haemorrhagic risk.
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The measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.
The activated partial thromboplastin time (aPTT) test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding or at risk of bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. High aPTT values should be interpreted with caution.
If required, more sensitive quantitative tests such as calibrated diluted Thrombin Time (dTT) should be performed (see section 5.1).
Patients who develop acute renal failure must discontinue Pradaxa (see section 4.3).
Limited data is available in patients < 50 kg (see section 5.2).
When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see section 4.9).
Agents that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see section 4.5).
Interaction with P- gp inducers
Concomitant administration of P-gp inducers (such as rifampicin, St. John`s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran plasma concentrations, and should 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 for bleeding. Therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate.
Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be considered in advance of any procedures. In such cases a coagulation test (see sections 4.4 and 5.1) may help to determine whether haemostasis is still impaired.
Preoperative phase
Table 2 summarizes discontinuation rules before invasive or surgical procedures.
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If an acute intervention is required, dabigatran etexilate should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention.
Spinal anaesthesia/epidural anaesthesia/lumbar puncture
Procedures such as spinal anaesthesia may require complete haemostatic function.
The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.
Post-surgical patients with an increased risk for bleeding
Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 ml/min), should be treated with caution (see sections 4.4 and 5.1). Resume treatment after complete haemostasis is achieved.
Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events
There are limited efficacy and safety data for dabigatran available in these patients and therefore they should be treated with caution.
Hip fracture surgery
There is no data on the use of Pradaxa in patients undergoing hip fracture surgery. Therefore treatment is not recommended.
Colorants
Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Anticoagulants and antiplatelet aggregation agents
The following treatments have not been studied and may increase the risk of bleeding when used concomitantly with Pradaxa: UFH, low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, dextran, sulfinpyrazone, rivaroxaban, and vitamin K antagonists (see section 4.4).
UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter (see sections 4.2 and 4.4).
Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUCmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCmax,ss were increased by about 30-40 % (see section 4.4).
ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively (see section 4.4).
NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use NSAIDs increased the risk of bleeding by approximately 50 % on both dabigatran and warfarin. Therefore, due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives > 12 hours, close observation for signs of bleeding is recommended (see section 4.4).
LMWH: The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.
Interactions linked to dabigatran etexilate and dabigatran metabolic profile
Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran.
Transporter interactions
P-gp inhibitors
Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of strong P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole and clarithromycin) is expected to result in increased dabigatran plasma concentrations.
If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure (see sections 4.2, 4.4 and 5.1).
Systemic ketoconazole, cyclosporine, itraconazole and tacrolimus are contraindicated (see section 4.3). Caution should be exercised with other strong P-gp inhibitors (e.g. amiodarone, quinidine or verapamil) (see sections 4.2 and 4.4).
Ketoconazole: Ketoconazole increased total dabigatran AUC0- and Cmax values by 138 % and 135 %, respectively, after a single dose of 400 mg , and 153 % and 149 %, respectively, after multiple dosing of 400 mg ketoconazole once daily. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole (see section 4.4). Concomitant treatment with systemic ketoconazole is contraindicated (see section 4.3).
Amiodarone: When Pradaxa was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 60 % and 50 %, respectively. The mechanism of the interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4).
Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and amiodarone (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with amiodarone and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUCmax,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4).
Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and quinidine (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
Verapamil: When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4).
The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of Cmax by about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an extended release formulation (increased of Cmax by about 90 % and AUC by about 70 %) or administration of multiple doses of verapamil (increased of Cmax by about 60 % and AUC by about 50 %).
Therefore, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with verapamil. In patients with normal renal function after the hip or knee replacement surgery, receiving dabigatran etexilate and verapamil concomitantly, the dose of Pradaxa should be reduced to 150 mg taken once daily as 2 capsules of 75 mg . In patients with moderate renal impairment and concomitantly treated 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 surveillance is recommended when dabigatran etexilate is combined with verapamil and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increased of Cmax by about 10 % and AUC by about 20 %). This is explained by completed dabigatran absorption after 2 hours (see section 4.4).
Clarithromycin: When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 19 % and Cmax by about 15 % was observed without any clinical safety concern. However, in patients receiving dabigatran, a clinically relevant interaction cannot be excluded when combined with clarithromycin. Therefore, a close monitoring should be exercised when dabigatran etexilate is combined with clarithromycin and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
The following potent P-gp inhibitors have not been clinically studied but from in vitro results a similar effect as with ketoconazole may be expected:
Itraconazole, tacrolimus and cyclosporine, which are contra-indicated (see section 4.3).
Neither clinical nor in vitro test results are available for posaconazole which is not recommended for concomitant treatment with Pradaxa. Inadequate clinical data are available regarding the co-administration of Pradaxa and dronedarone, and their co-administration is not recommended (see section 4.4).
P-gp inducers
Concomitant administration of a P-gp inducer (such as rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided (see sections 4.4 and 5.2).
Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5 and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.
Other drugs affecting P-gp
Protease inhibitors including ritonavir and its combinations with other protease inhibitors affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with Pradaxa.
P-gp substrate
Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was co-administered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.
Gastric pH
Pantoprazole: When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.
Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of Pradaxa in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Women of child-bearing potential should avoid pregnancy during treatment with dabigatran etexilate. Pradaxa should not be used during pregnancy unless clearly necessary.
Breast-feeding
There are no clinical data of the effect of dabigatran on infants during breast feeding.
Breast-feeding should be discontinued during treatment with Pradaxa.
Fertility
No data human available.
In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
A total of 10.084 patients were treated in 4 actively controlled VTE prevention trials with at least one dose of the medicinal product. Of these 5419 were treated with 150 mg or 220 mg daily of Pradaxa, while 389 received doses less than 150 mg daily and 1168 received doses in excess of 220 mg daily.
The most commonly reported adverse reactions are bleedings occurring in total in approximately 14 % of patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %.
Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Adverse reactions
Table 3 shows the adverse reactions ranked under headings of SOC and frequency using the following convention: very common (
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Bleeding
The table 4 shows the number (%) of patients
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