Pradaxa 75 mg, 110 mg, 150 mg Capsule

Prevention of venous thromboembolic events in patients who have undergone hip and knee replacement surgery.

To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation.

Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE).

PRADAXA can be taken with or without food. PRADAXA should be taken with a glass of water, to facilitate delivery to the stomach. If gastrointestinal symptoms develop it is recommended to take PRADAXA with a meal and/or a proton pump inhibitor such as pantoprazole.

Do not open the capsule. Instructions for use/handling: When removing a capsule from the blister, please note the following instructions:

• Tear off one individual blister from the blister card along the perforated line
• Peel off the backing foil and remove the capsule
• The capsule should not be pushed through the blister foil

Adults

Prevention of venous thromboembolism (VTE) in patients following hip and knee replacement surgery: The recommended dose of PRADAXA is 220 mg once daily taken as 2 capsules of 110 mg. Patients with moderate renal impairment have an increased risk for bleeding. For those patients the recommended dose of PRADAXA is 150 mg once daily.

VTE prevention following knee replacement surgery: Treatment with PRADAXA should be initiated orally within 1 u2013 4 hours of completed surgery with a single capsule (110 mg) and continuing with 2 capsules once daily thereafter for a total of 10 days. 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.

Patients with moderate renal impairment have an increased risk for bleeding. For those patients the PRADAXA 75 mg capsules should be used instead of the 110 mg capsules.

VTE prevention following hip replacement surgery: Treatment with PRADAXA should be initiated orally within 1 - 4 hours of completed surgery with a single capsule (110 mg) and continuing with 2 capsules once daily thereafter for a total of 28 days. 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.

Patients with moderate renal impairment have an increased risk for bleeding. For those patients the PRADAXA 75 mg capsules should be used instead of the 110 mg capsules.

To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation: The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg capsules twice daily. Therapy should be continued life-long.

Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg capsules twice daily following treatment with a parenteral anticoagulant for at least 5 days. Therapy should be continued for up to 6 months.

Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg capsules twice daily. Therapy could be continued life-long depending on the individual patientu2019s risk factors.

Children

PRADAXA has not been investigated in patients < 18 years of age. Treatment of children with PRADAXA is not recommended.

Renal impairment

Renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30 mL/min). There are no data to support use in patients with severe renal impairment (CrCl < 30 mL/min); treatment in this population with PRADAXA is not recommended (see section 4.3). While on treatment renal function should be assessed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolaemia, dehydration, and with certain co-medications that may decrease renal function such as with initiation of chemotherapeutics, or amphotericin B or under chronic treatment with NSAIDs). PRADAXA can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies.

Prevention of venous thromboembolic events in patients who have undergone hip and knee replacement surgery: Dosing should be reduced to 150 mg PRADAXA taken once daily as 2 capsules of 75 mg in patients with moderate renal impairment (CrCl 30 - 50 mL/min). Treatment with PRADAXA should be initiated orally within 1 - 4 hours of completed surgery with a single capsule of 75 mg and continuing with 2 capsules of 75 mg once daily thereafter for a total of 10 days (following knee replacement surgery) or 28 days (following hip replacement surgery). 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.

To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation: In patients with moderate renal impairment (CrCl 30 - 50 mL/min) the renal function should be assessed at least once a year. No dose adjustment is necessary. Patients should be treated with a daily dose of 300 mg taken orally as 150 mg capsules twice daily.

Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): No dose adjustment is necessary in patients with renal function over CrCl 30 mL/min. Patients should be treated with a daily dose of 300 mg taken orally as 150 mg capsules twice daily.

Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): In patients with moderate renal impairment (CrCl 30 - 50 mL/min) the renal function should be assessed at least once a year. No dose adjustment is necessary in patients with renal function over CrCl 30 mL/min. Patients should be treated with a daily dose of 300 mg taken orally as 150 mg capsules twice daily.

• Known hypersensitivity to dabigatran or dabigatran etexilate or to one of the excipients of PRADAXA
• Patients with severe renal impairment (CrCl < 30 mL/min)
• Haemorrhagic manifestations, patients with a bleeding diathesis, or patients with spontaneous or pharmacological impairment of haemostasis
• Moderate to severe hepatic impairment (Child-Pugh B/C)
• Organ lesions at risk of clinically significant bleeding, including haemorrhagic stroke within the last 6 months
• Patients with an indwelling spinal or epidural catheter and during the first hour after removal (see section 4.4)
• Prolonged co-administration with heparins or warfarin
• Concomitant treatment with systemic ketoconazole (see section 4.5)
• The following treatments should not be administered concomitantly with PRADAXA: unfractionated heparins and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, ticagrelor, dextran, sulfinpyrazone and Vitamin K antagonists. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter and that PRADAXA and Vitamin K antagonists (e.g. warfarin) can be administered together, but only for a few days during switching from PRADAXA to Vitamin K antagonist treatment
• In patients with suspected infective endocarditis
• Prosthetic heart valve replacement

Haemorrhagic risk

PRADAXA increases the risk of bleeding and can cause significant and sometimes fatal bleeding. PRADAXA should be used with caution in conditions with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAXA. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should prompt a search for a bleeding site. In the case of haemorrhagic complications treatment must be discontinued and the source of bleeding investigated. For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effects of dabigatran is required, the specific reversal agent idarucizumab is available (See Surgery and interventions, Pre-operative phase and section 4.9).

Careful clinical monitoring including renal function testing is required in certain clinical situations (see sections 5.1 and 4.2). PRADAXA does not in general require routine anticoagulation monitoring. However, the measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors. Coagulation testing should also be considered to assist with the management of patients in the perioperative setting, suspected overdose and emergency situations. The INR test is unreliable in patients on PRADAXA and false positive INR elevations have been reported. Therefore INR tests should not be performed. Tests of anticoagulant activity such as Thrombin Time (TT), diluted Thrombin Time (dTT), Ecarin Clotting Time (ECT) and activated Partial Thromboplastin Time (aPTT) are available to detect excessive dabigatran activity. PRADAXA related anticoagulation can be assessed by ECT or TT. If ECT or TT are not available, the aPTT test provides an approximation of PRADAXAu2019s anticoagulant activity.

To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation: In atrial fibrillation patients treated with 150 mg twice daily an aPTT of greater than 2,0 u2013 3,0 fold of normal range at trough was associated with an increased risk of bleeding.

Renal impairment

Renal function should be assessed by calculating the creatinine clearance (CrCl) by the Cockgroft-Gault method prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30 mL/min). Patients who develop acute renal failure should discontinue PRADAXA.

Patients with antiphospholipid syndrome

Patients with antiphospholipid syndrome (especially if triple-positive for antiphospholipid antibodies) are at an increased risk for thromboembolic events. While the efficacy of PRADAXA is established for the treatment and prevention of venous thromboembolism it has not been studied specifically in the subpopulation of patients with antiphospholipid syndrome. Therefore, careful consideration of all treatment options (including standard treatment such as vitamin K antagonists) is recommended before use of PRADAXA in patients with antiphospholipid syndrome.

Surgery and interventions

Patients on PRADAXA who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of PRADAXA (see also section 5.2). Patients can stay on PRADAXA while being cardioverted. PRADAXA treatment (150 mg twice daily) does not need to be interrupted in patients undergoing catheter ablation for atrial fibrillation (see section 4.2). In case of emergency surgery or urgent procedures when rapid reversal of the anticoagulation effect is required the specific reversal agent idarucizumab to PRADAXA is available. Reversing PRADAXA therapy exposes patients to the thrombotic risk of their underlying disease. PRADAXA treatment can be re-initiated 24 hours after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved.

Pre-operative phase

Due to an increased risk of bleeding PRADAXA should be stopped temporarily in advance of invasive or surgical procedures. Emergency surgery or urgent procedure the specific reversal agent idarucizumab of PRADAXA is available for the rapid reversal of the anticoagulation effect (see Surgery and interventions).

Acute surgery/intervention

PRADAXA should be temporarily discontinued. An acute surgery/intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed there may be an increase in the risk of bleeding. Neuraxial blocks are not recommended for within 24 hours after discontinuation of PRADAXA. Refer to Haemorrhagic risk above for information regarding correlation between plasma dabigatran concentration and degree of anticoagulant effect.

Elective surgery/intervention/spinal anaesthesia/epidural anaesthesia/lumbar puncture

If possible, PRADAXA should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding, or in major surgery where complete haemostasis may be required, consider stopping PRADAXA 2 - 4 days before surgery. Clearance of PRADAXA in patients with renal insufficiency may take longer. This should be considered in advance of any procedures (see section 5.2 and the table summarising discontinuation rules under section 4.2). 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 1 hour should elapse before the administration of the first dose of PRADAXA. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma. PRADAXA is contraindicated in patients with severe renal dysfunction (CrCl < 30 mL/min) but, should this occur, then PRADAXA should be stopped at least 5 days before major surgery. If an acute intervention is required, PRADAXA 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 there may be an increase in the risk of bleeding. This risk of bleeding should be weighed together with the urgency of intervention.

Post-procedural period

PRADAXA treatment can be resumed/started after complete haemostasis is achieved.

The concomitant use of PRADAXA with treatments that act on haemostasis or coagulation including Vitamin K antagonists and anti-platelet medicines can markedly increase the risk of bleeding. (See sections 4.3 and 4.4.)

PRADAXA is not metabolised by the cytochrome P450 system and in vitro interaction studies did not show any inhibition or induction of the principal isoenzymes of cytochrome P450. Therefore related interactions are not expected with PRADAXA. This has been confirmed by in vivo studies with healthy volunteers, who did not show any interaction between this treatment and the following medicines: atorvastatin (CYP3A4), digoxin (P-gp transporter interaction) and diclofenac (CYP2C9).

Atorvastatin

When PRADAXA was co-administered with atorvastatin, a CYP3A4 substrate, exposure of atorvastatin, atorvastatin metabolites and of PRADAXA were unchanged indicating a lack of interaction.

Diclofenac

When PRADAXA was co-administered with diclofenac, a CYP2C9 substrate, pharmacokinetic properties of both medicines remained unchanged indicating a lack of interaction between PRADAXA and diclofenac.

P-gp inhibitor/inducer interactions

The pro-drug dabigatran etexilate, but not dabigatran, is a substrate of the efflux transporter P-glycoprotein (P-gp). Therefore co-medications with P-gp transporter inhibitors and inducers have been investigated.

P-glycoprotein inhibitors

Concomitant administration of P-gp inhibitors (such as amiodarone, verapamil, quinidine, systemic ketoconazole, dronedarone, ticagrelor, clarithromycin and the fixed-dose combination glecaprevir/pibrentasvir) is expected to result in increased PRADAXA plasma concentrations. (See section 4.2.)

Concomitant administration of systemic ketoconazole is contraindicated.

Amiodarone

PRADAXA exposure in healthy subjects was increased by 1,6 fold (+ 60 %) in the presence of amiodarone.

To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation PRADAXA concentrations were increased by no more than 14 % and no increased risk of bleeding was observed.

Dronedarone

When PRADAXA and dronedarone were given at the same time total PRADAXA AUC 0- u221e and C max values increased by about 2,4 fold and 2,3 fold (+ 136 % and 125 %), respectively, after multiple dosing of 400 mg dronedarone twice daily, and about 2,1 fold and 1,9 fold (+ 114 % and 87 %), respectively, after a single dose of 400 mg. The terminal half-life and renal clearance of PRADAXA were not affected by dronedarone. When single and multiple doses of dronedarone were given 2 hours after PRADAXA, the decreases in dabigatran AUC 0- u221e were 1,3 fold and 1,6 fold, respectively.

Verapamil

When PRADAXA (150 mg) was co-administered with oral verapamil, the C max and AUC of dabigatran were increased but the magnitude of this change differs, depending on timing of administration and formulation of verapamil. The greatest elevation of PRADAXA exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to PRADAXA intake (increase of C max by about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an extended release formulation (increase of C max by about 90 % and AUC by about 70 %) or administration of multiple doses of verapamil (increase of C max by about 60 % and AUC by about 50 %). This can be explained by the induction of P-gp in the gut by chronic verapamil treatment. There was no meaningful interaction observed when verapamil was given 2 hours after PRADAXA (increase of C max by about 10 % and AUC by about 20 %). This is explained by completed dabigatran absorption after 2 hours. (See section 4.2.) No data are available for the parenteral application of verapamil; based on the mechanism of the interaction, no meaningful interaction is expected.

Quinidine

Quinidine was given as a 200 mg dose every 2 nd hour up to a total dose of 1 000 mg. PRADAXA was given twice daily over 3 consecutive days, on the 3 rd day either with or without quinidine. PRADAXA AUC u03c4 ,ss and C max,ss were increased on average by 1,5 fold (+53 % and 56 %), respectively, with concomitant quinidine.

Clarithromycin

When clarithromycin 500 mg twice daily was administered together with PRADAXA no clinically relevant pharmacokinetic (PK)-interaction was observed (increase of C max by about 15 % and AUC by about 19 %).

Ketoconazole

Systemic ketoconazole increased total PRADAXA AUC 0- u221e and C max values by about 2,4 fold (+138 % and 135 %, respectively), after a single dose of 400 mg, and 2,5 fold (+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 4.3).

Ticagrelor

When a single dose of 75 mg PRADAXA was co-administered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and C max were increased by 1,73 fold and 1,95 fold (+ 73 % and 95 %), respectively. After multiple doses of ticagrelor 90 mg twice daily the increase of dabigatran exposure after a single dose is reduced to 1,56 fold and 1,46 fold (+ 56 % and 46 %) for C max and AUC, respectively. Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg PRADAXA (in steady state) increased the dabigatran AUC u03c4 ,ss and by C max,ss by 1,49 fold and 1,65 fold (+ 49 % and 65 %), respectively, compared with PRADAXA given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg PRADAXA (in steady state), the increase of dabigatran AUC u03c4 ,ss and C max,ss was reduced to 1,27 fold and 1,23 fold (+ 27 % and 23 %), respectively, compared with PRADAXA given alone. Concomitant administration of 90 mg ticagrelor twice daily (maintenance dose) with 110 mg PRADAXA increased the adjusted dabigatran AUC u03c4 ,ss and C max,ss 1,26 fold and 1,29 fold, respectively, compared with PRADAXA given alone.

P-glycoprotein substrate

Digoxin: When PRADAXA was co-administered with digoxin, a P-gp substrate, no changes in digoxin and no clinically relevant changes in PRADAXA exposure have been observed. Neither dabigatran nor the pro-drug dabigatran etexilate is a clinically relevant P-gp inhibitor.

P-glycoprotein inducers

Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total PRADAXA peak and total exposure by 65,5 % and 67 %, respectively. The inducing effect was diminished resulting in PRADAXA exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.

The concomitant use with P-gp inducers (e.g. rifampicin) reduces exposure to PRADAXA and should be avoided (see section 4.4).

Safety in pregnancy and lactation has not been established.

No studies of the effects on the ability to drive and use machines have been performed.

Bleeding

Bleeding is the most relevant side effect of PRADAXA. Depending on the indication, bleeding of any type or severity occurred in approximately 14 % of patients treated short-term for elective hip or knee replacement surgery, in long-term treatment in nearly 16,6 % of patients with atrial fibrillation treated for the reduction of risk of stroke and systemic embolism and in 14,4 % of patients with acute DVT and/or PE. In the recurrent DVT/PE trials 19,4 % and 10,5 % of patients experienced any bleeding in the active controlled and placebo controlled studies, respectively.

Major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. Known bleeding complications from any organ including anticoagulant-related nephropathy in patients with predisposing risk factors have been reported for dabigatran etexilate. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Side effects in general

Adverse reactions classified by System Organ Class and Medical Dictionary for Regulatory Activities (MedDRA) preferred terms reported from any treatment group per population of all controlled studies are shown in the listings below. A second list with indication-specific side effects is also provided.

Frequency classes: Very common (> 1/10); Common (> 1/100 1/1 000 1/10 000 < 1/1 000); Very rare (< 1/10 000); Not known (cannot be estimated from the available information).

Side effects identified independent from indication, i.e. including:

• Risk reduction of thromboembolic stroke and systemic embolism in patients with atrial fibrillation (SPAF) with PRADAXA dosages of 110 or 150 mg taken twice daily.
• Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (aVTEt) with a PRADAXA dosage of 150 mg taken twice daily.
• Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (sVTEp) with a PRADAXA dosage of 150 mg taken twice daily.
• Primary VTE prevention (pVTEp) studies after hip and knee replacement surgery with PRADAXA dosages of 220 or 150 mg taken once daily.

MedDRA preferred term Frequency in SPAF Frequency in pVTEp Frequency in aVTEt Frequency in sVTEp Patients 12 042 6 684 2 553 2 114 Blood and the lymphatic system disorders Anaemia Common Uncommon Uncommon Rare Thrombocytopenia Uncommon Rare Rare Rare Immune system disorders Hypersensitivity Uncommon Uncommon Uncommon Uncommon Pruritis Uncommon Rare Rare Uncommon Rash Uncommon Rare Uncommon Uncommon Urticaria Rare Rare Rare Rare Bronchospasm Not known Not known Not known Not known Anaphylactic reaction Not known Not known Not known Not known Angioedema Rare Rare Rare Rare Nervous system disorders Intracranial haemorrhage Uncommon Rare Rare Rare Vascular disorders Haematoma Uncommon Uncommon Uncommon Uncommon Haemorrhage Uncommon Rare Uncommon Uncommon Respiratory, thoracic and mediastinal disorders Epistaxis Common Uncommon Common Common Haemoptysis Uncommon Rare Uncommon Uncommon Gastrointestinal disorders Gastrointestinal haemorrhage Common Uncommon Common Common Abdominal pain Common Rare Uncommon Uncommon Diarrhoea Common Uncommon Uncommon Uncommon Dyspepsia Common Rare Common Common Dysphagia Uncommon Rare Rare Rare Gastrointestinal ulcer, including oesophageal ulcer Uncommon Rare Uncommon Rare Gastro-oesophagitis Uncommon Rare Uncommon Uncommon Gastro-oesophageal reflux disease Uncommon Rare Uncommon Uncommon Nausea Common Uncommon Uncommon Uncommon Vomiting Uncommon Uncommon Uncommon Uncommon Hepatobiliary disorders Abnormal hepatic function Uncommon Common Uncommon Uncommon Skin and subcutaneous tissue disorders Skin haemorrhage Common Uncommon Common Common Musculoskeletal, connective tissue and bone disorders Haemarthrosis Rare Uncommon Uncommon Rare Renal and urinary disorders Urogenital haemorrhage Common Uncommon Common Common Haematuria Common Uncommon Common Common General disorders and administration site conditions Injection site haemorrhage Rare Rare Rare Rare Catheter site haemorrhage Rare Rare Rare Rare Injury, poisoning and procedural complications Traumatic haemorrhage Rare Uncommon Uncommon Rare Incision site haemorrhage Rare Rare Rare Rare

Other side effects identified specifically from the studies in the indication primary VTE prevention after hip and knee replacement surgery

Vascular disorders Uncommon: wound haemorrhage General disorders and administration site conditions Rare: bloody discharge Injury, poisoning and procedural complications Uncommon: post procedural haematoma, post procedural haemorrhage, post procedural discharge, wound secretion Rare: post operative anaemia Surgical and medical procedures Rare: wound drainage, post procedural drainage

Post-marketing experience

The following side effects have been identified during post-approval use of PRADAXA therefore the frequency is not known:

Blood and the lymphatic system disorders Neutropenia, agranulocytosis Skin and subcutaneous tissue disorders Alopecia Renal and urinary disorders Anticoagulant-related nephropathy

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Suspected adverse reactions can also be reported directly to the holder of the certificate of registration using the email address [email protected].

Symptoms

Overdose following administration of PRADAXA may lead to haemorrhagic complications due to its pharmacodynamic properties.

Therapy

A specific reversal agent antagonising the pharmacodynamic effect of PRADAXA is available, namely idarucizumab. (See section 4.4 - Haemorrhagic risk; Surgery and interventions, Pre-operative phase.) In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since PRADAXA is excreted predominantly by the renal route adequate diuresis must be maintained. Depending on the clinical situation appropriate standard treatment, e.g. surgical haemostasis as indicated and blood volume replacement, should be undertaken. In addition, consideration may be given to the use of fresh whole blood or fresh frozen plasma. Coagulation factor concentration (activated or non-activated) or recombinant Factor VIIa may be considered. There is some experimental evidence to support the role of these agents in reversing the anticoagulant effect of PRADAXA, but their usefulness in clinical settings has not yet been systematically demonstrated. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet medicines have been used. All symptomatic treatment has to be given according to the doctoru2019s judgement. As protein binding is low, PRADAXA is dialysable, however there is limited clinical experience in using dialysis in this setting (see section 5.2, Special populations, Renal insufficiency).