Dabiklot 75 mg, 110 mg, 150 mg Hard capsules

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

Reduction of the risk of a stroke and systemic embolism in patients with atrial fibrillation.

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

Posology

Adults: Prevention of venous thromboembolism (VTE) in patients following hip and knee replacement surgery: The recommended dose of DABIKLOT is 220 mg once daily taken as 2 capsules of 110 mg. There is an increased risk of bleeding in patients with moderate renal impairment. In these patients, the recommended dose of DABIKLOT is 150 mg once daily.

VTE prevention following knee replacement surgery: Treatment with DABIKLOT should be initiated orally within 1 - 4 hours of completed surgery with a single capsule (110 mg), 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, it should be initiated with 2 capsules once daily.

VTE prevention following hip replacement surgery: Treatment with DABIKLOT should be initiated orally within 1 - 4 hours of completed surgery, with a single capsule (110 mg), 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, treatment should be initiated with 2 capsules once daily.

To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation: The recommended daily dose of DABIKLOT is 300 mg taken orally, as two 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 DABIKLOT 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 DABIKLOT is 300 mg taken orally, as 150 mg capsules twice daily. Depending on the individual patientu2019s risk factors, therapy could be continued life-long.

Special populations

Renal impairment: Patients with severe renal impairment (i.e. CrCl < 30 mL/min) should be excluded from treatment. Renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of treatment. There is no data to support the use in patients with severe renal impairment (CrCl < 30 mL/min); treatment in this population with DABIKLOT is therefore not recommended (see section 4.3).

• hypersensitivity to dabigatran etexilate or to any of the ingredients of DABIKLOT
• patients with severe renal impairment (CrCl < 30 mL/min) (see section 4.2)
• 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) or liver disease expected to have any impact on survival
• 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, ciclosporin, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5)
• concomitant treatment with any of the following: unfractionated heparins and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic medicines, 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 DABIKLOT and vitamin K antagonists (e.g. warfarin) can be administered together, but only for a few days during switching from DABIKLOT to vitamin K antagonist treatment
• in patients with suspected infective endocarditis
• in patients with prosthetic heart valve replacement requiring anticoagulant treatment.

Haemorrhagic risk: DABIKLOT should be used with caution in a condition with an increased risk of bleeding or with concomitant use of medicines affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy with DABIKLOT.

An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran, as in DABIKLOT, is required, the specific reversal medicine (Praxbind, idarucizumab) is available (see section 4.9).

In clinical trials, dabigatran, as in DABIKLOT, was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (u2265 75 years) for the 150 mg twice daily dose regimen. Further risk factors comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non-steroidal anti-inflammatory medicines (NSAIDs), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.

Caution is advised as tests to monitor coagulation are not available. There is no correlation between plasma dabigatran concentration and degree of anticoagulant effect. However, this can only be partially measured by a combination of activated partial thromboplastin time aPTT, prothrombin time (PT, expressed as INR) thromboplastin time and ecarin clotting time tests, no single one of which provides a complete assessment of the anticoagulant effect of DABIKLOT. DABIKLOT treatment cannot be therapeutically monitored by coagulation tests. The INR test is unreliable in patients on DABIKLOT and false positive INR elevations have been reported. Therefore, INR tests should not be performed. Tests of anticoagulant activity such as thrombin time (TT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) are available to detect excessive DABIKLOT activity. DABIKLOT related anticoagulation can be assessed by ECT or TT. If ECT or TT is not available, the aPTT test provides an approximation of DABIKLOT anticoagulant activity. However, in patients who are bleeding, aPTT tests may help determine an excess of anticoagulant activity.

Precautions and management of the haemorrhagic risk: For the management of bleeding complications, see section 4.9. 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- to 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) prior to initiation of treatment with DABIKLOT to exclude patients for treatment with severe renal impairment (i.e. CrCl < 30 mL/min). Patients who develop acute renal failure should discontinue DABIKLOT.

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 1 hour should elapse before the administration of the first dose of DABIKLOT (see section 4.3). These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.

Surgery and interventions: Patients on DABIKLOT therapy who undergo surgery or invasive procedures are at increased risk for bleeding. As a result, surgical interventions may require the temporary discontinuation of DABIKLOT (see section 5.2).

Pre-operative phase: DABIKLOT may be stopped temporarily in advance of invasive or surgical procedures due to an increased risk of bleeding. If possible, DABIKLOT 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, stopping DABIKLOT 2 - 4 days before surgery should be considered. Clearance of DABIKLOT in patients with renal insufficiency may take longer. This should be considered in advance of any procedures (see sections 4.2 - table summarising discontinuation rules u2013 and 5.2).

DABIKLOT is contraindicated in patients with severe renal dysfunction (CrCl < 30 mL/min) (see section 4.3) but, should this occur, DABIKLOT treatment should be stopped at least 5 days before any major surgery. If an acute intervention is required, DABIKLOT 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.

For cardioversion see section 4.2.

Post-procedural period: Resume/start treatment as soon as possible provided the clinical situation allows and after complete haemostasis is achieved. 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).

Close clinical surveillance: Close observation for signs of bleeding or anaemia is recommended throughout the treatment period, especially if risk factors are combined.

The concomitant use of DABIKLOT 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). DABIKLOT is not metabolised by the cytochrome P450 system, 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 DABIKLOT. This has been confirmed by in vivo studies in healthy volunteers, who did not show any interaction between dabigatran etexilate and either of the following: atorvastatin (CYP3A4), digoxin (P-gp transporter interaction) and diclofenac (CYP2C9).

Atorvastatin: When co-administered with atorvastatin (a CYP3A4 substrate), exposure of atorvastatin, atorvastatin metabolites and those of DABIKLOT were unchanged, indicating a lack of interaction.

Diclofenac: When co-administered with diclofenac (a CYP2C9 substrate), pharmacokinetic properties of both medicines remained unchanged, indicating a lack of interaction between DABIKLOT 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 and clarithromycin) is expected to result in increased DABIKLOT plasma concentrations (see section 4.2).

Concomitant use contraindicated (see section 4.3): Ketoconazole: Systemic ketoconazole increased total dabigatran (as in DABIKLOT) 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.

Dronedarone: When dabigatran (as in DABIKLOT) and dronedarone were given at the same time, total dabigatran 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 dabigatran were not affected by dronedarone. When single and multiple doses of dronedarone were given 2 hours after dabigatran, the decreases in dabigatran AUC 0- u221e were 1,3-fold and 1,6-fold, respectively (see section 4.4).

Itraconazole, ciclosporin: Based on in vitro results a similar effect as with ketoconazole may be expected.

Glecaprevir /pibrentasvir: The concomitant use of dabigatran etexilate (as in DABIKLOT) with the fixed-dose combination of the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding.

Concomitant use not recommended: Tacrolimus Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and ciclosporin. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors.

Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4): Verapamil: When dabigatran etexilate 150 mg (as in DABIKLOT) 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 dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to DABIKLOT intake (increase in 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 DABIKLOT (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.

Amiodarone: DABIKLOT 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: DABIKLOT concentrations were increased by no more than 14 % and no increased risk of bleeding was observed.

Quinidine: Quinidine was given as a 200 mg dose every 2nd hour up to a total dose of 1 000 mg Dabigatran (as in DABIKLOT) was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUC t,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 is administered together with DABIKLOT no clinically relevant pharmacokinetic (PK)-interaction is observed (increase of C max by about 15 % and AUC by about 19 %).

Ticagrelor: When a single dose of 75 mg dabigatran (as in DABIKLOT) 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 dabigatran (in steady state) increased the dabigatran AUC- t ss and by C max ss by 1,49-fold and 1,65-fold (u00b149 % and 65 %) respectively compared with dabigatran given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg dabigatran (in steady state) the increase of dabigatran AUC- t ss and C max ss was reduced to 1,27-fold and 1,23-fold (u00b127 % and 23 %) respectively compared with dabigatran given alone. Concomitant administration of 90 mg ticagrelor twice daily (maintenance dose) with 110 mg dabigatran increased the adjusted dabigatran AUC -t ss and C max ss 1,26-fold and 1,29-fold respectively compared with dabigatran given alone.

Posaconazole: Posaconazole also inhibits P-gp to some extent but has not been clinically studied. Caution should be exercised when DABIKLOT is co-administered with posaconazole.

P-GP INDUCERS: Concomitant use should be avoided: Rifampicin, St. Johnu2019s wort (Hypericum perforatum), carbamazepine, or phenytoin: Concomitant administration is expected to result in decreased dabigatran concentrations. 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. The concomitant use with P-gp inducers (e.g. rifampicin) reduces exposure to DABIKLOT and should be avoided (see section 4.4).

Protease inhibitors such as ritonavir: Concomitant use not recommended: Ritonavir and its combinations with other protease inhibitors. These affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with DABIKLOT.

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

PLATELET-INHIBITORS: Acetylsalicylic acid (ASA): The effect of concomitant administration of dabigatran (as in DABIKLOT) and acetylsalicylic acid (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 twice daily may increase the risk for any bleeding from 12 % - 18 % and 24 % with 81 mg and 325 mg ASA, respectively. In clinical studies, it was observed that ASA or clopidogrel co-medication with DABIKLOT at dosages of 110 or 150 mg twice daily may increase the risk of major bleeding. The higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed in warfarin.

NSAIDs: NSAIDs given for short-term analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in the RE-LY study, NSAIDs increased the risk of bleeding by approximately 50 % on both dabigatran etexilate and warfarin.

Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran and clopidogrel resulted in no further prolongation of capillary bleeding times (CBT) compared to clopidogrel monotherapy. However, with a loading dose of 300 or 600 mg clopidogrel, dabigatran AUC t,ss and C max,ss were increased by about 1,3- to 1,4-fold (+ 30 - 40 %). (See above subsection on ASA and section 4.3).

Low molecular weight heparins (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.

Women of childbearing potential should avoid pregnancy during treatment with DABIKLOT.

Pregnancy: There is limited amount of data from the use of DABIKLOT in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. DABIKLOT should not be used during pregnancy.

Breastfeeding: There are no clinical data of the effect of dabigatran on infants during breastfeeding. Breastfeeding should be discontinued during treatment with DABIKLOT.

Fertility: No human data available.

DABIKLOT has no or negligible influence on the ability to drive and use machines. No studies of the effects on the ability to drive and use machines have been performed.

a). Summary of the safety profile

Undesirable effects, 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 table below. A second table, with indication-specific undesirable effects, is also provided.

Bleeding: Bleeding is the most relevant side effect of DABIKLOT. 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 16,5 % of patients with atrial fibrillation treated for the reduction of risk of stroke and systemic embolism and in 14,4 % of patients with active 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.

Undesirable effects identified independent from indication, including:

• risk reduction of thromboembolic stroke and systemic embolism in patients with atrial fibrillation (SPAF) at dosages of 110 or 150 mg taken twice daily
• treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (aVTEt) at dosage of 150 mg taken twice daily
• prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (sVTEp) at dosage of 150 mg taken twice daily, and
• primary VTE prevention (pVTEp) studies after hip and knee replacement surgery at dosages of 220 or 150 mg taken once daily:

b). Tabulated summary of adverse reactions

System Organ Class & Side effect Frequency SPAF pVTEp aVTEt sVTEp

Blood and lymphatic system disorders

• Anaemia Frequent Less frequent Less frequent Less frequent
• Thrombocytopenia Less frequent Less frequent Less frequent Less frequent
• Haemoglobin decreased Less frequent Frequent Frequency unknown Frequency unknown
• Haematocrit decreased Less frequent Less frequent Frequency unknown Frequency unknown
• Neutropenia Frequency unknown Frequency unknown Frequency unknown Frequency unknown
• Agranulocytosis Frequency unknown Frequency unknown Frequency unknown Frequency unknown

Immune system disorders

• Hypersensitivity Less frequent Less frequent Less frequent Less frequent
• Bronchospasm Frequency unknown Frequency unknown Frequency unknown Frequency unknown
• Anaphylactic reaction Frequency unknown Frequency unknown Frequency unknown Frequency unknown
• Angioedema Frequency unknown Frequency unknown Frequency unknown Frequency unknown

Nervous system disorders

• Intercranial haemorrhage Less frequent Less frequent Less frequent Less frequent

Vascular disorders

• Haematoma Less frequent Less frequent Less frequent Less frequent
• Haemorrhage Less frequent Less frequent Less frequent Less frequent
• Wound haemorrhage - Less frequent - -

Respiratory, thoracic and mediastinal disorders

• Epistaxis Frequent Less frequent Frequent Frequent
• Haemoptysis Less frequent Less frequent Less frequent Less frequent

Gastrointestinal disorders

• Gastrointestinal haemorrhage Frequent Less frequent Frequent Frequent
• Abdominal pain Frequent Less frequent Less frequent Less frequent
• Diarrhoea Frequent Less frequent Less frequent Less frequent
• Dyspepsia Frequent Less frequent frequent frequent
• Dysphagia Less frequent Less frequent Less frequent Less frequent
• Gastrointestinal ulcer, including oesophageal ulcer Less frequent Less frequent Less frequent Less frequent
• Gastro-oesophagitis Less frequent Less frequent Less frequent Less frequent
• Gastro-oesophageal reflux disease Less frequent Less frequent Less frequent Less frequent
• Nausea Frequent Less frequent Less frequent Less frequent
• Vomiting Less frequent Less frequent Less frequent Less frequent
• Rectal haemorrhage Frequent Less frequent Less frequent Less frequent
• Haemorrhoidal haemorrhage Less frequent Less frequent Less frequent Less frequent

Hepato-biliary disorders

• Abnormal hepatic function Less frequent Frequent Less frequent Less frequent
• Liver function test abnormal Less frequent Frequent Less frequent Less frequent
• Alanine aminotransferase increased Less frequent Less frequent Less frequent Less frequent
• Aspartate aminotransferase increased Less frequent Less frequent Less frequent Less frequent
• Hepatic enzyme increased Less frequent Less frequent Less frequent Less frequent
• Hyperbilirubinaemia Less frequent Less frequent Frequency unknown Frequency unknown

Skin and subcutaneous tissue disorders

• Skin haemorrhage Frequent Less frequent Frequent Frequent
• Pruritis Less frequent Less frequent Less frequent Less frequent
• Rash Less frequent Less frequent Less frequent Less frequent
• Urticaria Less frequent Less frequent Less frequent Less frequent
• Alopecia Frequency unknown Frequency unknown Frequency unknown Frequency unknown

Musculoskeletal, connective tissue and bone disorders

• Haemarthrosis Less frequent Less frequent Less frequent Less frequent

Renal and urinary disorders

• Urogenital haemorrhage Frequent Less frequent Frequent Frequent
• Haematuria Frequent Less frequent Frequent Frequent

General disorders and administrative site conditions

• Injection site haemorrhage Less frequent Less frequent Less frequent Less frequent
• Catheter site haemorrhage Less frequent Less frequent Less frequent Less frequent

Injury and poisoning

• Traumatic haemorrhage Less frequent Less frequent Less frequent Less frequent
• Anaemia postoperative - Less frequent - -

Surgical and medical procedures

• Incision site haemorrhage Less frequent Less frequent Less frequent Less frequent

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

System Organ Class Frequency Side effects

Vascular disorders

• Less frequent Wound haemorrhage

General disorders and administrative site conditions

• Less frequent Bloody discharge

Injury and poisoning

• Less frequent Post procedural haematoma, post procedural haemorrhage, post procedural discharge, wound secretion

Surgical and medical procedures

• Less frequent Wound drainage, post procedural drainage

c). Description of selected adverse reactions

Bleeding reactions: Due to the pharmacological mode of action, the use of DABIKLOT may be associated with an increased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. In the clinical studies, mucosal bleedings (e.g. gastrointestinal, genitourinary) were seen more frequently during long term dabigatran treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/ haematocrit is of value to detect occult bleeding. The risk of bleedings may be increased in certain patient groups e.g. those patients with moderate renal impairment and/or on concomitant treatment affecting haemostasis or strong P-gp inhibitors (see section 4.4 Haemorrhagic risk). Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock. Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion have been reported for DABIKLOT. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient. A specific reversal agent for dabigatran, idarucizumab, is available in case of uncontrollable bleeding (see section 4.9).

Overdose following administration of DABIKLOT may lead to haemorrhagic complications due to its pharmacodynamic properties. A specific reversal medicine antagonising the pharmacodynamics effect of DABIKLOT 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 the bleeding investigated. Since DABIKLOT 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 are some experimental evidence to support the role of these medicines in reversing the anticoagulant effect of DABIKLOT 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, DABIKLOT is dialysable, however there is limited clinical experience in using dialysis in this setting (see section 5.2, Special populations, Renal insufficiency).