ESC Congress 2017 In Review – Focus on Arrhythmias - Cover2

Your FORESIGHT. Their safety.
lower

lower

independent analyses

risk

of major
bleeding

a similar risk

vs rivaroxaban

of major bleeding vs apixaban

lower risk of

major bleeding
vs warfarin

independent analyses

FETY
Aa

risk
S

of major
bleeding
vs rivaroxaban
The assurance of an extensively
REVERSIBILITY
a
similar
risk
1-10
validated safety
of majorprofile
bleeding vs apixaban
a

lower
risk of
L

major
N T R O bleeding
vs warfarin

FETY

REVERSIBILITY
CO

NT R O

The reassurance of
immediate reversibility11

Not head-to-head studies.
In the EU, the licensed doses for Pradaxa® are 150 mg BID and 110 mg BID for the prevention of stroke and systemic embolism in adult patients with non-valvular AF.
In the United States, the licensed doses for Pradaxa® are 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with NVAF.
Prescribing Information (SPAF and DVT/PE UK) PRADAXA® (dabigatran etexilate)
Capsules containing 110 mg or 150 mg dabigatran etexilate (as mesilate). Action: Direct thrombin inhibitor.
Indications: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one
or more risk factors (SPAF), such as prior stroke, or transient ischaemic attack; age ≥ 75 years; heart failure (NYHA
Class ≥ II); diabetes mellitus; hypertension. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT and PE in adults (DVT/PE). Dose and Administration: Renal function should be assessed
by calculating CrCL prior to initiation to exclude patients with severe renal impairment (CrCL < 30 mL/min). SPAF:
Recommended daily dose 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term.
DVT/PE: Recommended daily dose 300 mg taken as one 150 mg capsule twice daily following treatment with
parenteral anticoagulant for at least 5 days. Duration of treatment should be individualised after careful assessment of
the treatment benefit against risk for bleeding. Short duration of therapy (at least three months) should be based on
transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent
risk factors or idiopathic DVT or PE. In case of intolerability to dabigatran, patients should be instructed to immediately
consult their doctor. For patients aged 80 years or above, or those receiving concomitant verapamil, the recommended
daily dose is Pradaxa 220 mg taken as 110 mg twice daily. Pradaxa and verapamil should be taken at the same time.
For the following patient groups, the daily dose of 300 mg or 220 mg should be selected based on an individual
assessment of the thromboembolic risk and risk of bleeding: aged 75 - 80 years; with moderate renal impairment
(CrCL 30-50 mL/min); with gastritis, oesophagitis or gastroesophageal reflux; other risk of increased bleeding. Close
clinical surveillance is recommended in patients with renal impairment. Use is contraindicated in patients with severe
renal impairment (CrCL < 30 mL/min). In all patients assess renal function by calculating CrCL prior to initiation to
exclude patients with severe renal impairment. Renal function should also be assessed when a decline in renal function
is suspected. Additionally in patients > 75 years or with mild to moderate renal impairment, renal function should also
be assessed at least once a year or more frequently as needed in certain clinical situations when it is suspected that
the renal function could decline or deteriorate. Patients with an increased risk of bleeding: closely monitor clinically
looking for signs of bleeding or anaemia. A coagulation test may help identify increased risk patients. No dose
adjustment required but close clinical surveillance in patients < 50 kg. Not recommended if liver enzymes > 2 Upper
Limit of Normal (ULN). If switching from Pradaxa to parenteral anticoagulant wait 12 hours after the last dose of
Pradaxa; if switching from parenteral anticoagulant to Pradaxa discontinue the parenteral anticoagulant and start
Pradaxa 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; if switching from Pradaxa to VKA adjust the starting time of the VKA
based on CrCL; if switching from VKA to Pradaxa stop VKA and give Pradaxa once INR <2.0. Cardioversion patients can
stay on Pradaxa whilst being cardioverted. No relevant use of Pradaxa in the paediatric population in the SPAF
indication. In DVT/PE indication safety and efficacy of Pradaxa in ages less than 18 years have not been established.
Pradaxa can be taken with or without food. Pradaxa should be swallowed as a whole with a glass of water to facilitate
delivery to the stomach. Patients should be instructed not to open the capsule as this may increase the risk of bleeding.
Contraindications: Hypersensitivity to any component; severe renal impairment (CrCL < 30 mL/min); active clinically
significant bleeding; lesion or condition, if considered a significant risk factor for major bleeding. This may include
current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or
spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected
oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular
abnormalities; concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular
weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin,
rivaroxaban, apixaban etc) except under specific circumstances of switching anticoagulant therapy or when UFH is
given at doses necessary to maintain an open central venous or arterial catheter; hepatic impairment or liver disease
expected to have any impact on survival; concomitant systemic ketoconazole, cyclosporine, itraconazole, dronedarone;
prosthetic heart valves requiring anticoagulant treatment. Warnings and Precautions: Not recommended if liver
enzymes > 2 ULN. Haemorrhagic risk: Close clinical surveillance (signs of bleeding or anaemia) is recommended
throughout the treatment period, especially when haemorrhagic risk is increased or risk factors combined. For
situations of life-threatening or uncontrolled bleeding, when rapid reversal of anticoagulation effect of dabigatran is
required, the specific reversal agent (Praxbind, idarucizumab) is available. Factors which may increase haemorrhagic
risk: age ≥ 75 years; moderate renal impairment (CrCL 30 - 50 mL/min); P-glycoprotein inhibitor co-medication; body
weight < 50 kg; acetylsalicylic acid (aspirin); NSAID; clopidogrel; selective serotonin re-uptake inhibitors (SSRIs) or
selective serotonin norepinephrine re-uptake inhibitors (SNRIs); other drugs which may impair haemostasis; diseases/
procedures associated with a risk of bleeding such as coagulation disorders, thrombocytopenia or functional platelet
defects, recent biopsy, major trauma, bacterial endocarditis, oesophagitis, gastritis or gastroesophageal reflux.
Concomitant use of ticagrelor. The measurement of dabigatran related anticoagulation may be helpful to avoid
excessive high exposure to dabigatran in the presence of additional risk factors. Patients who develop acute renal
failure must discontinue Pradaxa. If severe bleeding occurs, discontinue treatment and investigate the source of the
bleeding. Avoid or use with caution medicinal products which may increase the risk of haemorrhage. The use of
fibrinolytic medicinal products for the treatment of acute ischaemic stroke may be considered if the patient presents
with a dTT, ECT or aPTT not exceeding the ULN according to the local reference range. Avoid concomitant
administration with P-gp inducers. 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. In emergency surgery or urgent procedures, when rapid reversal of the anticoagulation effect is required the
specific reversal agent (Praxbind, idarucizumab) to dabigatran is available. Prescribers should consult the Summary of
Product Characteristics for further information relating to surgery and interventions. 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.

Treat with caution patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events.
Myocardial infarction. Efficacy and safety have not been established for DVT/PE patients with active cancer.
Interactions: Anticoagulants and antiplatelet aggregation medicinal products; P-gp inhibitors e.g. amiodarone,
quinidine, verapamil, clarithromycin, ticagrelor co-administration (close clinical surveillance); verapamil
co-administration reduce Pradaxa dose to 220 mg (see above) close clinical surveillance is recommended; caution
when co-administered with posaconazole; not recommended for concomitant treatment tacrolimus, protease inhibitors
including ritonavir and its combinations with other protease inhibitors; avoid with P-gp inducers e.g. rifampicin, St
John's wort, carbamazepine, phenytoin; SSRIs or SNRIs. Dabigatran etexilate and dabigatran are not metabolised by
cytochrome CYP450 system, therefore related medicinal product interactions not expected. 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 administration together with Pradaxa had no clinically relevant
effect on the extent of absorption of dabigatran. Fertility, pregnancy and lactation: Avoid pregnancy during treatment.
Do not use in pregnancy unless clearly necessary. Discontinue breast-feeding during treatment. Undesirable effects:
Most commonly reported adverse reactions are bleedings occurring in total in approximately 16.6 % in patients with
atrial fibrillation treated for the prevention of stroke and SEE and 14.4 % in patients treated for DVT/PE. Bleeding
occurred in 19.4% of patients in DVT/PE prevention trial RE-MEDY and in 10.5% of patients in DVT/PE prevention trial
RE-SONATE. Common (≥ 1/100 to <1/10): epistaxis; gastrointestinal haemorrhage; dyspepsia; skin haemorrhage;
genitourological haemorrhage, including haematuria. Additional common adverse events seen with Stroke and SEE
prevention in patients with atrial fibrillation: anaemia; abdominal pain; diarrhoea; nausea. Additional common adverse
event seen in patients with DVT/PE treatment and DVT/PE prevention: rectal haemorrhage. Prescribers should consult
the Summary of Product Characteristics for further information on side effects. Legal category: POM. MA numbers:
110 mg EU/1/08/442/007 (60 capsules) 150 mg EU/1/08/442/011 (60 capsules). Marketing Authorisation Holder:
Boehringer Ingelheim International GmbH, Binger Str. 173, D-55216 Ingelheim am Rhein, Germany. Prescribers should
consult the Summary of Product Characteristics for full prescribing information. Prepared in May 2017.
Prescribing Information (UK) PRAXBIND®▼ (idarucizumab) 2.5 g/50 mL, solution for injection/infusion. Vials
containing 2.5 g idarucizumab in 50 mL solution for injection/infusion. Indication: Praxbind is a specific reversal agent
for dabigatran and is indicated in adult patients treated with Pradaxa (dabigatran etexilate) when rapid reversal of its
anticoagulant effects is required: for emergency surgery/urgent procedures; in life-threatening or uncontrolled bleeding.
Dose and Administration: Restricted to hospital use only. Recommended dose is 5 g (2 x 2.5 g/ 50 mL), administered
intravenously as two consecutive infusions over 5 to 10 minutes each or as a bolus injection. Administration of a
second 5 g dose may be considered in the following situations: recurrence of clinically relevant bleeding together with
prolonged clotting times; if potential re-bleeding would be life- threatening and prolonged clotting times are observed;
patients require a second emergency surgery/urgent procedure and have prolonged clotting times. Restarting
antithrombotic therapy: If the patient is clinically stable and adequate haemostasis has been achieved following
administration of Praxbind, Pradaxa (dabigatran etexilate) treatment can be re-initiated after 24 hours; other
antithrombotic therapy (e.g. low-molecular weight heparin) can be started at any time. No dose adjustment is
required in patients with renal or hepatic impairment or in elderly patients aged 65 years and above. Safety and
efficacy in children below the age of 18 years have not yet been established. Contraindications: None. Warnings
and Precautions: Idarucizumab binds specifically to dabigatran and reverses its anticoagulant effect. It will
not reverse the effects of other anticoagulants. Treatment can be used in conjunction with medically appropriate
standard supportive measures. In patients with known hypersensitivity (e.g. anaphylactoid reaction) to idarucizumab or
to any of the excipients the risk of using Praxbind needs to be weighed cautiously against the potential benefit of the
emergency treatment, discontinue use if an anaphylactic reaction or other serious reaction occurs. The recommended
dose of Praxbind contains 4 g sorbitol as an excipient. In patients with hereditary fructose intolerance, parenteral
administration of sorbitol has been associated with reports of hypoglycaemia, hypophosphatemia, metabolic acidosis,
increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death. Consequently,
in these patients the risk of treatment with Praxbind must be weighed against the potential benefit, and if Praxbind is
administered intensified medical care during and within 24 hours of exposure is required. Reversing dabigatran therapy
exposes patients to the thrombotic risk of their underlying disease. To reduce this risk resumption of anticoagulant
therapy should be considered as soon as medically appropriate. Contains 2.2 mmol (50 mg) sodium per dose. Praxbind
causes transient proteinuria which is not indicative of renal damage but which should be taken into account for urine
testing. Interactions: No formal interaction studies have been performed. Based on pharmacokinetic properties and
high specificity in binding to dabigatran clinically relevant interactions with other medicinal products are considered
unlikely. Fertility, Pregnancy and Lactation: There are no data for use in pregnant women. Praxbind may be used
during pregnancy, if the expected clinical benefit outweighs the potential risks. There are no data on the effect on fertility.
It is unknown whether idarucizumab is excreted in human milk. Undesirable effects: No adverse reactions have been
identified. Legal category: POM MA numbers: EU/1/15/1056/001 Marketing Authorisation Holder: Boehringer
Ingelheim International GmbH, Binger Str. 173, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the
Summary of Product Characteristics for full prescribing information. Prepared in November 2015.
Adverse events should be reported. Reporting forms and information
can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to
Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone).

References: 1. Seeger JD et al. Thromb Haemost. 2015;114(6):1277-1289. 2. Villines TC et al. Thromb Haemost. 2015;114(6):1290-1298. 3. Larsen TB et al. BMJ. 2016;353:i3189. 4. Gorst-Rasmussen A et al. Pharmacoepidemiol Drug Saf.
2016;25(11):1236-1244. 5. Hernandez I et al. Am J Cardiovasc Drugs. 2017;17(1):37-47. 6. Graham DJ et al. JAMA Intern Med. 2016;176(11):1662-1671. 7. Lip GYH et al. Thromb Haemost. 2016;116(5):975-986. 8. Noseworthy PA et al.
Chest. 2016;150(6):1302-1312. 9. Tepper P et al. [ESC 2015 abstract 1975]. London, UK. 10. Amin AN et al. Blood. 2015;126(23):745.
11. Praxbind® (idarucizumab) Summary of Product Characteristics. 2015.
Pradaxa®, Praxbind®, and PRADAXA and PRAXBIND with associated design® are registered
trademarks of Boehringer Ingelheim Pharma GmBH and Co. KG and used under license.

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http://www.mhra.gov.uk/yellowcard

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