Bleeding with Pradaxa® and warfarin
can be managed in a similar way
Pradaxa®1–3
Warfarin4,5
Stop medication
Stop medication
Half-life: 12–14 hours
Half-life: 40 hours
(normal renal function)
Evaluation of anticoagulant activity
In emergency situations it is advisable to assess the anticoagulation status of
a patient receiving Pradaxa®. There is a close correlation between plasma
dabigatran concentration and the degree of anticoagulant effect.
The following tests can be used to obtain information, however results should
be interpreted with caution.
aPTT
1–3
Measure
anticoagulant effect
Measure
anticoagulant effect
•aPTT (qualitative)
•INR
•Diluted Thrombin Time
(dTT – quantitative)
Activated partial thromboplastin time (aPTT) may be used,
but only provides qualitative data.
dTT
1–3,6
For a quantitative measurement of dabigatran plasma
concentrations, a dabigatran calibrated diluted thrombin time (dTT)
can provide accurate information.
The INR test is unreliable in patients on Pradaxa® and should not be performed.
(INR should not be used to
assess the anticoagulant
effect of Pradaxa®)
Act
Act
Consider:
Administer:
•PCC or aPCC
(e.g. FEIBA)
•Vitamin K (oral or IV)
•PCC
•Recombinant
Factor VIIa
•Haemodialysis*
(Recommendation only – there
is limited clinical experience to
demonstrate this approach)
* Dabigatran has low protein binding therefore can be dialysed.1–3
The table below shows coagulation test thresholds at trough that may be
associated with an increased risk of bleeding:1–3
Indication
Test
pVTE orthopaedic surgery
SPAF and DVT/PE
dTT
[ng/mL]
>67
>200
ECT
[x-fold upper
limit of normal]
No data
>3 (~103 seconds)
aPTT
[x-fold upper
limit of normal]
>1.3 (~51 seconds)
>2 (~80 seconds)
(trough value)
INR
PCC = Prothrombin complex concentrate; aPCC = Activated prothrombin complex concentrate.
Should not be performed
Prescribing information can be found on page 2
1
References:
1. Boehringer Ingelheim. Pradaxa® 150mg hard capsules Summary of Product Characteristics.
2. Boehringer Ingelheim. Pradaxa® 110mg hard capsules Summary of Product Characteristics.
3. Boehringer Ingelheim. Pradaxa® 75mg hard capsules Summary of Product Characteristics.
4. Amdipharm Mercury Company Limited. Warfarin 5mg tablets Summary of Product Characteristics.
5.Keeling D, Baglin T, et al. Guidelines on oral anticoagulation with warfarin – fourth edition. BJH Guideline. Available at http://www.bcshguidelines.com/documents/warfarin_4th_ed.pdf [Accessed August 2015].
6. van Ryn J, Stangier J, et al. Thromb Haemost 2010; 103:1116–1127.
Prescribing Information (SPAF and DVT/PE UK) PRADAXA® (dabigatran etexilate)
Prescribing Information (pVTEp 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.
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;
Capsules containing 75 mg or 110 mg dabigatran etexilate (as mesilate) Action: Direct
thrombin inhibitor Indication: Primary prevention of venous thromboembolic events in
adult patients who have undergone elective total hip or knee replacement surgery. 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).
Recommended dose is 220 mg once daily orally taken as 2 capsules of 110 mg. Initiate
treatment within 1-4 hours of completed surgery with a single capsule continuing with 2
capsules once daily for a total of 10 days (knee replacement surgery) or 28 – 35 days (hip
replacement surgery). Delay initiation of treatment if haemostasis is not secured. If
treatment is not started on the day of surgery, initiate with 2 capsules once daily. For the
following groups the recommended daily dose of Pradaxa is 150 mg taken once daily as 2
capsules of 75 mg: patients with moderate renal impairment (CrCL 30-50 mL/min);
patients who receive concomitant verapamil, amiodarone, quinidine; patients aged 75 or
above. In patients with moderate renal impairment and concomitant verapamil, consider
75mg daily. Pradaxa is contraindicated in severe renal impairment (CrCL < 30 mL/min).
Assess renal function by calculating CrCL prior to initiation to exclude patients with severe
renal impairment. As renal impairment may be frequent in the elderly (> 75 years), assess
renal function prior to initiation to exclude patients with severe renal impairment. Renal
function should also be assessed while on treatment in certain clinical situations when it is
suspected that renal function could decline or deteriorate. Not recommended if liver
enzymes > 2 Upper Limit of Normal (ULN). No dose adjustment required but close clinical
surveillance in patients <50 kg or >110 kg. If switching from Pradaxa to parenteral
anticoagulant wait 24 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. No relevant use of Pradaxa in the
paediatric population in the indication. 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. 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
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; prescribers should consult
the Summary of Product Characteristics for further information. 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. Contains Sunset Yellow
(E110) which may cause allergic reactions. Interactions: Anticoagulants and antiplatelet
aggregation medicinal products; P-gp inhibitors e.g. amiodarone, quinidine, verapamil,
clarithromycin, ticagrelor co-administration (close clinical surveillance); verapamil coadministration 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. Pack sizes and NHS price:
110 mg 60 capsules £65.90 150 mg 60 capsules £65.90 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 February 2015.
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. 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; prescribers should consult the Summary of Product Characteristics
for further information. 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. No data on the use of Pradaxa in patients undergoing hip fracture surgery,
therefore treatment not recommended. Contains Sunset Yellow (E110) which may cause
allergic reactions. Interactions: Anticoagulants and antiplatelet aggregation medicinal
products; P-gp inhibitors co-administration (close clinical surveillance): amiodarone,
quinidine, verapamil reduce Pradaxa dose to 150mg (see above); consider dose reduction
to 75 mg daily in patients with both moderate renal impairment and on verapamil; close
monitoring with clarithromycin and ticagrelor; 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 14% of patients treated short-term for elective
hip or knee replacement surgery; major bleeds, including wound site bleedings < 2%.
Common (≥ 1/100 to <1/10): haemoglobin decreased; hepatic function abnormal/liver
function test abnormal. Prescribers should consult the Summary of Product Characteristics
for further information on side effects. Pack sizes and NHS price: 75 mg 10 capsules
£10.98; 60 capsules £65.90 110 mg 10 capsules £10.98; 60 capsules £65.90
Legal category POM MA numbers: 75 mg EU/1/08/442/001 (10 capsules);
EU/1/08/442/003 (60 capsules) 110 mg EU/1/08/442/005 (10 capsules);
EU/1/08/442/007 (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 June 2014.
Adverse events should be reported. Reporting forms and information
can be found at www.yellowcard.mhra.gov.uk.
Adverse events should also be reported to Boehringer Ingelheim
Drug Safety on 0800 328 1627 (freephone).
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).
Date of preparation: August 2015 Job code: UK/DBG-151143
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