PRADAXA 110 MG, HARD CAPSULES [SIN13698P]

Product Info

PRADAXA 110 MG, HARD CAPSULES

[SIN13698P]

4.1 Therapeutic Indications

75mg capsule:
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

110mg capsule:
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

150mg capsule:
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

4.2 Posology and method of administration

Primary prevention of Venous Thromboembolism (VTE) events in adult patients who have undergone elective knee replacement surgery:
The recommended dose of PRADAXA is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1 – 4 hours of completed surgery with a single capsule (110 mg) and continuing with 2 capsules once daily thereafter for a total of 10 days.

Primary prevention of Venous Thromboembolism (VTE) events in adult patients who have undergone elective hip replacement surgery:
The recommended dose of PRADAXA is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1 – 4 hours of completed surgery with a single capsule (110 mg) and continuing with 2 capsules once daily thereafter for a total of 28–35 days.

For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules of 110 mg once daily.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation:
The recommended daily dose of PRADAXA is 300 mg taken orally as 150 mg hard capsules twice daily.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults

The recommended daily dose of PRADAXA is 300mg taken as one 150 mg capsule twice daily following treatment with a parenteral anticoagulant for at least 5 days. The duration of therapy should be individualized after careful assessment of the treatment benefit against the risk of bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (eg. recent surgery, trauma, immobilization) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.

SPAF, DVT/PE

For the following groups the recommended daily dose of PRADAXA is 220mg taken as one 110mg capsule twice daily:

• Patients aged 80 years or above

• Patients who receive concomitant verapamil

For the following groups the daily dose of PRADAXA of 300mg or 220mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding:

• Patients between 75–80 years

• Patients with moderate renal impairment

• Patients with gastritis, esophagitis or gastroesophageal reflux

• Other patients at increased risk of bleeding

The recommendation for the use of PRADAXA 220mg taken as one 110mg capsule twice daily is based on pharmacokinetic and pharmacodynamics analyses and has not been studied in this clinical setting.

In case of intolerability to dabigatran, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and SEE associated with atrial fibrillation or for DVT/PE.

Special patient populations:

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 < 30ml/min).There are no data to support use in patients with severe renal impairment (creatinine clearance < 30 ml/min). Given the substantial increase in dabigatran exposure observed in this patient population, treatment in this population with PRADAXA is not recommended (see “Contraindications”).

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 hypovolemia, dehydration, and with certain comedications, etc).

Dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies.

Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery:
In patients with moderate renal impairment (creatinine clearance 30–50 ml/min), there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections on Special Warnings & Precautions and Properties – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

After knee replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules of 75 mg once daily thereafter for a total of 10 days.

After hip replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules of 75 mg once daily thereafter for a total of 28–35 days.

For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules of 75 mg once daily.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE in adults:
Treatment with PRADAXA in patients with severe renal impairment (CrCL<30mL/min) is contraindicated.

No dose adjustment is necessary in patients with mild renal impairment (CrCL 50 –≤80mL/min). For patients with moderate renal impairment (CrCL 30 –50mL/min) the recommended dose of PRADAXA is also 300mg taken as one 150mg capsule twice daily. However for patients with high risk of bleeding a dose reduction of PRADAXA to 220mg taken as one 110mg capsule twice daily should be considered. Close clinical surveillance is recommended in patients with renal impairment.

Elderly:

Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery:
As renal impairment may be frequent in the elderly (>75 years), 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 < 30ml/min ). The renal function should also be assessed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).

In elderly patients (> 75 years) there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections on Special Warnings & Precautions and Properties – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).
After knee replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.
After hip replacement surgery treatment should be initiated orally within 1 – 4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28–35 days.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibirillation; treatment of DVT and PE, and prevention of recurrent DVT and PE :
Patients between 75–80 years should be treated with a daily dose of 300mg taken as one 150mg capsule twice daily. A dose of 220mg taken as one 110mg capsule twice daily can be individually considered, at the discretion of the physician, when the thromboembolic risk is low and the bleeding risk is high.

Patients aged 80 years or above should be treated with a daily dose of 220mg taken as one 110mg capsule twice daily due to the increased risk of bleeding in this population.

As renal impairment may be frequent in the elderly (>75 years), 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 < 30ml/min ). The renal function should also be assessed at least once a year in patients treated with PRADAXA or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc).

Pharmacokinetic studies in older subjects demonstrate an increase in drug exposure in those patients with age-related decline of renal function.
See also dose and administration in renal impairment.

Hepatic impairment:
Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in clinical trials. No treatment experience is available for this subpopulation of patients, and therefore the use of PRADAXA is not recommended in this population (see sections “Special Warnings & Precautions” and “Pharmacokinetics” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).
Hepatic impairment or liver disease expected to have any impact on survival is contraindicated.

Weight:
There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at the recommended posology. Given the available clinical and kinetic data, no adjustment is necessary (see section “Pharmacokinetics” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information) but close clinical surveillance is recommended in patients with a body weight <50kg (see “Special Warnings & Precautions” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Gender:
Given the available clinical and kinetic data, no dose adjustment is necessary (see section “Pharmacokinetics” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Post-surgical patients with an increased risk for bleeding:
Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (creatinine clearance 30 – 50 ml/min), should be treated with caution (see sections on Special Warnings & Precautions and Properties – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Children and adolescents:
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery; Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation:
PRADAXA has not been investigated in patients <18 years of age. Treatment of children with PRADAXA is therefore not recommended.

Treatment of DVT and PE, and prevention of recurrent DVT and PE:
PRADAXA is under investigation in patients < 18 years.
The safety and efficacy in children has not yet been established. Treatment of children with PRADAXA is therefore not recommended.

Concomitant use of PRADAXA with strong P-glycoprotein inhibitors, e.g. Amiodarone, Quinidine or Verapamil:

Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery:
Dosing should be reduced to PRADAXA 150 mg taken once daily as 2 capsules of 75 mg in patients who concomitantly receive PRADAXA and amiodarone, quinidine or verapamil (see on “Drug Interactions” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).
Treatment initiation with verapamil should be avoided in patients who have undergone major orthopaedic surgery who are already treated with PRADAXA. Simultaneous initiation of treatment with PRADAXA and verapamil should also be avoided.

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 28–35 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 of 75 mg once daily.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE :
No dose adjustment is necessary for concomitant use of amiodarone or quinidine.
Dosing should be reduced to 220mg taken as one 110mg capsule twice daily in patients who receive concomitantly dabigatran etexilate and verapamil. In this situation PRADAXA and verapamil should be taken at the same time.

Patients at risk of bleeding (SPAF/DVT/PE)
Patients with an increased risk of bleeding (see Special Warnings and Precautions, Haemorrhagic risk, Table 1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information), should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient. A coagulation test may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposure is identified in patients at high risk of bleeding, a dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted.

For subjects with gastritis, esophagitis, or gastroesophageal reflux, the dose of 220 mg taken as one 110 mg capsule twice daily may be considered due to the elevated risk of major gastro-intestinal bleeding.

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

Table 1 summarises factors which may increase the haemorraghic risk. Please also refer to contraindications.

The measurement of dabigatran-related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.

In patients who are bleeding, an aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT > 80 sec at trough, i.e., when the next dose is due, is associated with a higher risk of bleeding (see Monitoring and Laboratory Tests).
Should severe bleeding occur, treatment with PRADAXA must be discontinued and the source of bleeding investigated promptly.

Assessment of renal function (SPAF, DVT/PE):

In all patients and especially in the elderly (>75 years), as renal impairment may be frequent in this age group:

• Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with PRADAXA to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min). PRADAXA is contraindicated in patients with severe renal impairment

• Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products)

Additional requirements in patients with mild to moderate renal impairment and in patients aged over 75 years:

• Renal function should be assessed during treatment with PRADAXA 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 (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products)

The method used to estimate renal function (CrCL in mL/min) during the clinical development of PRADAXA was the Cockgroft-Gault method. The formula is as follows:

This method is recommended when assessing patients’ CrCL prior to and during PRADAXA treatment.

Switching from PRADAXA treatment to parenteral anticoagulant:
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery:
It is recommended to wait 24 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant (see section on Drug Interactions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation;treatment of DVT and PE, and prevention of recurrent DVT and PE :
It is recommended to wait 12 hours after the last dose before switching from PRADAXA to a parenteral anticoagulant.

Switching from parenteral anticoagulants treatment to PRADAXA:
PRADAXA should be given 0–2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous UFH).

Switching from Vit. K antagonists to PRADAXA
Prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE:
The Vit. K antagonist should be stopped. PRADAXA can be given as soon as the INR is < 2.0.

Switching from PRADAXA to Vit. K antagonists (VKA)
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation:
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT, and PE in adults (DVT/PE):
As with any short-acting anticoagulant, there is a potential for inadequate anticoagulation when transitioning from PRADAXA to a VKA. It is important to maintain an adequate level of anticoagulation when transitioning patients from one anticoagulant to another. The starting time of the VKA should be adjusted according to the patient’s calculated creatinine clearance CrCL as follows:

• CrCL ≥ 50 ml/min, start VKA 3 days before discontinuing dabigatran etexilate.

• CrCL ≥ 30–< 50 ml/min, start VKA 2 days before discontinuing dabigatran etexilate.

In general, after starting VKA therapy, its clinically relevant anticoagulant effect is not readily apparent for at least 2 days, while the full therapeutic effect is achieved in about 5–7 days.

Because PRADAXA can impact the International Normalized Ratio (INR), the INR will better reflect VKA’s effect only after PRADAXA has been stopped for at least 2 days. Until then, INR values should be interpreted with caution.

Note that when converting a patient from PRADAXA to vitamin K antagonist therapy, the INR will not reliably reflect the anticoagulant effect of VKA until at least 2 days after discontinuation of PRADAXA. In switching from PRADAXA to VKA, the INR should only be used to assess the anticoagulant effect of the VKA, and not that of PRADAXA, since it is not a valid measure to assess the anticoagulant activity of PRADAXA. The INR is only calibrated and validated for VKA and should not be used for any other anticoagulant, including PRADAXA.

Catheter ablation for atrial fibrillation
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation:
Catheter ablation can be conducted in patients on 150 mg twice daily PRADAXA treatment. PRADAXA treatment does not need to be interrupted (see “Pharmacological Properties” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Cardioversion
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation:
Patients can stay on PRADAXA while being cardioverted.

Percutaneous coronary intervention (PCI) with stenting
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation:
Patients with non valvular atrial fibrillation who undergo a PCI with stenting can be treated with PRADAXA in combination with antiplatelets after haemostasis is achieved (see “Pharmacological Properties” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information)

Missed dose
Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery:
Continue with your remaining daily doses of PRADAXA at the same time of the next day. Do not take a double dose to make up for missed individual doses.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treatment of DVT and PE, and prevention of recurrent DVT and PE:
A forgotten PRADAXA dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.
Do not take a double dose to make up for missed individual doses.

Method of administration
PRADAXA hard capsules can be taken with or without food. PRADAXA hard capsules should be swallowed as a whole 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. Patients should be instructed not to open the capsule as this may increase the risk of bleeding.

Instruction for Use/Handling
When removing a hard 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

Any unused product or waste material should be disposed in accordance with local requirements.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients

• Patients with severe renal impairment (CrCl < 30 ml/min)

• Active clinically significant bleeding

• Hepatic impairment or liver disease expected to have any impact on survival

• Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole and dronedarone (see section on “Drug Interactions” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information)

• Prosthetic heart valve replacement requiring anticoagulant treatment (see section on Pharmacological Properties – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information)

• 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 anticoagulant agent e.g. unfractionated heparin (UFH, except at doses necessary to maintain patency of central venous or arterial catherter or during catheter ablation for aterial fibrillation), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban, etc.) except under specific circumstances. These are switching anticoagulant therapy (see section “Dosage and Administration”) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section “Drug Interactions” – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information)