Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
PROFESSIONAL INFORMATION FOR DABITRIN  
SCHEDULING STATUS  
S4  
1
2
NAME OF THE MEDICINE  
DABITRIN 75 mg, 110 mg &150 mg capsules.  
QUALITATIVE AND QUANTITATIVE COMPOSITION  
DABITRIN 75 mg: Each capsule contains dabigatran etexilate mesylate equivalent to 75 mg of  
Dabigatran Etexilate.  
Contains sugar: Sugar spheres 35 mg.  
DABITRIN 110 mg: Each capsule contains dabigatran etexilate mesylate equivalent to 110 mg of  
Dabigatran Etexilate.  
Contains sugar: Sugar spheres 51,33 mg.  
DABITRIN 150 mg: Each capsule contains dabigatran etexilate mesylate equivalent to 150 mg of  
Dabigatran Etexilate.  
Contains sugar: Sugar spheres 70 mg.  
For the full list of excipients, see Section 6.1.  
3
PHARMACEUTICAL FORM  
Dabigatran etexilate Capsules 75 mg:  
Cream opaque cap / Cream opaque body size '2' HPMC capsules imprinted with 'H' on cap and 'D10'  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
on body with black ink, filled with mixture of off white to yellowish white pellets, free from physical  
defects.  
Dabigatran etexilate Capsules 110 mg:  
Cream opaque cap / Cream opaque body size '1' HPMC capsules imprinted with 'H' on cap and 'D16'  
on body with black ink, filled with mixture of off white to yellowish white pellets, free from physical  
defects.  
Dabigatran etexilate Capsules 150 mg:  
Cream opaque cap / Cream opaque body size '0' HPMC capsules imprinted with 'H' on cap and 'D11'  
on body with black ink, filled with mixture of off white to yellowish white pellets, free from physical  
defects.  
4
CLINICAL PARTICULARS  
4.1  
Therapeutic indications  
Prevention of venous thromboembolic events in patients who have undergone hip and knee  
replacement surgery.  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation.  
Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary  
embolism (PE).  
4.2  
Posology and method of administration  
Posology:  
Adults:  
Prevention of venous thromboembolism (VTE) in patients following hip and knee replacement  
surgery:  
The recommended dose of DABITRIN is 220 mg once daily taken as 2 capsules of 110 mg.  
Patients with moderate renal impairment have an increased risk for bleeding. For those patients the  
July 2024  
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Page 2 of 33  
Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
recommended dose of DABITRIN is 150 mg once daily, taken as 2 capsules of 75 mg.  
VTE prevention following knee replacement surgery:  
Treatment with DABITRIN should be initiated orally within 1- 4 hours of completed surgery with a  
single capsule ( 110 mg) and continuing with 2 capsules once dally thereafter for a total of 10 days.  
If haemostasis is not secured, Initiation of treatment should be delayed. If treatment is not started on  
the day of surgery, then treatment should be initiated with 2 capsules once daily.  
Patients with moderate renal impairment have an increased risk for bleeding. For those patients, the  
DABITRIN 75 mg capsules should be used instead of the 110 mg capsules.  
VTE prevention following hip replacement surgery:  
Treatment with DABITRIN should be Initiated orally within 1 – 4 hours of completed surgery with a  
single capsule (110 mg) and continuing with 2 capsules once dally thereafter for a total of 28 days. If  
haemostasis is not secured, Initiation of treatment should be delayed. If treatment is not started on  
the day of surgery then treatment should be initiated with 2 capsules once daily.  
Patients with moderate renal impairment have an increased risk for bleeding. For those patients, the  
DABITRIN 75 mg capsules should be used instead of the 110 mg capsules.  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
The recommended daily dose of DABITRIN is 300 mg taken orally as 150 mg capsules twice daily.  
Therapy should be continued life-long.  
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): The recommended  
daily dose of DABITRIN 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 DABITRIN is 300 mg taken orally as 150 mg capsules twice daily.  
Therapy could be continued life-long depending on the individual patient’s risk factors.  
July 2024  
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Page 3 of 33  
Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Children: DABITRIN has not been investigated in patients <18 years of age. Treatment of children  
with DABITRIN is not recommended.  
Renal Impairment:  
Renal function should be assessed by calculating the creatinine clearance (CrCl) prior to initiation of  
treatment with DABITRIN to exclude patients for treatment with severe renal impairment (i.e. CrCl <  
30 mL/min).  
There are no data to support use in patients with severe renal impairment (CrCl < 30 mL/min);  
treatment in this population with DABITRIN is not recommended (see section 4.3).  
While on treatment renal function should be assessed in certain clinical situations when it is suspected  
that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with  
certain co-medications that may decrease renal function such as with initiation of chemotherapeutics,  
or amphotericin B or under chronic treatment with NSAIDs).  
DABITRIN can be dialysed; there is limited clinical experience to demonstrate the utility of this  
approach in clinical studies.  
Prevention of venous thromboembolic events in patients who have undergone hip and knee  
replacement surgery:  
Dosing should be reduced to 150 mg DABITRIN taken once daily as 2 capsules of 75 mg in patients  
with moderate renal Impairment (30 - 50 ml/min creatinine clearance).  
Treatment with DABITRIN should be initiated orally within 1 - 4 hours of completed surgery with a  
single capsule of 75 mg and continuing with 2 capsules of 75 mg once daily thereafter for a total of  
10 days (following knee replacement surgery) or 28 days (following hip replacement surgery). For  
both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment  
is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.  
July 2024  
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Page 4 of 33  
Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
In patients with moderate renal impairment (CrCl 30 - 50 mL/min) the renal function should be  
assessed at least once a year.  
No dose adjustment is necessary. Patients should be treated with a daily dose of 300 mg taken orally  
as 150 mg capsules twice daily.  
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE): No dose  
adjustment is necessary in patients with renal function over CrCl 30 mL/min. Patients should be  
treated with a daily dose of 300 mg taken orally as 150 mg capsules twice daily.  
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE): In patients  
with moderate renal impairment (CrCl 30 - 50 mL/min) the renal function should be assessed at least  
once a year.  
No dose adjustment is necessary in patients with renal function over CrCl 30 mL/min. Patients should  
be treated with a daily dose of 300 mg taken orally as 150 mg capsules twice daily.  
Special populations:  
Elderly:  
Pharmacokinetic studies in older subjects demonstrate an increase in dabigatran exposure in those  
patients with age-related decline of renal function. 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 DABITRIN to exclude patients for treatment with severe renal impairment  
(i.e. CrCl < 30 mL/min).The renal function should also be assessed at least once a year in patients  
treated with DABITRIN 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  
co-medications that may decrease renal function, such as with initiation or chemotherapeutics, or  
amphotericin B or under chronic treatment (with NSAIDS). (See Section 4.2 in Renal impairment).  
July 2024  
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Page 5 of 33  
Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Prevention of venous thromboembolic events in patients who have undergone hip and knee  
replacement surgery:  
No dose adjustment is necessary; patients should be treated with 220 mg DABITRIN taken once daily  
as 2 capsules of 110 mg.  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
Patients aged 80 years or above should be treated with a daily dose of 220 mg taken orally as 110  
mg capsules twice daily.  
Weight: No dose adjustment is necessary.  
Concomitant use of DABITRIN with strong P-glycoprotein Inhibitors, i.e., amiodarone,  
quinidine, or verapamil: Prevention of venous thromboembolic events in patients who have  
undergone hip and knee replacement surgery: Dosing should be reduced to DABITRIN 150 mg taken  
once daily as 2 capsules of 75 mg in patient, who concomitantly receive DABITRIN and amiodarone,  
quinidine, or verapamil (see Section 4.5).  
Treatment initiation with verapamil should be avoided in patients who have undergone hip and knee  
replacement surgery who are already treated with DABITRIN. Simultaneous initiation of treatment  
with DABITRIN and verapamil should also be avoided.  
Treatment with DABITRIN should be initiated orally within 1 - 4 hours of completed surgery with a  
single capsule of 75 mg and continuing with 2 capsules of 75 mg once daily thereafter for a total of  
10 days (following knee replacement surgery) or 28 days (following hip replacement surgery). For  
both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment  
is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.  
July 2024  
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Page 6 of 33  
Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
No dose adjustment is necessary, patients should be treated with a daily dose of 300 mg taken orally  
as 150 mg capsules twice daily.  
Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary  
embolism (PE): No dose adjustment is necessary, patients should be treated with a daily dose of 300  
mg taken orally as 150 mg capsules twice daily.  
Patients at risk of bleeding:  
The presence of the following factors is associated with an increased risk of bleeding: e.g. age ≥ 75  
years, moderate renal impairment (CrCl 30 - 50 mL/min), concomitant treatment with strong P-gp  
inhibitors (see section 4.5), antiplatelet medicines or previous gastro-intestinal bleed (see section 4.3  
and section 4.4).  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation: For patients with  
one or more than one of these risk factors, a reduced daily dose of 220 mg given as 110 mg twice  
daily may be considered at the discretion of the doctor.  
Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary  
embolism (PE): No dose adjustment is necessary for patients with single risk factors.  
Only limited clinical data are available for patients with multiple risk factors. Therefore, DABITRIN  
should only be given in these patients if the expected benefit outweighs bleeding risks.  
Switching from DABITRIN treatment to parenteral anticoagulation:  
Prevention of venous thromboembolic events in patients who have undergone hip and knee  
replacement surgery:  
Wait 24 hours after the last dose before switching from DABITRIN to a parenteral anticoagulant.  
July 2024  
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Page 7 of 33  
Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
Wait 12 hours after the last dose before switching from DABITRIN to a parenteral an anticoagulant.  
Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary  
embolism (PE): Wait 12 hours after the last dose before switching from DABITRIN to a parenteral  
anticoagulant.  
Switching from parenteral anticoagulant treatment to DABITRIN:  
DABITRIN 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 warfarin to DABITRIN:  
To reduce the risk of stroke and systemic embolism in patients with of atrial fibrillation:  
The warfarin should be stopped. DABITRIN can be given as soon as the INR is< 2,0.  
Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary  
embolism (PE): The warfarin should be stopped. DABITRIN can be given as soon as the INR is <  
2,0.  
Switching from DABITRIN to warfarin:  
The starting time of warfarin should be adjusted according to the patient’s CrCl as follows:  
•
•
CrCl ≥ 50 mL/min, start warfarin 3 days before discontinuing DABITRIN.  
CrCl ≥ 30 - < 50 mL/min, start warfarin 2 days before discontinuing DABITRIN.  
Cardioversion:  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
Patients can stay on DABITRIN while being cardioverted.  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Catheter ablation for atrial fibrillation:  
Catheter ablation can be conducted in non-valvular atrial fibrillation patients on 150 mg twice daily  
DABITRIN treatment. DABITRIN treatment does not need to be interrupted.  
There are no clinical data on continuation of DABITRIN treatment during catheter ablation in those  
non-valvular atrial fibrillation patients receiving 110 mg twice daily.  
Percutaneous coronary intervention (PCI) with stenting:  
Patients with non valvular atrial fibrillation who undergo a PCI with stenting can be treated with  
DABITRIN in combination with antiplatelets after haemostasis is achieved.  
Missed dose:  
Prevention of venous thromboembolic events in patients who have undergone hip and knee  
replacement surgery:  
Continue with your remaining daily doses of DABITRIN at the same time on the next day and do not  
take a double dose to make up for missed individual doses.  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
A forgotten DABITRIN dose may still be taken up to 6 hours prior to the next scheduled dose. From  
6 hours prior to the next scheduled dose, the missed dose should be omitted. Do not take a double  
dose to make up for missed individual doses.  
Treatment of acute and prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary  
embolism (PE): A forgotten DABITRIN dose may still be taken up to 6 hours prior to the next  
scheduled dose. From 6 hours prior to the next scheduled dose, the missed dose should be omitted.  
Patients should not take a double dose to make up for missed individual doses.  
Discontinuation rules before invasive or surgical procedures:  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Renal function  
Estimated half- Stop DABITRIN before elective  
(CrCl in mL/min)  
life  
surgery  
High  
(hours)  
risk  
of Standard risk  
or  
bleeding  
major surgery  
2 days before  
~ 13*  
~ 15*  
~ 18*  
24 hours before  
≥ 80  
2 - 3 days before 1 - 2 days before  
≥ 50 - < 80  
≥ 30 - < 50  
4 days before  
2 - 3 days before  
(> 48 hours)  
*for more details see the table in section 4.4 and section 5.2.  
Method of administration  
DABITRIN can be taken with or without food. DABITRIN should be taken with a glass of water, to  
facilitate delivery to the stomach. If gastrointestinal symptoms develop it is recommended to take  
DABITRIN with a meal and/or a proton pump inhibitor such as pantoprazole.  
Do not open the capsule.  
Instructions for use/handling:  
When removing a capsule from the blister, please note the following instructions:  
•
•
•
Tear off one individual blister from the blister card along the perforated line  
Peel off the backing foil and remove the capsule  
The capsule should not be pushed through the blister foil  
4.3  
Contraindications  
•
Hypersensitivity to the active substance or to any of the excipients of listed in (Section 6.1),  
Patients with severe renal impairment (CrCL < 30 ml/min),  
•
•
Haemorrhagic manifestations, patients with a bleeding diathesis, or patients with  
spontaneous or pharmacological impairment of haemostasis,  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
•
•
Moderate to severe hepatic impairment (Child-Pugh B/C),  
Organ lesions at risk of clinically significant bleeding, including haemorrhagic stroke within  
the last 6 months,  
•
Patients with an indwelling spinal or epidural catheter and during the first hour after removal  
(see Section 4.4),  
•
•
Prolonged coadministration with heparins or warfarin,  
Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole,  
ciclosporine,  
itraconazole,dronedarone  
and  
the  
fixed-dose  
combination  
glecaprevir/pibrentasvir (see Section 4.5),  
•
The following treatments should not be administered concomitantly with DABITRIN:  
unfractionated heparins and heparin derivatives, low molecular weight heparins (LMWH),  
fondaparinux. desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, clopidogrel,  
ticlopidine, ticagrelor, dextran, sulfinpyrazone, and Vitamin K antagonists. It should be noted  
that unfractionated heparin can be administered at doses necessary to maintain a patent  
central venous or arterial catheter. DABITRIN and Vitamin K antagonists (e.g. warfarin) can  
be administered together, but only for a few days during switching from DABITRIN to Vitamin  
K antagonist treatment.  
•
•
In patients with suspected infective endocarditis,  
Prosthetic heart valve requiring anticoagulant treatment (see section 5.1).  
4.4  
Special warnings and precautions for use  
Haemorrhagic risk:  
DABITRIN increases the risk of bleeding and can cause significant and sometimes fatal bleeding.  
DABITRIN should be used with caution in conditions with an increased risk of bleeding or with  
concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation.  
Bleeding can occur at any site during therapy with DABITRIN. An unexplained fall in haemoglobin  
and/or haematocrit or blood pressure should lead to a search for a bleeding site.  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation  
effect of dabigatran is required, the specific reversal agent (Praxbind, idarucizumab) is available (see  
Surgery and interventions, Pre-operative phase and section 4.9).  
DABITRIN does not in general require routine anticoagulation monitoring. However, the  
measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure  
to dabigatran in the presence of additional risk factors. Coagulation testing should also be considered  
to assist with the management of patients in the perioperative setting, suspected overdose and  
emergency situations.  
The INR test is unreliable in patients on DABITRIN and false positive INR elevations have been  
reported. Therefore INR tests should not be performed. Tests of anticoagulant activity such as  
Thrombin Time (TT), diluted Thrombin Time (dTT), Ecarin Clotting Time (ECT) and activated Partial  
Thromboplastin Time (aPTT) are available to detect excessive dabigatran activity.  
DABITRIN related anticoagulation can be assessed by ECT or TT. If ECT or TT are not available, the  
aPTT test provides an approximation of DABITRIN’s anticoagulant activity.  
To reduce the risk of stroke only systemic embolism in patients with atrial fibrillation:  
Major bleeding fulfilled one or more of the following criteria:  
•
Bleeding associated with a reduction in haemoglobin of at least 20 grams per liter or leading  
to a transfusion of at least 2 units of blood or packed cells,  
•
Symptomatic bleeding in a critical area or organ: intracranial, intraspinal, or intramuscular  
with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial  
bleeding.  
Major bleeds were classified as life-threatening if they fulfilled one or more of the following criteria:  
•
Fatal bleed: symptomatic intracranial bleed; reduction in haemoglobin of at least 50 grams  
per Liter; transfusion of at least 4 units of blood or packed cells; a bleed associated with  
hypotension requiring the use of intravenous inotropic agents; a bleed that necessitated  
surgical intervention.  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Renal impairment:  
Renal function should be assessed by calculating the creatinine clearance (CrCl) by the Cockgroft-  
Gault method prior to initiation of treatment with DABITRIN to exclude patients for treatment with  
severe renal impairment (i.e. CrCl < 30 mL/min).  
Pharmacokinetic studies demonstrated an increase in dabigatran as in DABITRIN exposure in  
patients with reduced renal function, including age-related decline of renal function. Patients who  
develop acute renal failure should discontinue DABITRIN.  
Factors, such as decreased renal function (30-50 ml/min CrCI), age > 75 years, or strong P-gp  
Inhibitor co-medication are associated with increased DABITRIN plasma levels. The presence of one  
or more than one of these factors may increase the risk of bleeding (see Section 4.2).  
Patients with antiphospholipid syndrome:  
Patients with antiphospholipid syndrome (especially if triple-positive for antiphospholipid antibodies)  
are at an increased risk for thromboembolic events.  
While the efficacy of DABITRIN is established for the treatment and prevention of venous  
thromboembolism it has not been studied specifically in the subpopulation of patients with  
antiphospholipid syndrome.  
Therefore, careful consideration of all treatment options (including standard treatment such as vitamin  
K antagonists) is recommended before use of DABITRIN in patients with antiphospholipid syndrome.  
Elderly:  
Elderly patients may be at increased risk of bleeding from dabigatran, particularly those with impaired  
renal function or low body weight.  
Amiodarone:  
July 2024  
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Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Dabigatran as in DABITRIN exposure in healthy subjects was increased by 60 % in the presence of  
amiodarone.  
The concomitant use of DABITRIN with the following treatments has not been studied and may  
increase the risk of bleeding: unfractionated heparins (except at doses necessary to maintain patency  
of a central venous or arterial catheter) and heparin derivatives, low molecular weight heparins  
(LMWHJ, fondaparinux, desirudin, thrombolytic agents, GPllb/Illa receptor antagonists, ticlopidine,  
dextran, sulfinpyrazone, rivaroxaban, prasugrel, Vitamin K antagonists, and the P-gp inhibitors  
itraconazole, fluconazole, tacrolimus, ciclosporin, ritonavir, tipranavir, nelfinavir and saquinavir.  
The concomitant use of DABITRIN with the fixed-dose combination of the P-gp inhibitors  
glecaprevir/pibrentasevir has been shown to increase exposure of dabigatran and may increase the  
risk of bleeding.  
The concomitant use of dronedarone increases exposure of DABITRIN and is not recommended.  
See section 4.5.  
Beeding risk may be increased in patients concomitantly treated with selective serotonin re-uptake  
inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs).  
Use of fibrinolytic agents for the treatment of acute ischaemic stroke:  
The use of fibrinolytic agents for the treatment of acute ischaemic stroke may be considered if the  
patient presents with a thrombin time (TT), or ecarin clotting time (ECT), or activated partial  
thromboplastin time (aPTT) not exceeding the upper limit of normal (ULN) according to the local  
reference range. In situations where there is an increased haemorrhagic risk (e.g. recent biopsy or  
major trauma, bacterial endocarditis) close observation (looking for signs of bleeding or anaemia) is  
generally required.  
Prevention of venous thromboembolic events in patients who have undergone hip and knee  
replacement surgery:  
NSAIDs given for short-term peri-operative analgesia have been shown not to be associated with  
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Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
increased bleeding risk when given in conjunction with DABITRIN.  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
Coadministration of oral anti-platelet (including aspirin and clopidogrel) and NSAID therapies increase  
the risk of bleeding.  
Interaction with P-gp inducers:  
The concomitant use of DABITRIN with the strong P· gp inducer rifampicin reduces dabigatran  
plasma concentrations. Other P-gp inducers such as St. John's Wort or carbamazepine are also  
expected to reduce dabigatran plasma concentrations and should be co-administered with caution  
(see Section 4.5).  
Surgery and interventions:  
Patients on DABITRIN who undergo surgery or invasive procedures are at increased risk for bleeding.  
Therefore surgical interventions may require the temporary discontinuation of DABITRIN (see  
section 5.2).  
Patients can stay on DABITRIN while being cardioverted. DABITRIN treatment (150 mg twice daily)  
does not need to be interrupted in patients undergoing catheter ablation for atrial fibrillation (see  
section 4.2).  
In case of emergency surgery or urgent procedures when rapid reversal of the anticoagulation effect  
is required the specific reversal agent idarucizumab to DABITRIN is available.  
Reversing DABITRIN therapy exposes patients to the thrombotic risk of their underlying disease.  
DABITRIN treatment can be re-initiated 24 hours after administration of idarucizumab, if the patient  
is clinically stable and adequate haemostasis has been achieved.  
Pre-operative phase: In advance of invasive or surgical procedures DABITRIN should be stopped  
temporarily due to an increased risk of bleeding. If possible, DABITRIN should be discontinued at  
least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding, or in major  
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Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
surgery where complete haemostasis may be required, consider stopping DABITRIN 2 – 4 days  
before surgery. Clearance of DABITRIN in patients with renal insufficiency may take longer. This  
should be considered in advance of any procedures (see section 5.2).  
DABITRIN is contra-indicated in patients with severe renal dysfunction (CrCI < 30 ml/min) but, should  
this occur, then DABITRIN should be stopped at least 5 days before major surgery.  
If an acute intervention is required, DABITRIN should be temporarily discontinued. A  
surgery/intervenion should be delayed if possible until at least 12 hours after the last dose. If surgery  
cannot be delayed there may be an increase in the risk of bleeding. This risk of bleeding should be  
weighed together with the urgency of intervention.  
Post-procedural period: Resume treatment after complete haemostasis is achieved.  
4.5  
Interaction with other medicines and other forms of interaction  
Transporter interactions:  
Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp  
inhibitors is expected to result in increased dabigatran plasma concentrations.  
If not otherwise specifically described close clinical surveillance (looking for signs of bleeding or  
anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions  
may be required in combination with some P-gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1).  
Atorvastatin: When dabigatran was co-administered with atorvastatin, a CYP3A4 substrate, exposure  
of atorvastatin, atorvastatin metabolites and of dabigatran were unchanged indicating a lack of  
interaction.  
Diclofenac: When dabigatran was co-administered with diclofenac, a CYP2C9 substrate,  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
pharmacokinetics of both medicines remained unchanged indicating a lack of interaction between  
dabigatran 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 had been investigated.  
P-glycoprotein inhibitors: Amiodarone: Dabigatran exposure in healthy subjects was increased by 60  
% in the presence of amiodarone.  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation: Dabigatran  
concentrations were increased by no more than 14 % and no increased risk of bleeding was observed.  
Verapamil: When dabigatran (150 mg) was co-administered with oral verapamil, the Cmax and AUC of  
dabigatran were increased but the magnitude of this change differs, depending on liming 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 dabigatran intake (increase of Cmax  
by about 180% and AUC by about 150%). The effect was progressively decreased with administration  
or an extended-release formulation (increase of Cmax by about 90% and AUC by about 70 %) or  
administration of multiple doses of verapamil (increase or Cmax by about 60 % and AUC by about 50  
%). This can be explained by the induction or P-gp in the gut by chronic verapamil treatment.  
Dronedarone:  
When dabigatran and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax  
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  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
hours after dabigatran , the decreases in dabigatran AUC0-∞ were 1,3 fold and 1,6 fold, respectively.  
(See section 4.4.)  
Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose or 1 000 mg.  
Dabigatran was-given twice dally over 3 consecutive days, on the 3rd day either with or without  
quinidine. Dabigatran AUC and Cmax were increased on average by 53 % and 56 %, respectively, with  
concomitant quinidine.  
Clarithromycin: When clarithromycin 500 mg twice daily was administered together with dabigatran  
no clinically relevant PK-interaction was observed (increase of Cmax by about 15 % and AUC by about  
19 %).  
Ketoconazole: Ketoconazole increased total dabigatran AUC0-and Cmax values by 138 % and 135 %,  
respectively, after a single dose or 400 mg, and 153 % and 149 %, respectively, after multiple dosing  
of 400 mg ketoconazole once dally.  
The time to peak, terminal half-life and mean residence time were not affected by ketoconazole (see  
Section 4.3).  
Ticagrelor:  
When a single dose of 75 mg dabigatran was co-administered simultaneously with a loading dose  
of 180 mg ticagrelor, the dabigatran AUC and Cmax 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  
Cmax and AUC, respectively.  
Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran (in steady  
state) increased the dabigatran AUCt,ss and by Cmax,ss by 1,49 fold and 1,65 fold (+ 49 % 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 AUCt,ss and  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Cmax,ss was reduced to 1,27 fold and 1,23 fold (+ 27 % 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 AUCt,ss and Cmax,ss 1,26 fold and  
1,29 fold, respectively, compared with dabigatran given alone.  
P-glycoprotein substrate:  
Digoxin: When dabigatran 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 pro-drug dabigatran etexilate is a clinically relevant P-gp inhibitor.  
P-glycoprotein inducers:  
Rifampicin: Pre-dosing of the probe Inducer rifampicin at a dose of 600 mg once dally 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.  
Caution should be exercised with strong P-glycoprotein inducers (see section 4.4).  
Platelet-inhibitors:  
Acetylsalicylic acid (ASA): The effect of concomitant administration) of dabigatran and acetylsalicylic  
acid (ASA) on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in  
which a randomised ASA co-administration was applied. Based on logistic regression analysis, co-  
administration of ASA and 150 mg dabigatran twice dally may increase the risk for any bleeding from  
12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively.  
NSAIDs given for short-term peri-operative analgesia have been shown not to be associated with  
increased bleeding risk when given in conjunction with dabigatran.  
Clopidogrel: In a study in young healthy male volunteers, the concomitant administration of dabigatran  
and clopidogrel resulted in no further prolongation of capillary bleeding times (CBTI) compared to  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
clopidogrel monotherapy. In addition, dabigatran AUCt,ss and Cmax,ss and the coagulation measures  
for dabigatran effect, aPTT, ECT or TT (anti FIia), or the inhibition or platelet aggregation (IPA) as a  
measure or clopidogrel effect remained essentially unchanged comparing combined treatment and  
the respective mono-treatments. With a loading dose of 300 or 600 mg clopidogrel, dabigatran AUCt,ss  
and Cmax,ss were increased by about 30 to 40 %.  
Selective serotonin re-uptake inhibitors (SSRIs):  
SSRIs increased the risk of bleeding (see section 4.4).  
Gastric pH-elevating agents:  
Pantoprazole: When dabigatran was co-administered with pantoprazole, a decrease in dabigatran  
area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole  
and other proton-pump Inhibitors (PPls) were co-administered with dabigatran in clinical trials and no  
effects on bleeding or efficacy were observed.  
Ranitidine: Ranitidine administration together with dabigatran had no meaningful effect on the extent  
of absorption of dabigatran.  
The changes in dabigatran exposure determined by population pharmacokinetic analysis caused by  
PPls and antacids were not considered clinically relevant because the magnitude of the effect was  
minor/fractional decrease in bioavailability not significant for antacids and 14,6 % for PPls).  
4.6  
Fertility, pregnancy and lactation  
Women of childbearing potential / Contraception in males and females:  
Women of childbearing potential should avoid pregnancy during treatment with DABITRIN.  
Pregnancy:  
Safety in pregnancy has not been established.  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Breastfeeding:  
Breast-feeding should be discontinued during treatment with DABITRIN.  
Fertility:  
No information available.  
4.7  
Effects on ability to drive and use machines  
DABITRIN has no or negligible influence on the ability to drive and use machines.  
4.8  
Undesirable effects  
Summary of the safety profile:  
Safety profile is tabulated as frequent, less frequent, and frequency unknown.  
Tabulated summary of adverse reactions:  
•
•
•
•
Risk reduction of thromboembolic stroke and systemic embolism in patients with atrial fibrillation  
(SPAF) with DABITRIN dosages of 110 or 150 mg taken twice daily.  
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (aVTEt) with a  
DABITRIN dosage of 150 mg taken twice daily.  
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (sVTEp) with  
a DABITRIN dosage of 150 mg taken twice daily.  
Primary VTE prevention (pVTEp) studies after hip and knee replacement surgery with DABITRIN  
dosages of 220 or 150 mg taken once daily.  
Discorders  
Frequency  
SPAF:  
in Frequency  
pVTEp:  
in Frequency  
aVTEt:  
in Frequency  
sVTEp:  
in  
Blood and the lymphatic system disorders:  
Anaemia Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Thrombocytopenia  
Immune system disorders:  
Hypersensitivity  
Pruritis  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Unknown  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Unknown  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Unknown  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Unknown  
Rash  
Urticaria  
Bronchospasm  
Frequency  
Frequency  
Frequency  
Frequency  
Anaphylactic reaction  
Unknown  
Unknown  
Unknown  
Unknown  
Frequency  
Frequency  
Frequency  
Frequency  
Angioedema  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Nervous system disorders:  
Intracranial haemorrhage  
Vascular disorders:  
Haematoma  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Haemorrhage  
Respiratory, thoracic and mediastinal disorders:  
Epistaxis  
Frequent  
Less Frequent  
Less Frequent  
Frequent  
Frequent  
Haemoptysis  
Gastrointestinal disorders:  
Gastrointestinal  
haemorrhage  
Abdominal pain  
Diarrhoea  
Less Frequent  
Less Frequent  
Less Frequent  
Frequent  
Less Frequent  
Frequent  
Frequent  
Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Frequent  
Less Frequent  
Less Frequent  
Frequent  
Frequent  
Dyspepsia  
Frequent  
Dysphagia  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Gastrointestinal  
ulcer, Less Frequent  
including  
oesophageal  
ulcer  
Gastro-oesophagitis  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Gastro-oesophageal reflux Less Frequent  
disease  
Nausea  
Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Vomiting  
Less Frequent  
Hepatobiliary disorders:  
Abnormal hepatic function  
Less Frequent  
Frequent  
Less Frequent  
Less Frequent  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Skin and subcutaneous tissue disorders:  
Skin haemorrhage Frequent  
Musculoskeletal, connective tissue and bone disorders:  
Less Frequent  
Frequent  
Frequent  
Haemarthrosis  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Renal and urinary disorders:  
Urogenital haemorrhage  
Haematuria  
Frequent  
Frequent  
Less Frequent  
Less Frequent  
Frequent  
Frequent  
Frequent  
Frequent  
General disorders and administration site conditions:  
Injection site haemorrhage  
Catheter site haemorrhage  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
Injury, poisoning and procedural complications:  
Traumatic haemorrhage  
Incision site haemorrhage  
Less Frequent  
Less Frequent  
Less Frequent  
Less Frequent  
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:  
Vascular disorders:  
Less Frequent: wound haemorrhage  
General disorders and administration site conditions:  
Less Frequent: bloody discharge  
Injury, poisoning and procedural complications:  
Less Frequent: post procedural haematoma, post procedural haemorrhage, post procedural  
discharge, wound secretion  
Less Frequent: post operative anaemia  
Surgical and medical procedures:  
Less Frequent: wound drainage, post procedural drainage  
Post-marketing experience:  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
The following side effects have been identified during post-approval use of DABITRIN therefore the  
frequency is unknown:  
Blood and the lymphatic system disorders:  
Neutropenia, agranulocytosis  
Skin and subcutaneous tissue disorders:  
Alopecia  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows  
continued monitoring of the benefit / risk balance of the medicine. Health care providers are asked  
to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions  
Reporting  
Form”,  
found  
online  
under  
SAHPRA’s  
publications:  
https://www.sahpra.org.za/publications/Index/8 or to the Holder of certificate of registration through  
the mail: pvg.cdma@heterogroups.com.  
4.9  
Overdose  
DABITRIN doses beyond those recommended, expose the patient to increased risk of bleeding.  
In case of an overdose suspicion, coagulation tests can help to determine a bleeding risk (see  
sections 4.4 and 5.1). A calibrated quantitative (dTT) test or repetitive dTT measurements allow  
prediction of the time by when certain dabigatran levels will be reached (see section 5.1), also in case  
additional measures e.g. dialysis have been initiated.  
Excessive anticoagulation may require interruption of DABITRIN treatment. Since dabigatran is  
excreted predominantly by the renal route adequate diuresis must be maintained. As protein binding  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
is low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this  
approach in clinical studies (see section 5.2).  
Management of bleeding complications  
In the event of haemorrhagic complications, DABITRIN treatment must be discontinued, and the  
source of bleeding investigated. Depending on the clinical situation appropriate supportive treatment,  
such as surgical haemostasis and blood volume replacement, should be undertaken at the  
prescriber's discretion. In addition, consideration may be given to the use of fresh whole blood or  
fresh frozen plasma.  
For situations when rapid reversal of the anticoagulant effect of DABITRIN is required the specific  
reversal agent (Praxbind, idarucizumab) antagonizing the pharmacodynamic effect of DABITRIN is  
available (see section 4.4).  
Coagulation factor concentrates (activated or non-activated) or recombinant Factor VIIa may be taken  
into account. There is some experimental evidence to support the role of these medicinal products in  
reversing the anticoagulant effect of dabigatran, but data on their usefulness in clinical settings and  
on the possible risk of rebound thromboembolism is very limited. Coagulation tests may become  
unreliable following administration of suggested coagulation factor concentrates.  
Caution should be exercised when interpreting these tests. Consideration should also be given to  
administration of platelet concentrates in cases where thrombocytopenia is present or long acting  
antiplatelet medicinal products have been used. All symptomatic treatment should be given according  
to the physician's judgement.  
Depending on local availability, a consultation of a coagulation expert should be considered in case  
of major bleedings.  
5
PHARMACOLOGICAL PROPERTIES  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Category and class: A 8.2 Anticoagulants  
Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors, ATC code: B01AE07.  
5.1  
Pharmacodynamic properties  
Dabigatran etexilate is a small molecule pro-drug which does not exhibit any pharmacological activity.  
After oral administration, dabigatran etexilate is rapidly absorbed and then converted to dabigatran  
by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a competitive, reversible  
direct thrombin inhibitor and is the main active principle in plasma.  
Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the  
coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits  
free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.  
In vivo and ex vivo animal studios have demonstrated antithrombotic efficacy and anticoagulant  
activity of dabigatran after intravenous administration and of dabigatran etexilate after oral  
administration in various animal models of thrombosis.  
There is a correlation between plasma dabigatran concentration and degree of anticoagulant effect.  
Prothrombin time (PT, expressed as International Normalised Ratio (INR)) is too insensitive to reliably  
detect anticoagulant activity of dabigatran and is therefore not recommended as a suitable tool for  
monitoring anticoagulant activity. Ecarin Clotting Time (ECT), Thrombin Time (TT) and diluted  
Thrombin Time (dTT) are sensitive assays that increase in direct proportion to dabigatran plasma  
concentration without any deviation from linearity at high plasma concentrations. However, ECT is  
not readily available in clinical practice. Activated Partial Thromboplastin Time (aPTT) increases in a  
non-linear manner to dabigatran concentration and is less proportional at higher dabigatran  
concentrations (see section 4.4). ECT, TT and aPTT are not standardised or validated with dabigatran  
for commercial use. In cases of emergency, TT and aPTT are the most accessible qualitative methods  
for determining the presence or absence of the anticoagulant effect of dabigatran.  
Interpretation of coagulation assay results should consider time of DABITRIN administration relative  
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DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
to time of blood sampling (see section 5.2).  
In patients undergoing elective hip replacement surgery, greater test variability with aPTT and ECT  
was observed. The mechanisms for this variability immediately after surgery are unclear and aPTT  
and ECT levels measured in the first 2-3 days following surgery should be interpreted with caution.  
Whilst DABITRIN does not require routine laboratory anticoagulant monitoring, careful clinical  
monitoring including renal function testing is required in certain clinical situations (see section 4.2 and  
section 4.4).  
5.2  
Pharmacokinetic properties  
After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which  
is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed  
hydrolysis to the active principal dabigatran is the predominant metabolic reaction. The absolute  
bioavailability of dabigatran following oral administration of dabigatran etexilate was approximately  
6.5 %.  
After oral administration of dabigatran etexilate in healthy volunteers, the pharmacokinetic profile of  
dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax  
attained within 0.5 and 2.0 hours post administration.  
Absorption:  
A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery,  
demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth  
plasma concentration-time profile without high peak plasma concentrations. Peak plasma  
concentrations are reached at 6 hours following administration or at 7 to 9 hours following surgery in  
a postoperative period due to contributing factors such as anaesthesia, GI paresis, and surgical  
effects will mean that a proportion of patients will exhibit absorption delay independent of the oral  
medicinal product formulation. It was demonstrated in a further study that slow and delayed  
absorption is usually only present on the day of surgery. On subsequent post-surgery days absorption  
of dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
administration.  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma  
concentrations by 2 hours.  
Cmax and AUC were dose proportional.  
The oral bioavailability may be increased by 75 % after a single dose and 37 % at steady state  
compared to the reference capsule formulation when the pellets are taken without the Hydroxypropyl  
methylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules should always be  
preserved in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate (see  
section 4.2).  
Distribution:  
Low (34-35 %) concentration independent binding of dabigatran to human plasma proteins was  
observed. The volume of distribution of dabigatran of 60-70 L exceeded the volume of total body  
water indicating moderate tissue distribution of dabigatran.  
Biotransformation:  
Metabolism and excretion of dabigatran were studied following a single intravenous dose of  
radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived  
radioactivity was eliminated primarily in the urine (85 %). Faecal excretion accounted for 6 % of the  
administered dose. Recovery of the total radioactivity ranged from 88-94 % of the administered dose  
by 168 hours post dose. After oral administration, dabigatran etexilate is rapidly and completely  
converted to dabigatran, which is the active form in plasma. The cleavage of the pro-drug dabigatran  
etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant  
metabolic reaction.  
Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of  
total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive  
analytical methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of  
approximately 100 mL/min corresponding to the glomerular filtration rate.  
Elimination:  
Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of  
11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was  
observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as  
shown in table 2.  
Special populations:  
Renal Insufficiency: The exposure (AUC) of dabigatran after the oral administration of dabigatran  
etexilate is approximately 2,7 fold higher in volunteers with moderate renal insufficiency (CrCI  
between 30 – 50 ml/min) than in those without renal insufficiency.  
In a small number of volunteers with severe renal insufficiency (CrCl-10-30 ml/min), the exposure  
(AUC) to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer  
than that observed in a population without renal insufficiency (see Section 4.2 and Section 4.3).  
Half-life of total dabigatran in healthy subjects and subjects with impaired renal function:  
glomerular  
(CrCI)  
filtration  
rate gMean (gCV %; range) half-life  
[h]  
[mL/min]  
13.4 (25.7 %; 11.0-21.6)  
15.3 (42.7 %;11.7-34.1)  
18.4 (18.5 %;13.3-23.0)  
27.2 (15.3 %; 21.6-35.0)  
≥ 80  
≥ 50-< 80  
≥ 30-< 50  
< 30  
Hepatic Insufficiency: No change in dabigatran exposure was seen in 12 subjects with moderate  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
hepatic insufficiency (Child-Pugh B) compared to 12 controls.  
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE):  
21,7 % of patients had mild renal impairment (CrCl > 50 - < 80 mL/min) and 4,5 % of patients had  
moderate renal impairment (CrCl between 30 - 50 mL/min). Patients with mild and moderate renal  
impairment had on average 1,7 fold and 3,4 fold higher steady state dabigatran trough concentrations,  
respectively, compared with patients with CrCl > 80 mL/min.  
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE):  
22,9 % and 22,5 % of the patients studied had a CrCl > 50 - < 80 mL/min, and 4,1 % and 4,8 % had  
a CrCl between 30 - 50 mL/min.  
Prevention of venous thromboembolic events (VTE) in patients who have undergone hip and knee  
replacement surgery:  
Patients with moderate and severe hepatic impairment (Child-Pugh classification B and C) or liver  
disease expected to have any impact on survival or with elevated liver enzymes ≥ 2 Upper Limit of  
Normal (ULN) were excluded in clinical trials.  
To reduce the risk of stroke and systemic embolism in patients with atrial fibrillation:  
Almost half (45,8 %) of the patients studied had a CrCl > 50 - < 80 mL/min. Patients with moderate  
renal impairment (CrCl between 30 - 50 mL/min) had on average 2,29 fold and 1,81 fold higher pre-  
and post-dose dabigatran plasma concentrations, respectively, when compared with patients without  
renal impairment (CrCl ≥ 80 mL/min).  
Elderly patients: Specific pharmacokinetic studies with elderly subjects showed an increase of 40 to  
60 % in the AUC and of more than 25 % in Cmax compared to young subjects.  
The AUCt,55 and Cmax in male and female elderly subjects (> 65 years) were approximately 1,9-fold  
and 1,6-fold higher for elderly females compared to young females and 2,2 and 2,0-fold higher for  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
elderly males than in male subjects of 18 – 40 years of age.  
The observed increase of dabigatran exposure correlated with the age-related reduction in creatinine  
clearance.  
The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31 %  
higher trough concentration for subjects ≥ 75 years and by about 22 % lower trough level for subjects  
< 65 years compared to subjects of age between 65 and 75 years.  
Body weight: The dabigatran trough concentrations were about 20 % lower in patients with a BW >  
100 kg compared with 50 – 100 kg. The majority (80,8 %) of the subjects were in the ≥ 50 kg and <  
100 kg category with no clear difference detected. Limited data in patients ≤ 50 kg are available.  
Gender:  
Dabigatran exposure in the primary VTE prevention studies was about 40 % to 50 % higher in female  
patients. In atrial fibrillation patients, females had on average 30 % higher trough and post-dose  
concentrations. This finding had no clinical relevance.  
5.3  
Preclinical safety data  
No information available.  
6
PHARMACEUTICAL PARTICULARS  
6.1  
List of excipients  
Tartaric Acid, Hypromellose, 2910,5cps (Methocel E5 premium LV), Talc (Luzenac  
Pharma), lsopropyl alcohol, Methylene Chloride, Sugar Spheres, Mesh 35-45 (355 -  
500 MICRONS), Hydroxypropyl cellulose (Klucel EXF).  
6.2  
Incompatibilities  
July 2024  
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Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
No information available.  
6.3  
6.4  
Shelf life  
24 months.  
Special precautions for storage  
Store at or below 25 ºC.  
Keep out of reach of children.  
6.5  
Nature and contents of container  
Dabigatran etexilate Capsules 75 mg:  
56's & 60's Count HDPE Container.  
Dabigatran etexilate Capsules 110 mg:  
56's & 60's Count HDPE Container.  
Dabigatran etexilate Capsules 150 mg:  
56's & 60's Count HDPE Container.  
6.6  
Special precautions for disposal <and other handling>  
N/A  
7
HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall corporate campus,  
Building no. 2, first floor,  
July 2024  
Initials…RJ………..  
Page 32 of 33  
Applicant/ PHCR:  
Product Proprietary Name:  
Hetero Drugs South Africa (Pty) Ltd  
DABITRIN  
MODULE 1  
1.3.1.1  
Dosage Form and Strength  
Capsule. Each capsule contains Dabigatran Etexilate  
mesylate equivalent to 75 mg, 110 mg, and 150 mg of  
Dabigatran Etexilate  
74 waterfall drive,  
Midrand 2066  
Tel: 0126441220.  
8
REGISTRATION NUMBER(S)  
DABITRIN 75 mg: 56/8.2/0689.686  
DABITRIN 110 mg: 56/8.2/0690.687  
DABITRIN 150 mg: 56/8.2/0691.688  
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
19 March 2024.  
10  
DATE OF REVISION OF THE TEXT  
N/A  
July 2024  
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