Abagat: composition and dosage form
One hard capsule contains 110 mg or 150 mg of dabigatran etexilate in the form of the mesilate. The capsules are taken with or without food, swallowed whole with a glass of water so that the contents reach the stomach more easily.
One instruction from the product information is worth remembering word for word: the capsule must not be opened, because doing so increases the risk of bleeding. The shell here is not decoration but part of the dose — powder tipped out of the capsule is absorbed differently, and the patient receives a dose other than the one the doctor prescribed.
How Abagat works
Dabigatran etexilate does nothing by itself: it is a low-molecular-weight prodrug with no pharmacological activity. After being taken by mouth it is absorbed quickly and converted into dabigatran by an esterase in the plasma and in the liver. It is dabigatran that turns out to be the active substance found in the plasma.
Dabigatran is a potent, competitive, reversible direct inhibitor of thrombin. Thrombin is a serine protease that turns fibrinogen into fibrin at the last stage of coagulation, so blocking it prevents a clot from forming. And the medicine inhibits both free thrombin and thrombin already bound to fibrin, as well as thrombin-induced platelet aggregation.
Indications
In adults the medicine is used in three directions. The first is the prevention of stroke and systemic embolism in non-valvular atrial fibrillation, where at least one risk factor is present: a previous stroke or transient ischaemic attack, age 75 or over, heart failure of NYHA class II or higher, diabetes, or arterial hypertension. The second is the treatment of deep vein thrombosis and pulmonary embolism, and the prevention of their recurrence.
The third direction belongs to the 110 mg dose: primary prevention of venous thromboembolism in adults after elective total replacement of the hip or knee joint.
Method of administration and dosage
In atrial fibrillation, and also in the treatment of deep vein thrombosis and pulmonary embolism, the standard daily dose is 300 mg — one 150 mg capsule twice a day. In venous thrombosis and pulmonary embolism this is preceded by at least five days of a parenteral anticoagulant. The capsules are taken morning and evening, as far as possible twelve hours apart. A missed dose can be taken if more than 6 hours remain until the next one; a double dose is never taken.
| Who | Daily dose | What decides the choice |
| Most adults | 300 mg: 150 mg twice a day | this is the default dose in atrial fibrillation and in venous thrombosis |
| Patients aged 80 and over | 220 mg: 110 mg twice a day | the dose reduction is mandatory, not open to discussion |
| Those taking verapamil | 220 mg: 110 mg twice a day | verapamil raises the concentration of dabigatran; both capsules are taken at the same time |
| Age 75 to 80 | 300 or 220 mg | the doctor weighs the risk of thrombosis against the risk of bleeding in the individual patient |
| Creatinine clearance 30-50 ml/min | 300 or 220 mg | the same weighing, plus close clinical observation |
| Gastritis, oesophagitis, reflux disease | 300 or 220 mg | in these patients the risk of major gastrointestinal bleeding is higher |
Everything begins with the kidneys. Before treatment starts, creatinine clearance is calculated by the Cockcroft-Gault method as a matter of course, to screen out patients with severe renal impairment, in whom the medicine is contraindicated. In people over 75 and where kidney function is mildly or moderately reduced, it is assessed at least once a year. The length of treatment depends on the indication: in atrial fibrillation the therapy is continued long term, while in venous thrombosis the minimum period of three months is chosen where the risk factor was temporary — an operation, an injury, immobility — and extended where the risk factors are permanent or the cause of the thrombosis is unclear.
Contraindications
The first group of prohibitions concerns the body itself: hypersensitivity to the active substance or to any excipient; severe renal impairment in adults with a creatinine clearance below 30 ml/min; active, clinically significant bleeding; impaired liver function or liver disease capable of affecting survival. Listed separately are conditions regarded in themselves as a significant risk factor for major bleeding: gastrointestinal ulceration now or in the recent past, malignant tumours carrying a high risk of bleeding, oesophageal varices, arteriovenous malformations, vascular aneurysms and significant vascular abnormalities of the brain or spinal cord.
The second group concerns combinations. The simultaneous use of any other anticoagulant is prohibited — unfractionated heparin, low-molecular-weight heparins, heparin derivatives, and oral anticoagulants such as warfarin, rivaroxaban and apixaban. Strong inhibitors of P-glycoprotein are prohibited too: systemic ketoconazole, ciclosporin, itraconazole, dronedarone and the combination of glecaprevir with pibrentasvir. The last contraindication is the state following implantation of an artificial heart valve requiring anticoagulant treatment.
Special warnings and precautions
Bleeding on this treatment can begin anywhere, and the product information's main practical piece of advice sounds mundane: an unexplained fall in haemoglobin, haematocrit or blood pressure is a reason to look for the source of bleeding rather than to wait for visible blood. The risk is raised by age 75 and over, moderately reduced kidney function, a low body weight below 50 kg, and anything that raises the plasma concentration of dabigatran. Medicines affecting haemostasis stand apart: acetylsalicylic acid and clopidogrel, non-steroidal anti-inflammatory drugs, and antidepressants of the SSRI and SNRI groups. To protect the stomach the doctor may add a proton pump inhibitor.
Laboratory monitoring is arranged unusually with this medicine. Coagulation does not need to be measured routinely, but where additional risk factors are present, assessing the anticoagulant effect helps to detect an excessive concentration: the international normalised ratio is unreliable on dabigatran and gives falsely raised values, so it should not be measured — that is an outright prohibition, not a recommendation. Of the rest, four situations matter. Before elective surgery the medicine is stopped at least 24 hours beforehand, and where the risk of bleeding is high or the procedure major, 2 to 4 days beforehand. Spinal and epidural anaesthesia and lumbar puncture require full haemostatic function, and after the catheter is removed at least two hours are allowed before the first dose. Where acute renal failure develops, treatment is stopped. And in antiphospholipid syndrome direct oral anticoagulants are not recommended: in patients with triple positivity, thrombotic recurrences on them occur more often than on vitamin K antagonists.
Interaction with other medicines
Dabigatran's interactions are strikingly uniform: it is not metabolised by the cytochrome P450 system and does not itself act on its enzymes, so the usual "hepatic" interactions do not exist for it at all. It is, however, a substrate of the transport protein P-glycoprotein, and almost the whole list comes down to who slows that transporter down and who speeds it up.
- strong P-glycoprotein inhibitors — systemic ketoconazole, ciclosporin, itraconazole, dronedarone, glecaprevir with pibrentasvir — are contraindicated: ketoconazole and dronedarone raise the concentration of dabigatran roughly 2.4-fold;
- moderate and weak inhibitors — amiodarone, quinidine, verapamil, ticagrelor, clarithromycin — call for close observation, and verapamil for a dose reduction as well; because amiodarone is eliminated slowly, the interaction persists for several weeks after it is withdrawn;
- P-glycoprotein inducers should be avoided: rifampicin reduced the concentration of dabigatran by 65.5%, and alongside it the list holds St John's wort, carbamazepine and phenytoin;
- protease inhibitors such as ritonavir are not recommended, since they can behave both as inhibitors and as inducers of P-glycoprotein;
- antiplatelet drugs and anticoagulants raise the risk: in the RE-LY study taking aspirin or clopidogrel at the same time on average doubled the rate of major bleeding, and taking other anticoagulants increased it 2.5-fold;
One interaction is worth knowing with the opposite sign, because it does not interfere with treatment. Pantoprazole reduces the area under the concentration curve of dabigatran by about 30%, but proton pump inhibitors did not affect the efficacy of treatment in clinical studies.
Pregnancy and breastfeeding
The product information begins not with pregnancy but with preventing it: women of childbearing age should avoid becoming pregnant during treatment with dabigatran. There is little data on its use in pregnant women, animal studies showed a harmful effect on reproduction, and the potential risk to humans is unknown, so the medicine is not used in pregnancy unless it is absolutely necessary.
With breastfeeding the wording is firmer than usual: there is no clinical data on the effect of dabigatran on breastfed infants, and breastfeeding should be stopped for the duration of treatment. The data on fertility comes from animals alone: in females at a dose of 70 mg/kg the number of implantations of the fertilised egg fell and its loss before implantation became more frequent, while in males no effect on fertility was found.
Adverse effects
Dabigatran was studied in about 64,000 patients, of whom some 35,000 received the medicine itself, and the frequency of adverse reactions depends heavily on why it was prescribed. After elective hip or knee replacement — that is, on a short course of up to 42 days — reactions occurred in about 9% of patients; in atrial fibrillation with long-term use of up to three years, in 22%; in the treatment of venous thrombosis and pulmonary embolism, in 14%, and in the prevention of their recurrence, in 15%. The commonest event was, predictably, bleeding: about 14% on the short post-operative course, 16.6% in atrial fibrillation and 14.4% in the treatment of venous thrombosis.
Behind those percentages lie mostly small bleeds — from the nose, from the rectum, from haemorrhoids, into the skin, into the urinary tract with blood in the urine — but a major bleed at any site can be life-threatening, can lead to disability and to death, and intracranial haemorrhage is on the list too. Besides bleeding, anaemia and a fall in haemoglobin are common, as are digestive complaints — abdominal pain, diarrhoea, dyspepsia, nausea — and abnormal liver function tests.
Overdose
An overdose of dabigatran means one thing: an increased risk of bleeding. Coagulation tests help to assess it, above all the calibrated quantitative dilute thrombin time test, which makes it possible to tell when the concentration of the medicine will fall to the level required. Since dabigatran is eliminated chiefly by the kidneys, maintaining an adequate urine output matters.
What sets this medicine apart from most anticoagulants is that there are two ways to reverse its effect. Dabigatran binds to proteins weakly, so it can be removed by dialysis. And for adults there is a specific reversal agent, idarucizumab; its efficacy and safety have not been established in children and adolescents, and treatment with dabigatran is resumed 24 hours after idarucizumab is given, provided the patient is stable and haemostasis has been achieved. Where bleeding occurs, the medicine is stopped, its source is looked for, and supportive treatment is given, up to surgical haemostasis and transfusion.
How to get a prescription for Abagat online
With dabigatran everything begins with the kidneys: below a creatinine clearance of 30 ml/min the medicine is contraindicated, between 30 and 50 ml/min the dose is chosen individually, and in older people kidney function is checked at least once a year. A recent test result therefore matters more here than a description of the symptoms. On e-zdrowie.com you fill in a medical questionnaire, the doctor reviews the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and any Polish pharmacy will dispense the capsules against it.
Begin the questionnaire with your creatinine and creatinine clearance and the date of the test, and give your age and body weight: after 80 the dose is reduced as a matter of course, between 75 and 80 the doctor chooses it, and below 50 kg closer observation is needed. Name the diagnosis for which the anticoagulant is needed, and every bleed, ulcer, operation on the brain, spinal cord or eye, and head injury you have had. List the medicines you take: aspirin and clopidogrel, painkillers from the non-steroidal anti-inflammatory group, antidepressants, verapamil, amiodarone, quinidine, ticagrelor, clarithromycin, antifungals and rifampicin — every one of them either changes the dose or closes the medicine off. Report liver disease, an artificial heart valve and antiphospholipid syndrome: these are outright contraindications or grounds for choosing a different treatment. And state any planned operations and dental procedures — the medicine will have to be stopped in advance.
