DABIGATRAN PART 1/3

Dabigatran (Pradaxa in Australia, Canada, Europe and USA, Prazaxa in Japan) is an oral anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in some cases it offers an alternative towarfarin as the preferred orally administered anticoagulant (“blood thinner”) since it cannot be monitored by blood tests forinternational normalized ratio (INR) monitoring while offering similar results in terms of efficacy. There is no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,^[2][3] unlike warfarin,^[4] although a potential dabigatran antidote (pINN: idarucizumab) is undergoing clinical studies.^[5] It was developed by the pharmaceutical company Boehringer Ingelheim.

Medical uses

Dabigatran is used to prevent strokes in those with atrial fibrillation (afib) due to non heart valve causes, as well as deep venous thrombosis (DVT) and pulmonary embolism (PE) in persons who have been treated for 5–10 days with parenteral anticoagulant (usually low molecular weight heparin), and to prevent DVT and PE in some circumstances.^[6]

It appears to be as effective as warfarin in preventing nonhemorrhagic strokes and embolic events in those with afib not due to valve problems.^[7]

Contraindications

Dabigatran is contraindicated in patients who have active pathological bleeding since dabigatran can increase bleeding risk and can also cause serious and potentially life-threatening bleeds.^[8] Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g. anaphylaxis or anaphylactic shock).^[8] The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valve due to the increased risk of thromboembolic events (e.g. valve thrombosis, stroke, and myocardial infarction) and major bleeding associated with dabigatran in this population.^[8][9][10]

Adverse effects

The most commonly reported side effect of dabigatran is GI upset. When compared to people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of GI bleeding was significantly higher. Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. The lower pH has previously been associated with dyspepsia; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding.^[11]

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.^[12]

Reduced doses should be used in those with poor kidney function.^[13]

Pharmacokinetics

Dabigatran has a half-life of approximately 12-14 h and exert a maximum anticoagulation effect within 2-3 h after ingestion.^[14] Fatty foods delay the absorption of dabigatran, although the bio-availability of the drug is unaffected.^[1] One study showed that absorption may be moderately decreased if taken with a proton pump inhibitor.^[15] Drug excretion through P-glycoprotein pumps is slowed in patients taking strong p-glycoprotein pump inhibitors such as quinidine, verapamil, and amiodarone, thus raising plasma levels of dabigatran.^[16]

History

Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin, but also trypsin. Addition of ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed prodrug, BIBR 1048 (dabigatran etexilate).^[17]

On March 18, 2008, the European Medicines Agency granted marketing authorisation for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery and for non-valvular atrial fibrillation.^[18]

The National Health Service in Britain authorised the use of dabigatran for use in preventing blood clots in hip and knee surgery patients. According to a BBC article in 2008, Dabigatran was expected to cost the NHS £4.20 per day, which was similar to several other anticoagulants.^[19]

Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,^[20] for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery. Approval for atrial fibrillation patients at risk of stroke came in October 2010.^[21][22]

The U.S. Food and Drug Administration (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.^{[23][24][25][26]} The approval came after an advisory committee recommended the drug for approval on September 20, 2010^[27] although caution is still urged by some outside experts.^[28]

On February 14, 2011, the American College of Cardiology Foundation and American Heart Association added dabigatran to their guidelines for management of non-valvular atrial fibrillation with a class I recommendation.^[29]

In May 2014 the FDA reported the results of a large study comparing dabigatran to warfarin in 134,000 Medicare patients. The Agency concluded that dabigatran is associated with a lower risk of overall mortality, ischemic stroke, and bleeding in the brain than warfarin. Gastrointestinal bleeding was more common in those treated with dabigatran than in those treated with warfarin. The risk of heart attack was similar between the two drugs. The Agency reiterated its opinion that dabigatran’s overall risk/benefit ratio is favorable.^[30]

On July 26, 2014, the British Medical Journal (BMJ) published a series of investigations that accused Boehringer of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. Review of internal communications between Boehringer researchers and employees, the FDA and the EMA revealed that Boehringer researchers found evidence that serum levels of dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require monitoring.^[31][32]

Research

In August 2015, an article found that idarucizumab was able to reverse the anticoagulation effects of dabigatran within minutes.^[33]

References

Dabigatran etexilate

Systematic (IUPAC) name
Ethyl N-[(2-{[(4-{N‍ ’​-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl]-N-2-pyridinyl-β-alaninate
Clinical data
Trade names	Pradaxa, Pradax, Prazaxa
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	CA: Schedule VI UK: Prescription-only (POM) US: ℞-only
Routes of administration	oral
Pharmacokinetic data
Bioavailability	3–7%[1]
Protein binding	35%[1]
Biological half-life	12–17 hours[1]
Identifiers
CAS Registry Number	211915-06-9
ATC code	B01AE07
PubChem	CID: 6445226
DrugBank	DB06695
ChemSpider	4948999
ChEMBL	CHEMBL539697
Chemical data
Formula	C34H41N7O5
Molecular mass	627.734 g/mol

External links

• Pradaxa.com. Boehringer Ingelheim.
• dabigatran.com. Boehringer Ingelheim.
• Pradaxa For U.S. Health Care Professionals. Boehringer Ingelheim.
• Pradaxa Prescribing Information. Boehringer Ingelheim.
• Pradaxa Medication Guide. Boehringer Ingelheim.
• Dabigatran. MedlinePlus. United States National Library of Medicine (NLM).
• Dabigatran. Drug Information Portal. United States National Library of Medicine (NLM).

The chemical name for dabigatran etexilate mesylate, a direct thrombininhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The empirical formula is C₃₄H₄₁N₇O₅ • CH₄O₃S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:

Dabigatran etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.

The 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, and the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. The capsule shell is composed of carrageenan, FD&C Blue No. 2 (150 mg only), FD&C Yellow No. 6, hypromellose, potassium chloride, titanium dioxide, and black edible ink. The 75 mg capsule contains 86.48 mg dabigatran etexilate mesylate, equivalent to 75 mg dabigatran etexilate, and is otherwise similar to the 150 mg capsule.

/////////Dabigatran, Pradaxa