The European Medicines Agency (EMA) has requested a label update to provide clearer guidance on the safe use of the anticoagulant Pradaxa (dabigatran).

The review has confirmed the drug’s positive benefit-risk balance as a stroke prevention treatment for certain patients, but stated the need for clearer notes on the medicine’s risks and what to do in case of bleeding.

The Boehringer Ingelheim drug is recommended for patients with non-valvular atrial fibrillation or following hip or knee replacement.

Because all blood-thinning drugs can cause bleeding, the EMA has maintained close post-market surveillance of this product.

The EMA’s scientific advisory committee, the CHMP, found that the incidence of fatal bleedings with Pradaxa in post-marketing data was significantly lower than in the clinical trials that led to the drug’s authorisation in 2008.

In November 2011, a safety review concluded that the drug should be used with caution, and at lower doses, with patients who were elderly or had moderate renal impairment.

Pradaxa “remains an important alternative to other blood-thinning agents,” the EMA said.

However, the guidance for doctors and patients should be strengthened to include details of the risks, when the drug must not be used, and how to manage patients if bleeding occurs.

In particular, patients taking Pradaxa should seek urgent medical attention of they fall or suffer any injury.

The European Commission is expected to confirm this opinion.

NICE has recommended Xarelto (rivaroxaban) in final guidance as an option for the prevention of stroke and systemic embolism in people with atrial fibrillation (AF).

The recommendation means patients will get access to the first single tablet, once-daily, oral stroke prevention medicine since the introduction of warfarin in the 1950s

Luis-Felipe Graterol, Medical Director, Bayer HealthCare UK, said the company is “delighted” with NICE’s decision and will now work with local NHS fundraisers to “help evolve services” with Xarelto.

Up to 700,000 people in England and Wales have AF. People with the condition are at a higher risk of developing blood clots and subsequent stroke.

Xarelto is an orally administered drug that helped prevent blood from clotting and has a UK marketing authorisation for the prevention of stroke and system embolism in those with non-valvular AF who have associated risks.

The guidance adds that the decision to swap treatment from warfarin to Xarelto should be discussed between the clinician and patient to highlight any reported risks and benefits.

“We know that some people taking warfarin can find it difficult to maintain their blood clotting at a proper level,” said Professor Carole Longson, NICE Health Technology Evaluation Centre Director. 

“Rivaroxaban, like dabigatran etexilate, which NICE recently approved as an option for this indication, can benefit people with AF. We are therefore pleased to recommend rivaroxaban as another cost-effective option for the prevention of stroke and systemic embolism in people with atrial fibrillation.”

NICE recommended Boehringer Ingelheim’s Pradaxa as a treatment option in final guidance for the same indication back in March.

Boehringer Ingelheim has reduced the UK price of its oral anticoagulant Pradaxa (dabigatran etexilate) by 13%, two weeks after receiving NICE recommendation.

While NICE had judged Pradaxa to be cost-effective for stroke prevention in patients with atrial fibrillation (AF) at £2.52 per day, the new price of £2.20 will increase its appeal to prescribers.

The timing of the price change reflects growing industry awareness that NICE approval is only a step on the way to meeting the value criteria of the NHS.

The final NICE guidance recommended that Pradaxa be considered for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) with one or more risk factors, a potential 900,000 people.

The price drop will help to drive access to the first new oral anticoagulant for stroke prevention in patients with AF in 60 years.

According to a recent BMJ report, drug therapy for stroke prevention in patients with AF is sub-optimal in many cases. Up to 30% receive no treatment, a significant proportion of those treated with warfarin are not well controlled, and treatment with aspirin is not adequate.

There is therefore a large unmet need for effective stroke prevention treatment in these patients, whose risk of stroke may be significantly reduced by Pradaxa.

Duncan Cantor, Boehringer’s Director of Communications, said: “We are committed to working with the NHS to offer the very best value we can. Although NICE deem Pradaxa to be cost effective at £2.52 per day, we believe it is important to make our medicines as affordable as possible in this tough financial climate.

“By lowering the price by 13% to £2.20, the NHS now has every opportunity to make sure this medicine is available to all eligible patients.”

NICE has recommended the use of Pradaxa (dabigatran) as an option for the prevention of stroke and systemic embolism in people with atrial fibrillation (AF) in final guidance.

The treatment is the first new oral-anticoagulant in nearly 60 years to be recommended after NICE concluded it was more effective than warfarin.

Boehringer Ingelheim called the appraisal a “landmark decision”.

The recommendation comes after a failed appeal on the draft guidance by NHS Salford who argued that NICE had failed to act fairly and had exceeded its powers.

It claimed NICE had underestimated the likely use of Pradaxa and that its recommendation would require a design overhaul of anticoagulant services at a PCT level.

But its objections were dismissed on all points by an independent Appeal Panel chaired by NICE’s chair Professor Sir Michael Rawlins.

The guidance recommends Pradaxa as a treatment option in accordance with its licensed indications, and that treatment should start after an informed discussion about its risks and benefits compared with warfarin.

Pradaxa has a UK marketing authorisation for the prevention of stroke and systemic embolism in adults with nonvalvular AF who have previously suffered a stroke, transient ischaemic attack or systemic embolism and other heart related problems. It is also authorised for those aged 65 years old or over with AF who have diabetes, coronary heart disease or hypertension.

It’s estimated that there are around 700,000 people with AF in England and Wales. Boehringer believes that the use of Pradaxa twice daily has the potential to prevent around 530 more strokes per 100,000 compared to warfarin. And, if all eligible patients received Pradaxa twice daily, it could prevent up to 5,000 strokes and save the NHS up to £59 million in the first year of use.

Charles De Wet, Medical Director at Boehringer Ingelheim, said “We are committed to sharing value and our priority and commitment now is to work closely with the Trusts to ensure dabigatran is accessible to all eligible patients on the NHS and appropriately prescribed by clinicians”.

The FDA has delayed making a decision on whether to approve the use of Eliquis (apixaban) for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

Further data supplied by Pfizer and Bristol-Myers Squibb on patient trials after the original application will take an additional three months to review, the Agency has said.

Pfizer and BMS said in a joint statement they will continue to work closely with FDA during the review period.

Eliquis is not yet approved in any country for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

It faces competition from Boehringer’s Pradaxa (dabigatran) and J&J’s Xarelto (rivaroxaban) for the indication.

Industry analysts predict all three have the potential to become ‘blockbuster’ brands as doctors and patients search for an alternative to warfarin.

Eliquis was approved in May 2011 by the European Union as a treatment option for the prevention of blood clots in patients who have undergone hip or knee replacement surgery.

BernsteinResearch analyst Dr Timothy Anderson forecasts total sales of Eliquis to reach $395 million this year, rising to $2.5 billion in 2015 and $3.7 billion by 2020.

The European Medicines Agency (EMA) has reviewed the use of the anticoagulant drug Pradaxa (dabigatran etexilate), taking account of new evidence regarding its serious potential side-effects.

Reported cases of fatal bleeding in users of the drug have led to revisions of the formerly approved EU product information, restricting its use and requiring closer monitoring of at-risk patients.

The updated guidance confirms the safety and efficacy of the drug within the new product guidelines provided by Boehringer Ingelheim in October.

Pradaxa was authorised in March 2008 as a drug for stroke prevention in adults who have had total hip or knee replacement surgery. In August 2011, it was also authorised for stroke prevention in adults with non-valvular atrial fibrillation.

The Agency did not challenge the clinical efficacy of Pradaxa, but needed to examine the manufacturer’s response to recent reports of fatal bleeding in some patients treated with the drug.

Since its initial EU marketing authorisation, Pradaxa’s product information has been changed to recommend: doctors should check for signs of bleeding; the drug should not be used in patients with severe bleeding or severe renal impairment; it should be used with caution and at lower doses in elderly patients and patients with moderate renal impairment.

In October 2011, the Agency's Committee for Medicinal Products for Human Use (CHMP) responded to further reports of fatal bleeding by recommending that renal function should be assessed in all patients before starting treatment with Pradaxa, and then at least once a year in patients over 75 years old or with a suspected decline in renal function.

A worldwide total of 256 cases of fatal bleeding related to the use of Pradaxa has been recorded, though the CHMP noted that more widespread use of the drug has increased the number of such incidents.

The CHMP concluded that the recommended changes to the use of Pradaxa will adequately manage the risks.

NICE has recommended Boehringer Ingleheim’s Pradaxa (dabigatran) for the prevention of stroke and systemic embolism in people with atrial fibrillation (AF) in final draft guidance.

The positive recommendation follows the disclosure of further information from Boehringer that had been requested on a number of areas, including its cost effectiveness and use in clinical practice.

Professor Carole Longson, NICE Health Technology Evaluation Centre Director, says the medication “represents a significant potential benefit for many people with AF”.

Questions were initially raised by NICE’s Independent Appraisal Committee over the cost to the NHS and a “more plausible set of assumptions” on Pradaxa’s use were required from Boehringer.

But NICE says it is “pleased” the additional information and analysis it received has enabled the Committee to recommend the treatment as a cost-effective use of NHS resources.

“The Independent Appraisal Committee accepted evidence that showed dabigatran 150mg twice daily is more clinically effective than warfarin in reducing the risk of stroke or systemic embolism, and that dabigatran 110mg twice daily is as effective as warfarin. However, there were a number of uncertainties relating to the drug’s cost-effectiveness in the original evidence submission from the manufacturer which required clarification,” said Professor Longson.

Dr Charles de Wet, Medical Director at Boehringer Ingelheim, welcomed the revised decision by NICE. “Pradaxa is the first new oral anticoagulant in 50 years and we are committed to working closely with the NHS to ensure appropriate prescribing in suitable patients with AF who are at risk of stroke,” he said.

Pradaxa has a UK marketing authorisation for the prevention of stroke and systemic embolism in patients aged 75 years with AF who have had a previous stroke, heart attack or systemic embolism.

It is also authorised for people with AF over 65 who have diabetes, coronary heart disease or hypertension.

Final guidance is now expected to be published next month.

NICE has requested more information from Boehringer Ingelheim on Pradaxa (dabigatran) for the prevention of stroke and systemic embolism in people with atrial fibrillation (AF).

The Institute’s independent Appraisal Committee is seeking clarification on a number of areas, in particular over its cost effectiveness, during preliminary recommendations.

Dr Gillian Leng, NICE Deputy Chief Executive and Chief Operating Officer for NHS Evidence, says a “more plausible set of assumptions” during Pradaxa’s use in clinical practice is needed.

Pradaxa has a UK marketing authorisation for the prevention of stroke and systemic embolism in patients aged 75 years with AF who have had a previous stroke, heart attack or systemic embolism.

It is also authorised for people with AF over 65 who have diabetes, coronary heart disease or hypertension.

NICE says that Pradaxa “may have potential benefits” for people with AF, and that evidence has shown it to be more clinically effective than warfarin, but additional information on its cost to the NHS is required.

“In particular it (NICE’s Appraisal Committee) is seeking clarification on the cost effectiveness of the licensed regimen, in which people aged under 80 years begin treatment with dabigatran 150mg twice daily, and at age 80 years switch to dabigatran 110mg twice daily,” said Dr Leng.

Final guidance is now expected to be published in December.