Bleeding rates raise questions about Pradaxa dosing in elderly
This article was originally published in Scrip
Further data on bleeding rates with Boehringer Ingelheim's direct thrombin inhibitor Pradaxa (dabigatran) in the elderly in the US have raised concerns over the one-size-fits-all dose regimen approved by the FDA.
The data from the US non-profit Institute for Safe Medication Practices' QuarterWatch adverse event surveillance programme show that in the first quarter of 2011, there were 505 cases of haemorrhage associated with the drug, more than any other monitored drug including warfarin (which ranked second with 176 cases during the three months). Of these 505 cases, 120 appeared to be haemorrhagic stroke, the ISMP said, "which is particularly problematic given that the drug's primary indication is to prevent ischaemic strokes".
The haemorrhage-related adverse events occurred mainly in elderly patients, with a median age of 80, and a quarter were 84 years or older, raising the question of safe dosing and monitoring in elderly patients.
Pradaxa was approved in the US in late 2010 for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation with one or more risk factors, putting it ahead of its rival new anticoagulants in the race to bring warfarin alternatives to the market there for this patient population.
The approval was based on the RE-LY trial, a non-inferiority study comparing Pradaxa to warfarin, which showed that Pradaxa reduced the risk of stroke and systemic embolism by 35% beyond that achieved with warfarin. This study found that bleeding rates were about the same in the warfarin and 150mg Pradaxa dose arms, but there was significantly lower life-threatening and intracranial bleeding with both the 150mg and 110mg Pradaxa doses tested than for warfarin.
Although the lower 110mg dose was approved in the EU, Canada and Japan, this was rejected by the FDA in favour of the 150mg dose, which is standard for all patients except for a small subset with severe renal impairment in whom the approved dose is 75mg. The US approval did come with a medication guide informing patients about the bleeding risks with the product.
The ISMP notes that renal impairment is common in the elderly and that even moderate impairment could result in dabigatran blood levels three times higher than in patients with normal kidney function. "We believe FDA and the manufacturer should re-evaluate dosing in the elderly or those with moderate renal impairment to determine optimal dosing and monitoring requirements," it said.
There are two factors could give some explanation of the high levels of bleeding seen in elderly patients with Pradaxa: firstly, new drugs are always subject to greater scrutiny and therefore higher reporting rates; and secondly, given the difficulties in using warfarin in the elderly patients, more could have been prescribed Pradaxa who would otherwise not have received any anticoagulant treatment.
Boehringer Ingelheim told Scrip Intelligence that it was not surprised by the reports: "Spontaneous reports of serious and fatal bleeding are lower than what could have been expected from the results seen in the pivotal RE-LY trial, which is reassuring.
"The cases reported by QuarterWatch are in line with the cases from Boehringer Ingelheim's adverse drug reactions database. Boehringer Ingelheim closely monitors Pradaxa worldwide and has provided all global adverse event data collected to date to US FDA and other regulatory agencies. Apart from that Boehringer Ingelheim plans regular publications on the Internet accessible to all healthcare personnel of severe side-effects that occur under treatment with Pradaxa in order to objectify the discussion. This will start in the next few weeks."
Boehringer Ingelheim said it continued to discuss the US Pradaxa label with the FDA to assure that Pradaxa is used appropriately following the approved label, but declined to comment on whether it would again seek approval of the 110mg dose.
Overall, Boehringer Ingelheim said it "did not see a change in the favourable benefit/risk profile of Pradaxa in its approved indications, with the effectiveness and safety of the novel treatment proven and well-documented in an extensive clinical trial programme".
In November 2011, the EMA said it would update the safety information for the drug following reports that 256 patients had died due to serious bleeding- but it noted that the deaths had occurred following increased uptake of the drug when the stroke prevention indication was approved (Pradaxa was approved earlier in the EU for surgical settings).