The thrombolysis taskforce of the European Stroke Organisation (ESO) executive committee has provided an update on current shortages of alteplase and tenecteplase, detailing outcomes from a recent meeting with Boehringer Ingelheim (BI)—the company that markets both drugs in Europe—and correspondence with the European Medicines Agency (EMA).
In its third letter to date on these supply shortages—which have impacted much of Europe and other countries around the world—the ESO states that, in August 2022, the German Federal Institute for Drugs and Medical Devices (BfArM) approved a variation for an optimised drug substance manufacturing process that will lead to a higher yield of alteplase.
Several measures for healthcare institutions to follow on alteplase allocation have already been introduced in cooperation with the EMA and national health authorities, the letter notes. Many of these have been detailed in prior ESO statements released earlier in 2022—including localising storage; setting inventory targets; ensuring the correct dosages are present; establishing communications with pharmacy providers; and networking with local emergency services.
“Follow the information regarding extension of the shelf life of thrombolytic agents, and be prepared to use the 10mg and 20mg vials instead of the 50mg vials, when available/introduced in your country, so to avoid waste through leftovers,” the letter also advises.
More medium- and long-term plans include the introduction of an additional alteplase production facility, which is expected to be submitted for a variation application in Q2 2024, as well as the registration of a new indication of tenecteplase for patients with acute ischemic stroke—which BI is currently discussing with the EMA.
Furthermore, in its recent letter, the ESO reports that—as of November 2022—BI foresees a worldwide increase in Actilyse (the brand name under which the company sells alteplase in Europe) allocation in 2023, as compared to 2022.
EMA correspondence
In the second part of its letter, penned on 19 December, the ESO shares an update on recent communications with the EMA, under which it advocated the emergency approval of Activase (the product name under which Genentech markets alteplase in North America) in the European Union (EU). Activase is currently registered in the USA and Canada, and indicated for treating acute ischaemic stroke within three hours of symptom onset.
Having made this outreach in October, the ESO says it received a reply on 29 November in which the EMA initially said it is “aware of this critical shortage” and is in a “continuous exchange” with national competent authorities (NCAs) across Europe, and BI. This shortage “has been given the highest priority”, it further detailed.
“[The] EMA has explored options of dealing with the shortage, which include importing medicinal products from other countries outside [the] EU/EEA [European Economic Area],” the ESO letter relays. “There is no additional product (Activase) available from the USA/Canada markets. Furthermore, [the] EMA explained, should Activase become available, NCAs can import the product without the need for an emergency approval with necessary support from [the] EMA.”
The EMA further stated that “there are no products from other regions of the world”, in addition to acknowledging that—while ‘bio-copies’ may currently be in use—it has not been able to evaluate these products “as respective dossiers are not made available to [the] EMA”.
Lastly, its response to the ESO details efforts to mitigate these shortages via regular supply and demand monitoring, and overseeing the distribution process in cooperation with NCAs and BI; and supporting increased production needs by expediting the regulatory review and approval of critical manufacturing changes.
The third and final salient point outlined by the ESO is that its upcoming, expedited recommendations for the use of tenecteplase in acute ischaemic stroke are currently under review in the European Stroke Journal.
How did we get here?
BI first alluded to the increase in global demand for alteplase, and resulting manufacturing capacity constraints, in an April 2022 announcement, before also predicting tenecteplase shortages in August. While both drugs are approved for treating myocardial infarction (MI) across North America and Europe, alteplase is also the gold standard in intravenous thrombolysis (IVT) for ischaemic stroke, and tenecteplase’s utility for this indication is currently being explored via clinical trials too.
A National Patient Safety Alert put out by the UK Department of Health and Social Care (DHSC) at the time noted that, while medications like streptokinase and urokinase offer valid alternatives for other indications—such as pulmonary embolism, limb-threatening ischaemia and MI—suitable stand-in options are much more limited in stroke care.
“Only alteplase is licensed for the treatment of ischaemic stroke,” the alert stated. “Stroke teams may also have experience of using tenecteplase from participation in clinical trials, though this would be an unlicensed use. Mechanical thrombectomy is also used to treat some patients with acute ischaemic stroke but should be used in conjunction with alteplase in the majority of patients. There are no other therapeutic options for the treatment of acute ischaemic stroke.”
As such, the alert emphasised the need to reserve alteplase stocks for acute ischaemic stroke patients, owing to the “significant risk of harm” without receipt of treatment.
While alteplase supplies are now predicted to recover in 2023, greater uncertainty remains regarding its new-generation counterpart, tenecteplase. The EMA advised in September 2022 that—with supply shortages expected to continue into 2024—the drug’s shelf-life would be extended from 24 to 36 months, and a new manufacturing site would be set up over the next three years to meet the growing demand.
“In the meantime, healthcare professionals should use existing supplies in the most efficient way possible,” the EMA statement read. “This means using them only for patients within the approved indications and avoiding disposal of unused supplies.”
Elsewhere in the world, a previous, jointly released statement from the Australian Therapeutic Goods Administration (TGA) anticipated tenecteplase shortages extending “until the end of 2023”. A Medicine Availability Working Group led by the TGA further agreed that usage of the drug “must be reduced by at least 35% nationally, or tenecteplase stock will be exhausted in Australia by the end of 2022”, and advised implementing similar approaches to its European equivalents—including prioritisation of tenecteplase for pre-hospital thrombolysis; increased use of alteplase in metropolitan and larger regional hospitals to conserve tenecteplase; and a 12-month extension to the shelf-life of certain tenecteplase batches.
In July 2022, the ESO released the first of its three letters pertaining to current alteplase and tenecteplase supply difficulties, describing the causes of these shortages and announcing the establishment of a thrombolysis taskforce. It also noted at the time that the situation “may not be the same in all European countries”.
In its second letter, dated September of this year, the ESO said shortages were anticipated to last into 2024—but also detailed a number of measures being taken by BI to tackle the issue, including prioritising production of Actilyse versus Metalyse (tenecteplase); introducing measures to reduce wasted alteplase while maintaining a consistent total production quantity; working with EU health authorities towards a shelf-life extension on specific batches of tenecteplase; and establishing a fair and equitable allocation process, worldwide, and on national levels.
As per the results of small-scale survey involving stroke society representatives from 22 European countries, the ESO also concluded in September that, “overall, the situation is regarded as stable and action plans have been installed in most participating countries”, before conceding that there are still “some countries where there is insufficient communication and supply”.
