Medicines and Healthcare products Regulatory Agency (MHRA) announces the risk of aneurysm and artery dissection associated with the use of systemically administered vascular endothelial growth factor (VEGF) pathway inhibitors.
A recent European review concluded that all systemically administered VEGF pathway inhibitors may promote the formation of aneurysm and artery dissection. The product information for all systemically administered VEGF pathway inhibitors has been updated to include a warning about the risk of aneurysm and artery dissection and to recommend carefully considering these risks before initiating in patients with risk factors, such as hypertension. Patients who receive a systemic VEGF pathway inhibitor should be monitored and treated for hypertension in accordance with recommendations in the Summary of Product Characteristics for the relevant systemic VEGF pathway inhibitor. Action should also be considered for other modifiable risk factors such as smoking. The patient information leaflet for all products will also include advice for patients to inform their doctor or nurse if they have had a previous aneurysm or dissection.
Before the latest safety review, the product information of four systemic VEGF pathway inhibitors included aortic dissection (Kisplyx▼ and Lenvima▼), aneurysm rupture (Inlyta), or aortic aneurysm and dissection (Sutent) as side effects. In addition, the product information for all systemic VEGF pathway inhibitors already described the risk of hypertension, which is an important predisposing factor for artery dissection and aneurysm.
As part of the review, a search of the European database of worldwide reports of suspected adverse drug reactions identified 660 case reports of aneurysm or artery dissection for VEGF pathway inhibitors up to 31 Dec 2018. The most frequently reported adverse events were aortic dissection (n=163), aneurysm (n=146), retinal aneurysm (n=93), aortic aneurysm (n=89), ruptured aortic aneurysm (n=43), intracranial aneurysm (n=34) and aneurysm ruptured (n=31). Fatal cases have been reported, mainly in relation to aortic aneurysm rupture and aortic dissection. Of the 529 case reports where medical history was available, most (74%) reported risk factors, most commonly hypertension (49%). Other risk factors reported included diabetes mellitus, hypercholesterolaemia or hyperlipidaemia, a previous history of aortic aneurysm, cardiovascular disease and tobacco use. Aortic dissection and aortic aneurysm were more frequently reported in older patients (aged 65 years or older).
Based on the available data it is difficult to estimate the magnitude of the risk of aneurysm and artery dissection with systemic VEGF pathway inhibitors, therefore the risk of these adverse reactions is included in the product information with a frequency category of not known. Clinical trial data suggest that the frequency of artery dissection and aneurysm in patients receiving systemic VEGF pathway inhibitors ranges from rare (0.02% of participants) to uncommon (0.15% of participants exposed). The data do not allow for differentiation in the risk of artery dissection and aneurysm between the different systemic VEGF pathway inhibitors and clinical trial data were not available for 6 products.
The mechanism by which systemically administered VEGF pathway inhibitors can cause aneurysm or artery dissection is unclear but may be due to impairment of vascular wall integrity as well through hypertension or aggravation of pre-existing hypertension. Aortic dissection is a rare but life-threatening event with an estimated annual incidence of between 2.9 to 3.5 cases per 100,000 people.1 It is usually accompanied by sudden, severe abdominal, chest, or back pain. Most abdominal aortic aneurysms are asymptomatic, and it is therefore difficult to establish their prevalence, however a national screening programme in the United Kingdom that enrols men at age years 65 years suggests a prevalence of about 1.3% in this population. The most common symptom of a ruptured aortic aneurysm is sudden and severe pain in the abdomen or back. Ruptured aortic aneurysms are associated with a high mortality rate.
The risk of artery dissection or aortic aneurysm is increased in the presence of risk factors such as hypertension, diabetes mellitus, family history of aneurysm, coronary, cerebrovascular or peripheral arterial disease, tobacco use and hyperlipidaemia. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease and the use of fluoroquinolones are also risk factors.
Systemically administered VEGF pathway inhibitors authorised in the United Kingdom include: Avastin, Zirabev▼ and Mvasi▼ (bevacizumab); Caprelsa▼ (vandetanib); Cabometyx▼ and Cometriq▼ (cabozantinib); Cyramza (ramucirumab); Fotivda▼ (tivozanib); Iclusig▼ (ponatinib); Inlyta (axitinib); Kisplyx▼ and Lenvima▼ (lenvatinib); Nexavar (sorafenib); Ofev and Vargatef (nintedanib); Stivarga (regorafenib); Sutent (sunitinib); Votrient (pazopanib); and Zaltrap (aflibercept).
The review concluded that there was insufficient evidence to determine that these risks apply to the two VEGF pathway inhibitors that are administered by intravitreal injection, ranibizumab (Lucentis) and aflibercept (Eylea).
Healthcare professionals are advised:
- Use of systemically administered VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms or artery dissections.
- Aneurysms or artery dissections are thought to occur infrequently in patients taking systemic VEGF pathway inhibitors, but some fatal cases have been reported, mainly in relation to aortic aneurysm rupture and aortic dissection.
- Before initiating a systemic VEGF pathway inhibitor, carefully consider the risk of aneurysm and artery dissection in patients with risk factors such as hypertension, history of aneurysm, smoking, diabetes mellitus, coronary, cerebrovascular or peripheral arterial disease, and hyperlipidaemia; other risk factors include Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, and the use of fluoroquinolones.
- In patients who receive a systemic VEGF pathway inhibitor, reduce as far as possible any modifiable risk factors such as smoking and hypertension.
- Monitor patients for and treat hypertension in accordance with recommendations in the Summary of Product Characteristics for the relevant systemic VEGF pathway inhibitor.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/systemically-administered-vegf-pathway-inhibitors-risk-of-aneurysm-and-artery-dissection
In Hong Kong, there are registered pharmaceutical products for systemic administration containing bevacizumab (6 products), vandetanib (2 products), cabozantinib (3 products), ramucirumab (2 products), ponatinib (2 products), axitinib (2 products), lenvatinib (2 products), sorafenib (3 products), nintedanib (4 products), regorafenib (1 product), sunitinib (4 products), pazopanib (4 products) and aflibercept (1 product). All products are prescription-only medicines. There is no registered pharmaceutical product containing tivozanib.
Related news was previously issued by Health Canada and Singapore Health Sciences Authority, and was posted on the Drug Office website on 4 Dec 2018 and 31 Jul 2020 respectively. Letters to inform local healthcare professionals were issued by the Department of Health (DH) on 4 Dec 2018. In Sep 2019, the Registration Committee of the Pharmacy and Poisons Board discussed the matter and decided to remain vigilant on safety update issued by other overseas drug regulatory authorities.
So far, the DH has received cases of adverse drug reaction related to bevacizumab (62 cases), vandetanib (1 case), cabozantinib (19 cases), ramucirumab (14 cases), ponatinib (1 case), axitinib (26 cases), lenvatinib (6 cases), sorafenib (16 cases), nintedanib (2 cases), regorafenib (31 cases), sunitinib (9 cases), pazopanib (7 cases) and aflibercept (7 cases), but these cases are not related to aneurysm or artery dissection.
In light of the above MHRA’s announcement, the matter will be further discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Saturday, Aug 1, 2020
Issued at HKT 13:30
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