HSA would like to update healthcare professionals on the association of venous and arterial thromboembolic events with lenalidomide and thalidomide.
Thalidomide is an immunomodulatory agent with anti-angiogenic and anti-neoplastic properties. It is licensed in some countries for use in combination with dexamethasone or melphalan and prednisone in patients with multiple myeloma (MM). Although thalidomide is not registered locally, it had been made available on a named-patient basis for patients who have been assessed to have no suitable therapeutic alternatives.
Lenalidomide (Revlimid®, Celgene), a thalidomide analogue, has been licensed locally since June 2009 for use in combination with dexamethasone for the treatment of MM in patients who have received at least one prior therapy. In view of its potential teratogenic effects, the **RevAssure Programme1 was implemented at the point of product licensure to minimise the risk of foetal exposure. Under this programme, healthcare professionals are required to fulfill certain conditions such as the need to obtain the patient's written informed consent to confirm their understanding of the risks associated with Revlimid®, provide appropriate counselling on effective contraception methods and to rule out pregnancy in women of childbearing potential before prescribing and dispensing Revlimid® .
** Complete details of the RevAssure programme can be obtained from Celgene Pte Ltd
Post-marketing data on venous and arterial thromboembolism
Although MM is an independent risk factor for thromboembolic complications, there has been evidence from post-marketing reports that both thalidomide and lenalidomide may further increase the risk of venous and arterial thromboembolic reactions in patients with MM.2-4
(A) Thalidomide
From a recent review of overseas post-marketing data, it was observed that patients treated with thalidomide had an increased risk of arterial thromboembolism, in addition to the established risk of venous thromboembolism.
Approximately one third of all thromboembolic reactions reported in association with thalidomide were of arterial origin. The majority of these thromboembolic events were arterial MI (54.2%) or cerebrovascular events (19.8%).2,4
Although the mechanisms involved in the pathogenesis of arterial thromboses remain unknown, the risk appears to be the greatest during the first five months of treatment. In addition, most patients presenting with venous or arterial thromboembolic events in association with thalidomide treatment have identifiable risk factors for thromboembolism.
(B) Lenalidomide
The combination of lenalidomide and dexamethsaone has also been associated with an increased risk of venous and arterial thromboembolism (predominantly deep vein thrombosis, pulmonary embolism, MI and cerebrovascular accident).3
A review of the Celgene pharmacovigilance database found that a total of 493 medically confirmed reports of arterial thromboembolic events associated with lenalidomide have been received. These reports showed a predominance of cardiac events (65% of reports) and 17% of the reports were contributed by cerebral vascular events, including transient ischaemic attacks. While a causal relationship between lenalidomide and arterial thromboembolic events cannot be excluded, the predisposing factors and mechanisms leading to MI have not been identified.
Of note was that majority of the patients with venous (>80%) and arterial (>60%) thromboembolic events were not documented to have received thromboprophylaxis. In addition, most of the patients with medically confirmed venous thromboembolic events had risk factors predisposing them to such events.
Local situation
As of 6 June 2011, HSA has received one suspected report of MI associated with the use of lenalidomide. This occurred in an 87 year-old female who had developed two episodes of non-ST elevation MI (NSTEMI) while taking lenalidomide for the treatment of MM. The patient first developed breathlessness due to pulmonary oedema caused by NSTEMI. The MI event was reported to have resolved following treatment and therapy with lenalidomide was continued. About a month later, the patient was re-admitted to hospital for life-threatening NSTEMI accompanied by acute pulmonary oedema and shortness of breath.
The local package insert for Revlimid® is being revised to include risk of arterial thromboembolism, in addition to the existing warning of the increased risk of venous thromboembolism associated with the use of the product.
HSA's advisory
Healthcare professionals are advised to take into consideration the above safety information, the presence of venous and arterial thromboembolic risk factors (eg, smoking, hypertension, hyperlipidaemia) as well as the need for thrombo-prophylaxis, when evaluating if their patients are suitable for treatment with thalidomide or lenalidomide.
Healthcare professionals are also advised to closely monitor their patients for signs and symptoms of thromboembolism and to inform their patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Healthcare professionals are encouraged to report suspected cases of venous or arterial thromboembolic events associated with the use of thalidomide and lenalidomide to the Vigilance Branch of HSA.
References
- https://www-hsa-gov-sg.cwp.sg/announcements/safety-alerts/compliance-to-the-safety-monitoring-protocols-of-the-revassure-programme-of-lenalidomide-(revlimid-)
- Direct Healthcare Professional Communication on the association between Thalidomide CelgeneTM (thalidomide) and thromboembolism. http://www.imb.ie/images/uploaded/documents/DHPC%20Association%20betweeen%20Thalidomide%20Celgene%20and%20thromboembolism.pdf
- Direct Healthcare Professional Communication on the association of Revlimid® (lenalidomide) with venous and arterial thromboembolic events.
http://www.imb.ie/images/uploaded/documents/Revlimid%20-%20Jan%202011%20for%20Website.pdf
- http://www.afssaps.fr/Infos-de-securite/Lettres-aux-professionnels-de-sante/Thalidomide-Celgene-R-thalidomide-et-risque-d-evenements-thromboemboliques-arteriels-Lettre-aux-professionnels-de-sante