Safety Alerts
Update on strontium ranelate (Protos®): Risk of cardiac events and enhancing awareness of the local risk management plan to mitigate the risk of serious skin reactions
31 December 2013
Audiences
Healthcare professional
Industry member
Product-type
Therapeutic Products
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HSA would like to update healthcare professionals on two issues related to strontium ranelate (Protos®, Servier (S) Pte Ltd): (1) Risk of cardiac events raised by the European Medicines Agency (EMA); and (2) Enhancing awareness of the local risk management plan (RMP) to mitigate the risk of serious skin reactions.
Protos® is indicated locally for the treatment of severe osteoporosis in postmenopausal women at high risk for fracture to reduce the risk of vertebral and hip fractures.
(1) Risk of cardiac events
Background
In April 2013, the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of strontium ranelate as part of a routine benefit-risk assessment of the drug and concluded that there was an increased risk of myocardial infarction and other cardiac events in patients taking strontium ranelate.1 This was in addition to the earlier recognised risk of venous thromboembolism that had been previously identified from Phase III clinical trials.2
A review of the pooled data from randomised studies in around 7,500 post-menopausal women with osteoporosis showed an increase in the risk of myocardial infarction with strontium ranelate (1.7%) as compared with placebo (1.1%), with a relative risk of 1.6 (95% CI 1.07, 2.38). There was also an imbalance in the number of serious cardiac events seen with the drug in two other studies, one in men with osteoporosis and another in patients with osteoarthritis. However, no increased risk in mortality was observed.3
The PRAC concluded that certain restrictions in the use of the drug should be put in place to ensure that its benefit-risk balance remains favourable. The Committee recommended the use of strontium ranelate be restricted to severe osteoporosis in postmenopausal women at high risk of fracture and severe osteoporosis in men at increased risk of fracture.3 In addition, several measures were taken in the European Union to minimise the risk of cardiac events until a full evaluation is completed by the EMA, such as contraindicating the use of strontium ranelate in patients with current or past history of cardiovascular diseases and closely monitoring patients for such events during treatment.
Local situation and actions taken
As of end-September 2013, HSA has received 97 adverse event reports associated with strontium ranelate, none of which was related to cardiac events. The majority of the reports (90%) described hypersensitivity reactions. The local safety concern was primarily related to serious skin reactions.
Following the review by EMA, HSA had strengthened the local package insert (PI) to restrict the use of strontium ranelate to postmenopausal women with severe osteoporosis who were at high risk of fracture. The use of strontium ranelate in men is not an approved indication in Singapore.
The local PI had also been updated with measures to mitigate the risk of cardiac events. These measures included3:
Treatment with strontium ranelate should only be started by a physician experienced in the treatment of osteoporosis.
Strontium ranelate is contraindicated in patients with a current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease, or in patients with uncontrolled hypertension.
Physicians should base their decisions to prescribe strontium ranelate on an assessment of the individual patient's risks. The patient's risk of developing cardiovascular disease should be evaluated before and at regular intervals during treatment.
Treatment should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease or cerebrovascular disease, or if hypertension becomes uncontrolled.
In addition, the local Patient Medication Guide (PMG) had been updated with information on cardiac events. A Dear Healthcare Professional Letter (DHCPL) dated 1 August 2013 was issued by Servier to update healthcare professionals about the latest safety development and changes to the local PI.
(2) Enhancing awareness of the local RMP to mitigate the risk of serious skin reactions
Background
Following an increase in number of local reports of serious skin reactions observed with strontium ranelate, HSA, in consultation with its Product Vigilance Advisory Committee (PVAC), implemented a RMP to mitigate the risk of occurrence of serious skin reactions locally.4 The components of the RMP included strengthening of the local PI to include information on the higher risk of serious skin reactions in the Asian population, the development of a PMG to alert patients to the signs and symptoms of serious skin reactions, and collection of data to allow an estimate of the number of patients newly started on Protos®. For the latter, Servier regularly provides HSA with an estimated number of new patients on strontium ranelate collected through a “Patient Care Program (PCP)”* initiated by the company in March 2013.
* The PCP is managed by the company to support new patients in the close monitoring of adverse reactions following Protos® treatment. Enrolment of patients into this programme is on a voluntary basis.
Additional requirement for company to obtain signed acknowledgment from doctors before supply to clinics
As HSA continued to receive reports of Stevens-Johnson syndrome (SJS) and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) (1 case of each) from April to May 2013, bringing the total number of cumulative reports to eight for SJS or toxic epidermal necrolysis (TEN) and four for DRESS since 2006, a second review on the benefit-risk profile of strontium ranelate was initiated in August 2013 in consultation with its PVAC and experts from endocrinology, rheumatology and orthopaedics. The review concluded that strontium ranelate continues to have a role in therapy and the measures to address the risk of cardiac events are adequate. However, there is a need to further enhance the awareness of healthcare professionals and patients regarding the risk of serious skin reactions associated with strontium ranelate.
As part of a new licensing condition to the company, HSA has required that with effect from 1 January 2014, Servier will need to obtain the signed acknowledgement from doctors that they are aware of the risk of serious skin reactions and that they have received the PMG for distribution to their patients before the company can supply strontium ranelate to the respective clinics and hospitals. Of note is that the enrolment of patients into the PCP is an initiative by the company and it is a voluntary participation on the part of doctors to enrol their patients into the programme. A HSA DHCPL will be disseminated to healthcare professionals who have yet to provide acknowledgement of their awareness of the RMP and receipt of the PMG.
HSA's advisory
As a risk management measure to minimise the risk of serious skin reactions associated with the use of strontium ranelate, HSA strongly encourages doctors who have yet to sign the acknowledgement form to follow up accordingly with Servier. No further action is required of the doctors who have already signed the letter of acknowledgement.
Healthcare professionals are advised to continue close monitoring of their patients for serious adverse events such as cardiac events and early signs of serious skin reactions. In addition, healthcare professionals are reminded of the new restricted indication and recommendations outlined above to mitigate the risk of cardiac events. As HSA continues to monitor the safety of the drug closely, healthcare professionals are encouraged to report any adverse events associated with strontium ranelate to the Vigilance Branch of HSA.
References
Singapore package insert for Protos®, approved June 2013
HSA Dear Healthcare Professional Letter: Update on the risk management plan for strontium ranelate (Protos®) to mitigate the risks of serious skin reactions. 7 Mar 2013, No. 48.