Increase in local reports of serious skin reactions related to strontium ranelate (Protos®)

The Health Sciences Authority (HSA) would like to alert healthcare professionals on its concern on the increase in the number of local reports of serious skin reactions suspected to be associated with strontium ranelate (Protos®, Servier). In view of this signal, an interim benefit-risk assessment of the drug was conducted by HSA and its Product Vigilance Advisory Committee (PVAC), which recommended closer monitoring of the drug and that a risk management plan be initiated to manage the risks of the drug. Protos® has been registered in Singapore since July 2006 for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures.

Background

HSA had earlier highlighted the risk of serious skin reactions with strontium ranelate to healthcare professionals in the March 2008 and August 2011 issues of the HSA Adverse Drug Reaction News Bulletin. The local package insert (PI) was also strengthened in 2008 and 2010 to alert healthcare professionals on the occurrence of serious skin reactions observed through post-marketing surveillance.

Local serious skin reaction reports

As of end June 2012, HSA has received a total of 59 local reports of suspected adverse reactions associated with strontium ranelate, of which 49 (83%) described skin reactions. Twelve (24%) of these reports were assessed as serious. The frequency of reporting of serious skin reactions had increased from one suspected case per year in 2007 - 2010 to four cases per year respectively in 2011 and in the first half of 2012. These include one report of generalised maculopapular rash with mucosal involvement, two reports of drug rash with eosinophilia and systemic symptoms (DRESS), two reports of exfoliative dermatitis, four reports of Stevens-Johnson syndrome (SJS) and three reports of toxic epidermal necrolysis (TEN). Of these, one report of SJS and two reports of TEN were associated with fatal outcomes.

The 12 reports all involved female patients between 53 to 83 years of age with co-morbidities such as hypertension or hyperlipidaemia. In eight of the reports, strontium ranelate was identified by the reporting physician as the only suspected drug due to its recent initiation to the patient's regular drug regimen. The time to onset ranged from eight to 122 days. Some of these patients presented with initial flu-like symptoms such as fever, cough and sore throat, followed by development of rash over trunk and limbs. Five of the patients had taken other drugs for osteoporosis before switching to strontium ranelate.

Overseas serious skin reaction reports

From 2005 to June 2012, 492 (33%) of 1,485 global adverse drug reaction (ADR) reports associated with strontium ranelate captured in World Health Organisation's (WHO's) global pharmacovigilance database (Vigibase) involved the skin and subcutaneous skin tissues, with some describing serious conditions such as exfoliative dermatitis, photosensitivity reaction, alopecia and angioedema. DRESS was more frequently reported, with a total of 28 cases captured mainly in Europe. A total of one report of SJS/TEN overlap, two reports of TEN and five reports of SJS were also reported by some European countries. Other than Singapore, Malaysia was the other Asian country with three reports of SJS.

Regulatory actions taken by the European Medicines Agency (EMA)

In November 2007, the EMA's Committee for Medicinal Products for Human Use (CHMP) had reviewed this safety concern and included a warning on DRESS in the drug's prescribing information.1 In March 2012, a second review by CHMP following a study in France2 found that skin reactions accounted for 26% of all post-marketing reports associated with strontium ranelate.The CHMP concluded that the benefits of strontium ranelate continue to outweigh its risks and recommended an update of the warnings on the serious skin reactions seen with drug.3 The recommendations by the CHMP have since been incorporated in the latest version of the local package insert (PI) that was approved recently.4

HSA’s regulatory actions and outcome of the PVAC meeting

n view of the emerging local signal of an increased incidence of serious skin reactions with strontium ranelate, HSA convened a meeting with its PVAC on 29 June 2012 to seek the committee's advice on the benefit-risk profile of Protos®, with focus on the recent increase in the number of reports of serious skin reactions. The frequencies of serious skin reactions in the local context for 2011 are estimated to be up to 1.18/1,000 patient-years for SJS/TEN and 0.39/1,000 patient-years for DRESS, based on sales data provided by the company. The review took into consideration the efficacy data of Protos® for the prevention of vertebral and hip fractures, opinions from orthopaedic and rheumatology experts, overseas safety data with regard to serious skin reactions and the estimated frequencies of serious skin reactions locally.

The PVAC's interim conclusion was that strontium ranelate has a role in the treatment of postmenopausal osteoporosis and its benefits continue to outweigh the risks when used appropriately. As an increased risk of serious skin reactions has been detected locally, the committee recommended the quantification of  the risk by capturing the actual number of patients taking the product. As serious skin reactions are unpredictable, a strong risk management plan was to be in place to minimise the risk and close surveillance of the drug implemented.

Following the meeting, HSA issued a Dear Healthcare Professional Letter (DHCPL) on 13 July 2012 to alert healthcare professionals on the increase in the number of local reports of serious skin reactions and the outcome of the PVAC meeting. HSA is currently working with the company on the details of the risk management plan which would include a close monitoring programme for strontium ranelate with the cooperation of healthcare professionals. The warnings on DRESS, SJS and TEN in the local PI will be strengthened to include information that the incidence of SJS and TEN may be higher in Asians. Healthcare professionals will be updated on the details of the risk management plan for strontium ranelate once they are finalised.  

HSA's advisory

Doctors are strongly advised to prescribe strontium ranelate according to its approved indication, keeping in mind the MOH Clinical Practice Guidelines for Osteoporosis when selecting the appropriate choice of pharmacotherapy. The choice of therapy for osteoporosis should be based on the benefits and risks of treatment and must carefully be weighed for each individual patient.

Healthcare professionals are advised to monitor their patients closely for serious skin reactions. In managing the risk of serious skin reactions, healthcare professionals are reminded that the highest risk of occurrence of DRESS, SJS and TEN is within the first eight weeks of treatment, with poorer prognosis in elderly. Patients who are prescribed strontium ranelate should be advised of the likely time to onset and signs and symptoms of DRESS, SJS and TEN and monitored closely for skin reactions.

Patients should also be educated on early recognition of these serious skin reactions. As early withdrawal of any suspect drug is associated with a better prognosis, patients should be advised to stop treatment immediately and permanently if symptoms of serious allergic skin reactions occur and to seek medical advice. These include extended skin rashes, blisters and sores, accompanied with flu-like symptoms in some cases. Treatment should not be re-started at any time in these patients.

As HSA continues to monitor the issue closely, healthcare professionals are encouraged to report any serious adverse events suspected to be associated with strontium ranelate to the Vigilance Branch of HSA

References

  1. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/11/WC500015595.pdf
  2. http://www.ncbi.nlm.nih.gov/pubmed/21885232
  3. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/03/news_detail_001471.jsp&mid=WC0b01ac058004d5c1
  4. Singapore package insert for Protos®. Approved 2 July 2012.
Healthcare professional, Industry member, Therapeutic Products
Published:

Safety Alerts

12 Dec 2019