Serious skin reactions associated with strontium ranelate (Protos®)

HSA would like to alert healthcare professionals on the occurrence of suspected serious skin reactions associated with the use of strontium ranelate (Protos®) locally. Protos® has been registered in Singapore since July 2006 for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures.

Local reports

As of 31 July 2011, the Vigilance Branch (VB) has received a total of 37 local suspected ADR reports associated with strontium, out of which 30 described skin reactions. Eighteen reports were assessed as serious in nature by the reporting physicians. These serious reports include one report of dermatitis exfoliative, two reports of Stevens-Johnson syndrome (SJS) and three reports of toxic epidermal necrolysis (TEN), of which two were associated with fatal outcomes. These reports were received over a period of four years.

All the patients were elderly females (65 - 82 years old) with co-morbidities such as hypertension or hyperlipidaemia and were on concomitant medications (eg, anti-hypertensives, lipid-lowering agents, cyclooxygenase-2 inhibitor). Five of the patients were Chinese and one was a Malay. In some cases, strontium was identified as the only suspected drug due to its recent initiation to the patient's regular drug regimen. The time to onset ranged from nine to 34 days. Some of these cases presented with initial flu-like symptoms followed by the development of rash over the trunk and limbs.

Overseas reports

From 2005 to May 2011, a total of 1,220 global ADR reports associated with strontium ranelate were reported in the World Health Organisation (WHO) Vigibase*.

Of these reports, more than 30% involved the skin and subcutaneous tissues, with some describing serious conditions such as drug rash with eosinophilia, alopecia and angioedema. Other than the above reports from Singapore, a total of six other reports of SJS and three reports of TEN were reported by some European countries and Malaysia.

*_{WHO Vigibase is a global database of adverse reaction reports on medicinal products which are contributed by more than 80 pharmacovigilance centres worldwide, including Singapore.}

Regulatory actions taken to date

Serious skin reactions with strontium ranelate is not a new occurrence. In November 2007, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) alerted on an increasing number of reports of ‘drug rash with eosinophilia and systemic symptoms' (DRESS)** associated with the use of strontium.² The CHMP noted that symptoms of DRESS appeared within three to six weeks after the patients started to take strontium. It was also concerned that the link between strontium and DRESS was not recognised immediately, leading to a delay in stopping the causative agent. This in turn led to poor prognoses of the patients. Hence, the committee concluded that a warning on the risks of DRESS should be introduced in the medicine's prescribing information, stating that patients showing symptoms of DRESS should stop treatment and contact their doctor immediately.

The March 2008 issue of the HSA Adverse Drug Reaction News bulletin³ similarly carried an article to alert prescribers of the risk of serious skin reactions with strontium. Consequently, the package insert (PI) of Protos® was revised to include DRESS and SJS in 2008. Following reports of TEN through post-market surveillance effort,, the PI of Protos® was revised again in 2010 to include TEN as part of the “skin and subcutaneous tissue disorders” adverse reactions. HSA continues to work with the company to closely monitor reports of serious skin reactions related to strontium ranelate to ensure that the benefit-risk profile of the drug remains favourable.

_{** DRESS is a rare but serious and life-threatening type of allergic reaction to a drug. The condition starts with a skin rash, accompanied by a fever, swollen glands, eosinophilia, adenopathy and systemic involvement which may include hepatic, renal and pulmonary impairment.}

HSA's advisory

In view that these serious skin reactions are associated with significant morbidity and mortality, healthcare professionals are advised to be mindful of the local cases of serious skin reactions associated with strontium ranelate when prescribing the drug for treatment of postmenopausal osteoporosis.

As early signs of rash and skin reactions may be indicative of a more serious reaction such as SJS and TEN, healthcare professionals are advised to educate their patients on the early recognition of allergic reactions and to seek medical attention promptly. In addition, patients who have stopped treatment due to hypersensitivity reactions should not re-start therapy with strontium.

HSA will continue to monitor the situation closely and update healthcare professionals on any significant new findings. In the meantime, healthcare professionals are strongly encouraged to report all suspected ADRs associated with strontium ranelate to the Vigilance Branch of HSA.

References

1. Osteoporosis Int. 2009; 20 (1): 161-162
2. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/11/WC500015595.pdf
3. HSA Adverse Drug Reaction News. March 2008, Vol 10 No. 1

Published: 22 Aug 2011

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