STRONTIUM RANELATE ARISTO Granules Ref.[8499] Active ingredients: Strontium ranelate

Cardiac ischaemic events

In pooled randomised placebo-controlled studies of post-menopausal osteoporotic patients, a significant increase in myocardial infarction has been observed in Strontium ranelate Aristo treated patients compared to placebo (see section 4.8).

Before starting treatment, patients should be evaluated with respect to cardiovascular risk.

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with strontium ranelate after careful consideration (see sections 4.3 and 4.8).

During Strontium ranelate Aristo treatment, these cardiovascular risks should be monitored on a regular basis generally every 6 to 12 months.

Treatment should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or if hypertension is uncontrolled (see section 4.3).

Venous thromboembolism

In phase III placebo-controlled studies, strontium ranelate treatment was associated with an increase in the annual incidence of venous thromboembolism (VTE), including pulmonary embolism (see section 4.8). The cause of this finding is unknown. Strontium ranelate Aristo is contra-indicated in patients with a past history of venous thromboembolic events (see section 4.3) and should be used with caution in patients at risk of VTE.

When treating patients over 80 years at risk of VTE, the need for continued treatment with Strontium ranelate Aristo should be re-evaluated. Strontium ranelate Aristo should be discontinued as soon as possible in the event of an illness or a condition leading to immobilisation (see section 4.3) and adequate preventive measures taken. Therapy should not be restarted until the initiating condition has resolved and the patient is fully mobile. When a VTE occurs, Strontium ranelate Aristo should be stopped.

Use in patients with renal impairment

In the absence of bone safety data in patients with severe renal impairment treated with strontium ranelate, Strontium ranelate Aristo is not recommended in patients with a creatinine clearance below 30 ml/min (see section 5.2). In accordance with good medical practice, periodic assessment of renal function is recommended in patients with chronic renal impairment. Continuation of treatment with Strontium ranelate Aristo in patients developing severe renal impairment should be considered on an individual basis.

Skin reactions

Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS)) have been reported with the use of strontium ranelate.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment and usually around 3-6 weeks for DRESS.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) or DRESS (e.g. rash, fever, eosinophilia and systemic involvement (e.g. adenopathy, hepatitis, interstitial nephropathy, interstitial lung disease) are present, Strontium ranelate Aristo treatment should be discontinued immediately.

The best results in managing SJS, TEN or DRESS come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. The outcome of DRESS is favorable in most cases upon discontinuation of strontium ranelate and after initiation of corticosteroid therapy when necessary. Recovery could be slow and recurrences of the syndrome have been reported in some cases after discontinuation of corticosteroid therapy.

If the patient has developed SJS, TEN or DRESS with the use of strontium ranelate, Strontium ranelate Aristo must not be re-started in this patient at any time.

A higher incidence, although still rare, of hypersensitivity reactions including skin rash, SJS or TEN in patients of Asian origin has been reported.

Interaction with laboratory test

Strontium interferes with colorimetric methods for the determination of blood and urinary calcium concentrations. Therefore, in medical practice, inductively coupled plasma atomic emission spectrometry or atomic absorption spectrometry methods should be used to ensure an accurate assessment of blood and urinary calcium concentrations.

Excipient

Strontium ranelate Aristo contains aspartame, a source of phenylalanine, which may be harmful for people with phenylketonuria.

Food, milk and derivative products, and medicinal products containing calcium may reduce the bioavailability of strontium ranelate by approximately 60-70%. Therefore, administration of Strontium ranelate Aristo and such products should be separated by at least two hours (see sections 4.2 and 5.2).

As divalent cations can form complexes with oral tetracycline (e.g. doxycycline) and quinolone antibiotics (e.g. ciprofloxacin) at the gastro-intestinal level and thereby reduce their absorption, simultaneous administration of strontium ranelate with these medicinal products is not recommended. As a precautionary measure, Strontium ranelate Aristo treatment should be suspended during treatment with oral tetracycline or quinolone antibiotics.

An in vivo clinical interaction study showed that the administration of aluminium and magnesium hydroxides either two hours before or together with strontium ranelate caused a slight decrease in the absorption of strontium ranelate (20-25% AUC decrease), while absorption was almost unaffected when the antacid was given two hours after strontium ranelate. It is therefore preferable to take antacids at least two hours after Strontium ranelate Aristo. However, when this dosing regimen is impractical due to the recommended administration of Strontium ranelate Aristo at bedtime, concomitant intake remains acceptable.

No interaction was observed with oral supplementation of vitamin D.

No evidence of clinical interactions or relevant increase of blood strontium levels with medicinal products expected to be commonly prescribed concomitantly with strontium ranelate in the target population were found during clinical trials. These included: nonsteroidal anti-inflammatory agents (including acetylsalicylic acid), anilides (such as paracetamol), H₂ blockers and proton pump inhibitors, diuretics, digoxin and cardiac glycosides, organic nitrates and other vasodilators for cardiac diseases, calcium channel blockers, beta blockers, ACE inhibitors, angiotensin II antagonists, selective beta-2 adrenoceptor agonists, oral anticoagulants, platelet aggregation inhibitors, statins, fibrates and benzodiazepine derivatives.

Pregnancy

There are no data from the use of strontium ranelate in pregnant women.

At high doses, animal studies have shown reversible bone effects in the offspring of rats and rabbits treated during pregnancy (see section 5.3). If Strontium ranelate Aristo is used inadvertently during pregnancy, treatment must be stopped.

Breastfeeding

Physico-chemical data suggest excretion of strontium ranelate in human milk. Strontium ranelate Aristo should not be used during breast-feeding.

Fertility

No effects were observed on males and females fertility in animal studies.

Strontium ranelate Aristo has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Strontium ranelate has been studied in clinical trials involving nearly 8,000 participants. Long-term safety has been evaluated in postmenopausal women with osteoporosis treated for up to 60 months with strontium ranelate 2 g/day (n=3,352) or placebo (n=3,317) in phase III studies. Mean age was 75 years at inclusion and 23% of the patients enrolled were 80 to 100 years of age.

In a pooled analysis of randomised placebo-controlled studies in post-menopausal osteoporotic patients, the most common adverse reactions consisted of nausea and diarrhoea, which were generally reported at the beginning of treatment with no noticeable difference between groups afterwards. Discontinuation of therapy was mainly due to nausea.

There were no differences in the nature of adverse reactions between treatment groups regardless of whether patients were aged below or above 80 at inclusion.

Tabulated list of adverse reactions

The following adverse reactions have been reported during clinical studies and/or post marketing use with strontium ranelate.

Adverse reactions are listed below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

^§ Frequency in Clinical Trials was similar in the drug and placebo group.
^* In Asian countries reported as rare
^# For adverse reaction not observed in clinical trials, the upper limit of the 95% confidence interval is not higher than 3/X with X representing the total sample size summed up across all relevant clinical trials and studies.
^a Musculo-skeletal fraction >3 times the upper limit of the normal range. In most cases, these values spontaneously reverted to normal without change in treatment.

Description of selected adverse reactions

Venous thromboembolism

In phase III studies, the annual incidence of venous thromboembolism (VTE) observed over 5 years was approximately 0.7%, with a relative risk of 1.4 (95% CI = [1.0 ; 2.0]) in strontium ranelate treated patients as compared to placebo (see section 4.4).

Myocardial infarction

In pooled randomised placebo-controlled studies of post-menopausal osteoporotic patients, a significant increase of myocardial infarction has been observed in strontium ranelate treated patients as compared to placebo (1.7% versus 1.1 ), with a relative risk of 1.6 (95 CI = [1.07 ; 2.38]).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

Not applicable.