Strontium ranelate

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. However, when this dosing regimen is impractical due to the recommended administration of strontium ranelate at bedtime, concomitant intake remains acceptable.

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 and such products should be separated by at least two hours.

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 treatment should be suspended during treatment with oral tetracycline or quinolone antibiotics.

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. If strontium ranelate is used inadvertently during pregnancy, treatment must be stopped.

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

Fertility

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

Strontium ranelate 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.

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]).