Strontium Ranelate

Treatment of severe osteoporosis in postmenopausal women, and in adult men, at high risk of fracture, for whom treatment with other medicinal products is contraindicated or intolerant. In postmenopausal women, Strontium Ranelate reduces the risk of vertebral and hip fractures.

The decision to prescribe Strontium Ranelate should be based on an assessment of the individual patient's overall risks.

Treatment should only be initiated by a physician with experience in the treatment of osteoporosis.

The recommended dose is one 2 g sachet once daily by oral administration.

Due to the nature of the treated disease, Strontium Ranelate is intended for long-term use.

The absorption of Strontium Ranelate is reduced by food, milk and derivative products and therefore, Protos should be administered in-between meals. Given the slow absorption, Protos should be taken at bedtime, preferably at least 2 hours after eating.

Patients treated with Strontium Ranelate should receive vitamin D and calcium supplements if dietary intake is inadequate.

Elderly: The efficacy and safety of Strontium Ranelate have been established in a broad age range (up to 100 years at inclusion) of adult men and postmenopausal women with osteoporosis. No dose adjustment is required in relation to age.

Renal Impairment: Strontium Ranelate is not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min). No dose adjustment is required in patients with mild-to-moderate renal impairment (30-70 mL/min creatinine clearance).

Hepatic Impairment: No dose adjustment is required in patients with hepatic impairment.

Paediatric Population: The safety and efficacy of Protos in children aged <18 years have not been established. No data are available.

Administration: For oral use.

The granules in the sachets must be taken as a suspension in a glass containing a minimum of 30 mL (approximately ¹/₃ of a standard glass) of water.

Although in-use studies have demonstrated that Strontium Ranelate is stable in suspension for 24 hours after preparation, the suspension should be drunk immediately after being prepared.

Hypersensitivity to Strontium Ranelate or to any of the excipients of Protos. Current or previous venous thromboembolic events (VTE), including deep vein thrombosis and pulmonary embolism. Temporary or permanent immobilisation due to eg, post-surgical recovery or prolonged bed rest. Established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease. Uncontrolled hypertension.

Food, milk and derivative products, and medicinal products containing calcium may reduce the bioavailability of Strontium Ranelate by approximately 60-70%. Therefore, administration of Protos and such products should be separated by at least 2 hours.

As divalent cations can form complexes with oral tetracycline (eg, doxycycline) and quinolone antibiotics (eg, ciprofloxacin) at the gastrointestinal level and thereby reduce their absorption, simultaneous administration of Strontium Ranelate with these medicinal products is not recommended. As a precautionary measure, Protos 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 2 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 2 hours after Strontium Ranelate. It is therefore preferable to take antacids at least 2 hours after Protos. However, when this dosing regimen is impractical due to the recommended administration of Protos 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 Protos in the target population were found during clinical trials. These included: Nonsteroidal anti-inflammatory agents (including acetylsalicylic acid), anilides (eg, paracetamol), H₂ blockers and proton pump inhibitors, diuretics, digoxin and cardiac glycosides, organic nitrates and other vasodilators for cardiac diseases, calcium channel blockers, β-blockers, ACE inhibitors, angiotensin II antagonists, selective β-2 adrenoceptor agonists, oral anticoagulants, platelet aggregation inhibitors, statins, fibrates and benzodiazepine derivatives.

Summary of the Safety Profile: Protos has been studied in clinical trials involving nearly 8000 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=3352) or placebo (n=3317) in phase III studies. Mean age was 75 years at inclusion and 23% of the patients enrolled were 80-100 years.

In a pooled analysis of randomised placebo-controlled studies in postmenopausal 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.

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: 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).

Blood and Lymphatic Disorders: Uncommon: Lymphadenopathy (in association with hypersensitivity skin reactions). Rare: Bone marrow failure^#, eosinophilia (in association with hypersensitivity skin reactions).

Metabolism and Nutrition Disorders: Common: Hypercholesterolaemia.

Psychiatric Disorders: Common: Insomnia. Uncommon: Confusion.

Nervous System Disorders: Common: Headache, disturbances in consciousness, memory loss, dizziness, paraesthesia. Uncommon: Seizures.

Ear and Labyrinth Disorders: Common: Vertigo.

Cardiac Disorders: Common: Myocardial infarction.

Vascular Disorders: Common: Venous thromboembolism (VTE).

Respiratory, Thoracic and Mediastinal Disorders: Common: Bronchial hyper-reactivity.

Gastrointestinal Disorders: Common: Nausea, diarrhoea and loose stools, vomiting, abdominal pain, gastrointestinal pain, gastrooesophageal reflux, dyspepsia, constipation, flatulence. Uncommon:

Oral mucosal irritation (stomatitis and/or mouth ulceration), dry mouth.

Hepatobiliary Disorders: Common: Hepatitis. Uncommon: Increased serum transaminase (in association with hypersensitivity skin reactions).

Skin and Subcutaneous Tissue Disorders: Very common: Hypersensitivity skin reactions (rash, pruritus, urticaria, angioedema)^§. Common: Eczema. Uncommon: Dermatitis, alopecia. Rare: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) ^#. Very rare: Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome and toxic epidermal necrolysis^{* #}.

Musculoskeletal and Connective Tissue Disorders: Very common: Musculoskeletal pain (muscle spasm, myalgia, bone pain, arthralgia and pain in extremity)^§.

General Disorders and Administration Site Conditions: Common: Peripheral oedema. Uncommon: Pyrexia (in association with hypersensitivity skin reactions), malaise.

Investigations: Common: Increased blood creatine phosphokinase (CPK).

^§ 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 VTE observed over 5 years was approximately 0.7%, with a relative risk of 1.4 [95% CI=(1; 2)] 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% vs 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 the national reporting system.

Strontium Ranelate, a strontium(II) salt of ranelic acid, is a medication for osteoporosis. Studies indicate it can also slow the course of osteoarthritis of the knee. The drug is unusual in that it both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts. It is therefore promoted as a “dual action bone agent” (DABA).