- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
PosologyThe 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, PROTELOS should be administered in-between meals. Given the slow absorption, PROTELOS should be taken at bedtime, preferably at least two hours after eating (see sections 4.5 and 5.2).Patients treated with strontium ranelate should receive vitamin D and calcium supplements if dietary intake is inadequate.
Elderly patientsThe 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.
Patients with renal impairmentStrontium ranelate is not recommended for patients with severe renal impairment (creatinine clearance below 30 ml/min) (see sections 4.4 and 5.2). No dose adjustment is required in patients with mild-to-moderate renal impairment (30-70 ml/min creatinine clearance) (see sections 4.4 and 5.2).
Patients with hepatic impairmentNo dose adjustment is required in patients with hepatic impairment (see section 5.2).
Paediatric populationThe safety and efficacy of PROTELOS in children aged below 18 years have not been established. No data are available.
Method of administrationFor oral use.The granules in the sachets must be taken as a suspension in a glass containing a minimum of 30 ml (approximately one third 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.
Cardiac ischaemic eventsIn pooled randomised placebo-controlled studies of post-menopausal osteoporotic patients, a significant increase in myocardial infarction has been observed in PROTELOS 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 PROTELOS 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 thromboembolismIn 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. PROTELOS 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 PROTELOS should be re-evaluated. PROTELOS 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, PROTELOS should be stopped.
Use in patients with renal impairmentIn the absence of bone safety data in patients with severe renal impairment treated with strontium ranelate, PROTELOS 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 PROTELOS in patients developing severe renal impairment should be considered on an individual basis.
Skin reactionsLife-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 PROTELOS.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, PROTELOS 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 favourable in most cases upon discontinuation of PROTELOS 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 PROTELOS, PROTELOS 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 testStrontium 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.
ExcipientPROTELOS contains aspartame, a source of phenylalanine, which may be harmful for people with phenylketonuria.
PregnancyThere 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 PROTELOS is used inadvertently during pregnancy, treatment must be stopped.
Breast-feedingPhysico-chemical data suggest excretion of Strontium ranelate in human milk. PROTELOS should not be used during breast-feeding.
FertilityNo effects were observed on males and females fertility in animal studies.
Summary of the safety profilePROTELOS 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 reactionsThe 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).
|System Organ Class||Frequency||Adverse reaction|
|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|
|Nervous system disorders||Common||Headache|
|Disturbances in consciousness|
|Ear and labyrinth disorders||Common||Vertigo|
|Cardiac disorders||Common||Myocardial infarction|
|Vascular disorders||Common||Venous thromboembolism (VTE)|
|Respiratory, thoracic and mediastinal disorders||Common||Bronchial hyperreactivity|
|Diarrhoea and Loose stools|
|Uncommon||Oral mucosal irritation (stomatitis and/or mouth ulceration)|
|Uncommon||Serum transaminase increased (in association with hypersensitivity skin reactions)|
|Skin and subcutaneous tissue disorders||Very common||Hypersensitivity skin reactions (rash, pruritus, urticaria, angioedema)§|
|Rare||Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (see section 4.4)#|
|Very rare||Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome and toxic epidermal necrolysis* (see section 4.4)#|
|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)|
|Investigations||Common||Blood Creatine phosphokinase (CPK) increaseda|
Description of selected adverse reactions
Venous thromboembolismIn 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 infarctionIn 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 reactionsReporting 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard
SymptomsGood tolerance was shown in a clinical study investigating the repeated administration of 4 g strontium ranelate per day over 25 days in healthy postmenopausal women. Single administration of doses up to 11 g in healthy young male volunteers did not cause any particular symptoms.
ManagementFollowing episodes of overdoses during clinical trials (up to 4 g/day for a maximal duration of 147 days), no clinically relevant events were observed.Administration of milk or antacids may be helpful to reduce the absorption of the active substance. In the event of substantial overdose, vomiting may be considered to remove unabsorbed active substance.
Mechanism of actionIn vitro, strontium ranelate:- increases bone formation in bone tissue culture as well as osteoblast precursor replication and collagen synthesis in bone cell culture.- reduces bone resorption by decreasing osteoclast differentiation and resorbing activity.This results in a rebalance of bone turnover in favour of bone formation.The activity of strontium ranelate was studied in various non-clinical models. In particular, in intact rats, strontium ranelate increases trabecular bone mass, trabeculae number and thickness; this results in an improvement of bone strength.In bone tissue of treated animals and humans, strontium is mainly adsorbed onto the crystal surface and only slightly substitutes for calcium in the apatite crystal of newly formed bone. Strontium ranelate does not modify the bone crystal characteristics. In iliac crest bone biopsies obtained after up to 60 months of treatment with strontium ranelate 2 g/day in phase III trials, no deleterious effects on bone quality or mineralisation were observed.The combined effects of strontium distribution in bone (see section 5.2) and increased X-ray absorption of strontium as compared to calcium, leads to an amplification of bone mineral density (BMD) measurement by dual-photon X-ray absorptiometry (DXA). Available data indicate that these factors account for approximately 50% of the measured change in BMD over 3 years of treatment with PROTELOS 2 g/day. This should be taken into account when interpreting BMD changes during treatment with PROTELOS. In phase III studies, which demonstrated the anti-fracture efficacy of PROTELOS treatment, measured mean BMD increased from baseline with PROTELOS by approximately 4% per year at the lumbar spine and 2% per year at the femoral neck, reaching 13% to 15% and 5% to 6% respectively after 3 years, depending on the study.In phase III studies, as compared to placebo, biochemical markers of bone formation (bone-specific alkaline phosphatase and C-terminal propeptide of type I procollagen) increased and those of bone resorption (serum C-telopeptide and urinary N-telopeptide cross links) decreased from the third month of treatment up to 3 years.Secondary to the pharmacological effects of strontium ranelate, slight decreases in calcium and parathyroid hormone (PTH) serum concentrations, increases in blood phosphorus concentrations and in total alkaline phosphatase activity were observed, with no observed clinical consequences.
Clinical efficacyOsteoporosis is defined as BMD of the spine or hip 2.5 SD or more below the mean value of a normal young population. A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors.
Treatment of postmenopausal osteoporosis:The anti-fracture studies program of PROTELOS was made up of two placebo-controlled phase III studies: SOTI study and TROPOS study. SOTI involved 1,649 postmenopausal women with established osteoporosis (low lumbar BMD and prevalent vertebral fracture) and a mean age of 70 years. TROPOS involved 5,091 postmenopausal women with osteoporosis (low femoral neck BMD and prevalent fracture in more than half of them) and a mean age of 77 years. Together, SOTI and TROPOS enrolled 1,556 patients over 80 years at inclusion (23.1% of the study population). In addition to their treatment (2 g/day strontium ranelate or placebo), the patients received adapted calcium and vitamin D supplements throughout both studies.PROTELOS reduced the relative risk of new vertebral fracture by 41% over 3 years in the SOTI study (table 1). The effect was significant from the first year. Similar benefits were demonstrated in women with multiple fractures at baseline. With respect to clinical vertebral fractures (defined as fractures associated with back pain and/or a body height loss of at least 1 cm), the relative risk was reduced by 38%. PROTELOS also decreased the number of patients with a body height loss of at least 1 cm as compared to placebo. Quality of life assessment on the QUALIOST specific scale as well as the General Health perception score of the SF-36 general scale indicated benefit of PROTELOS, compared with placebo.Efficacy of PROTELOS to reduce the risk of new vertebral fracture was confirmed in the TROPOS study, including for osteoporotic patients without fragility fracture at baseline. Table 1 : Incidence of patients with vertebral fracture and relative risk reduction
|Study||Placebo||PROTELOS||Relative Risk Reduction vs. placebo (95%CI), p value|
|New vertebral fracture over 3 years||32.8%||20.9%||41% (27-52), p<0.001|
|New vertebral fracture over the 1st year||11.8%||6.1%||49% (26-64), p<0.001|
|New clinical vertebral fracture over 3 years||17.4%||11.3%||38% (17-53), p<0.001|
|New vertebral fracture over 3 years||20.0%||12.5%||39% (27-49), p<0.001|
|Study||Placebo||PROTELOS||Relative Risk Reduction vs. placebo (95%CI), p value|
|Hip fracture over 3 years||6.4%||4.3%||36% (0-59), p=0.046|
Treatment of Osteoporosis in men:The efficacy of PROTELOS was demonstrated in men with osteoporosis in a 2-year, double-blind, placebo-controlled study with a main analysis after one year in 243 patients (Intention to treat population, 161 patients received strontium ranelate) at high risk of fracture (mean age 72.7 years; mean lumbar BMD T-score value of -2.6; 28% of prevalent vertebral fracture).All patients received daily supplemental calcium (1000 mg) and vitamin D (800 UI).Statistically significant increases in BMD were observed as early as 6 months following initiation of PROTELOS treatment versus placebo.Over 12 months, a statistically significant increase in mean lumbar spine BMD, main efficacy criteria (E (SE) = 5.32% (0.75); 95%CI = [3.86 ; 6.79]; p<0.001), similar to that observed in the pivotal anti-fracture phase III studies carried-out in postmenopausal women, was observed.Statistically significant increases in femoral neck BMD and total hip BMD (p<0.001) were observed after 12 months.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with PROTELOS in all subsets of the paediatric population in osteoporosis (see section 4.2 for information on paediatric use).
AbsorptionThe absolute bioavailability of strontium is about 25% (range 19-27%) after an oral dose of 2 g strontium ranelate. Maximum plasma concentrations are reached 3-5 hours after a single dose of 2 g. Steady state is reached after 2 weeks of treatment. Intake of strontium ranelate with calcium or food reduces the bioavailability of strontium by approximately 60-70%, compared with administration 3 hours after a meal. Due to the relatively slow absorption of strontium, food and calcium intake should be avoided both before and after administration of PROTELOS. Oral supplementation with vitamin D has no effect on strontium exposure.
DistributionStrontium has a volume of distribution of about 1 l/kg. The binding of strontium to human plasma proteins is low (25%) and strontium has a high affinity for bone tissue. Measurement of strontium concentration in iliac crest bone biopsies from patients treated for up to 60 months with strontium ranelate 2 g/day indicate that bone strontium concentrations may reach a plateau after about 3 years of treatment. There are no data in patients to demonstrate elimination kinetics of strontium from bone off-therapy.
BiotransformationAs a divalent cation, strontium is not metabolised. Strontium ranelate does not inhibit cytochrome P450 enzymes.
EliminationThe elimination of strontium is time and dose independent. The effective half-life of strontium is about 60 hours. Strontium excretion occurs via the kidneys and the gastrointestinal tract. Its plasma clearance is about 12 ml/min (CV 22%) and its renal clearance about 7 ml/min (CV 28%).
Pharmacokinetics in special populations
Older peoplePopulation pharmacokinetic data showed no relationship between age and apparent clearance of strontium in the target population.
Renal impairmentIn patients with mild-to-moderate renal impairment (30-70 ml/min creatinine clearance), strontium clearance decreases as creatinine clearance decreases (approximately 30% decrease over the creatinine clearance range 30 to 70 ml/min) and thereby induces an increase in strontium plasma levels. In phase III studies, 85% of the patients had a creatinine clearance between 30 and 70 ml/min and 6% below 30 ml/min at inclusion, and the mean creatinine clearance was about 50 ml/min. No dosage adjustment is therefore required in patients with mild-to-moderate renal impairment.There is no pharmacokinetic data in patients with severe renal impairment (creatinine clearance below 30 ml/min).
Hepatic impairmentThere is no pharmacokinetic data in patients with hepatic impairment. Due to the pharmacokinetic properties of strontium, no effect is expected.
Environmental Risk Assessment (ERA)The environmental risk assessment of strontium ranelate has been conducted in accordance to European guidelines on ERA.Strontium ranelate does not present a risk for the environment.
Pack sizesBoxes containing 7, 14, 28, 56, 84 or 100 sachets.Not all pack sizes may be marketed.
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