Protelos

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
PROTELOS 2 g granules for oral suspension 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each sachet contains 2 g of strontium ranelate. 
 
Excipient with known effect:  
Each sachet also contains 20 mg of aspartame (E951). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Granules for oral suspension 
Yellow granules 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of severe osteoporosis: 

- in postmenopausal women, 
- in adult men, 

at high risk of fracture, for whom treatment with other medicinal products approved for the treatment 
of osteoporosis is not possible due to, for example, contraindications or intolerance. In 
postmenopausal women, strontium ranelate reduces the risk of vertebral and hip fractures (see section 
5.1). 
The decision to prescribe strontium ranelate  should be based on an assessment of the individual 
patient's overall risks (see sections 4.3 and 4.4). 
 
4.2 Posology and method of administration 
 
Treatment should  only be initiated by a physician with experience in the treatment of osteoporosis. 
 
Posology 
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, 
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  
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. 

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Renal impairment 
Strontium 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).  
 
Hepatic impairment 
No dose adjustment is required in patients with hepatic impairment (see section 5.2). 
 
Paediatric population 
The safety and efficacy of PROTELOS in children aged below 18 years have not been established. No 
data are available. 
 
Method of 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 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. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
- Current or previous venous thromboembolic events (VTE), including deep vein thrombosis and 
pulmonary embolism. 
- Temporary or permanent immobilisation due to e.g. 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.  
 
4.4 Special warnings and precautions for use 
 
Cardiac ischaemic events 
In 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 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. 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 

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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 impairment 
In 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 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 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 favorable 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 (see section 4.8). 
HLA-A*33:03 and HLA-B*58:01 alleles have been identified as potential genetic risk factors for 
strontium ranelate-associated SJS/TEN in Han Chinese patients from a retrospective, case-control, 
pharmacogenetic study. Where possible, screening for HLA-A*33:03 and HLA-B*58:01 alleles could 
be considered before starting treatment with PROTELOS in patients of Han Chinese origin. If tests 
are positive for one or both alleles, PROTELOS should not be started. However, absence of these 
alleles upon genotyping does not exclude that SJS/TEN can still occur.   
 
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 
PROTELOS contains aspartame, a source of phenylalanine, which may be harmful for people with 
phenylketonuria. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Food, milk and derivative products, and medicinal products containing calcium may reduce the 
bioavailability of strontium ranelate by approximately 60-70%. Therefore, administration of 
PROTELOS 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, 

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simultaneous administration of strontium ranelate with these medicinal products is not recommended. 
As a precautionary measure, PROTELOS 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 PROTELOS. However, when this dosing regimen is impractical due 
to the recommended administration of PROTELOS 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 PROTELOS 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. 
 
4.6 Fertility, pregnancy and lactation 
 
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 PROTELOS is used inadvertently during pregnancy, 
treatment must be stopped. 
 
Breast-feeding 
Physico-chemical data suggest excretion of Strontium ranelate in human milk. PROTELOS should not 
be used during breast-feeding. 
 
Fertility  
No effects were observed on males and females fertility in animal studies. 
 
4.7 Effects on ability to drive and use machines 
 
Strontium ranelate has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
PROTELOS 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. 

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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 reactionsare 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 

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 hyperreactivity 

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 Serum transaminase increased (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) (see section 

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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) 
Malaise 

Investigations Common Blood Creatine phosphokinase (CPK) 
increaseda 

§ 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 the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
Good 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. 
 
Management 
Following 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 

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5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Drugs for the treatment of bone diseases - Other drugs affecting bone 
structure and mineralisation, ATC code: M05BX03. 
 
Mechanism of action 
In 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 efficacy 
Osteoporosis 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 

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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 

SOTI N=723 N=719  

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 

TROPOS N=1823 N=1817  

New vertebral fracture 
over 3 years 

20.0% 12.5% 39% (27-49), p<0.001 

 
In patients over 80 years of age at inclusion, a pooled analysis of SOTI and TROPOS studies showed 
that PROTELOS reduced the relative risk of experiencing new vertebral fractures by 32% over 
3 years (incidence of 19.1% with strontium ranelate vs. 26.5% with placebo). 
 
In an a-posteriori analysis of patients from the pooled SOTI and TROPOS studies with baseline 
lumbar spine and / or femoral neck BMD in the osteopenic range and without prevalent fracture but 
with at least one additional risk factor for fracture (N=176), PROTELOS reduced the risk of a first 
vertebral fracture by 72% over 3 years (incidence of vertebral fracture 3.6% with strontium ranelate 
vs. 12.0% with placebo). 
 
An a-posteriori analysis was performed on a subgroup of patients from the TROPOS study of 
particular medical interest and at high-risk of fracture [defined by a femoral neck BMD T-score ≤ -
3 SD (manufacturer’s range corresponding to -2.4 SD using NHANES III) and an age ≥ 74 years 
(n=1,977, i.e. 40% of the TROPOS study population)]. In this group, over 3 years of treatment, 
PROTELOS reduced the risk of hip fracture by 36% relative to the placebo group (table 2). 
 

Table 2: Incidence of patients with hip fracture and relative risk reduction in patients with 
BMD ≤ -2.4 SD (NHANES III) and age ≥ 74 years 

Study Placebo PROTELOS Relative Risk Reduction vs. 
placebo (95%CI), p value 

TROPOS N=995 N=982  

Hip fracture over 3 years 6.4% 4.3% 36% (0-59), p=0.046 

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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 
treatpopulation, 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 inpostmenopausal women, was observed. 
Statistically significant increases in femoral neck BMD and total hip BMD (p<0,001) were observed 
after 12 months. 
 
Paediatric population 
The 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). 
 
5.2 Pharmacokinetic properties 
 
Strontium ranelate is made up of 2 atoms of stable strontium and 1 molecule of ranelic acid, the 
organic part permitting the best compromise in terms of molecular weight, pharmacokinetics and 
acceptability of the medicinal product. The pharmacokinetics of strontium and ranelic acid have been 
assessed in healthy young men and healthy postmenopausal women, as well as during long-term 
exposure in men with osteoporosis and postmenopausal osteoporotic women including elderly 
women. 
 
Due to its high polarity, the absorption, distribution and binding to plasma proteins of ranelic acid are 
low. There is no accumulation of ranelic acid and no evidence of metabolism in animals and humans. 
Absorbed ranelic acid is rapidly eliminated unchanged via the kidneys. 
 
Absorption 
The 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. 
 
Distribution 
Strontium 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. 
 
Biotransformation 
As a divalent cation, strontium is not metabolised. Strontium ranelate does not inhibit cytochrome 
P450 enzymes. 
 
Elimination 

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The 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 
 
ElderlyPopulation pharmacokinetic data showed no relationship between age and apparent clearance 
of strontium in the target population. 
 
Renal impairment 
In 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 impairment 
There is no pharmacokinetic data in patients with hepatic impairment. Due to the pharmacokinetic 
properties of strontium, no effect is expected. 
 
5.3 Preclinical safety data 
 
Non-clinical data revealed no special hazard for humans based on conventional studies of safety 
pharmacology, genotoxicity and carcinogenic potential. 
 
Chronic oral administration of strontium ranelate at high doses in rodents induced bone and tooth 
abnormalities, mainly consisting of spontaneous fractures and delayed mineralisation that were 
reversible after cessation of treatment. These effects were reported at bone strontium levels 2-3 times 
higher than bone strontium levels in humans up to 3 years of treatment. The data on skeletal strontium 
ranelate accumulation in longer term exposure is limited. 
 
Developmental toxicity studies in rats and rabbits resulted in bone and tooth abnormalities (e.g. bent 
long bones and wavy ribs) in the offspring. In rats, these effects were reversible 8 weeks after 
cessation of treatment. 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Aspartame (E951) 
Maltodextrin 
Mannitol (E421) 
 
6.2 Incompatibilities 
 
Not applicable. 

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6.3 Shelf life 
 
- 3 years. 
- Once reconstituted in water, the suspension is stable for 24 hours. However, it is recommended 

to drink the suspension immediately after preparation (see section 4.2) 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Paper/polyethylene/aluminium/polyethylene sachets. 
 
Pack sizes 
Boxes containing 7, 14, 28, 56, 84 or 100 sachets. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
LES LABORATOIRES SERVIER 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/288/001 
EU/1/04/288/002 
EU/1/04/288/003 
EU/1/04/288/004 
EU/1/04/288/005 
EU/1/04/288/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21/09/2004 
Date of latest renewal: 22/05/2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency  http://www.ema.europa.eu 

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http://www.ema.europa.eu/


 13 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 

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A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Les Laboratoires Servier Industrie, 905, route de Saran - 45520 Gidy, France 
Przedsiebiorstwo Farmaceutyczne ANPHARM S.A., ul. Annopol 6B – 03-236 Warszawa, Poland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product 
are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) 
of Directive 2001/83/EC and any subsequent updates published on the European medicines 
web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 

 
Additional risk minimisation measures 

 
In each Member State where PROTELOS is marketed, the Marketing Authorisation Holder 
(MAH) shall agree the final educational programme with the National Competent Authority.  

The MAH shall ensure that, following discussion and agreement with the National Competent 
Authority in each Member State where PROTELOS is marketed, all physicians who are 
expected to prescribe PROTELOS are provided with the following educational package: 

• SmPC 

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• Package leaflet 
• Prescriber guide and checklist 
• Patient alert card 

 
The prescriber guide and checklist shall contain the following key messages: 

• PROTELOS is only indicated for use in patients with severe osteoporosis at high risk of 
fracture, for whom treatment with other medicinal products approved for the treatment 
of osteoporosis is not possible due to, for example, contraindications or intolerance.   

• The initiation of treatment with PROTELOS should be based on an assessment of the 
individual patient’s overall risk. 

• All patients should be fully informed that cardiovascular risks should be monitored on a 
regular basis generally every 6-12 months. 

• The patient alert card should be given to every patient. 
• PROTELOS is contraindicated and must not be used in patients with : 

o Established, current or past history of ischaemic heart disease, peripheral 
arterial disease and/or cerebrovascular disease. 

o Uncontrolled hypertension. 
o Current or previous venous thromboembolic events (VTE), including deep vein 

thrombosis and pulmonary embolism. 
o Temporary or permanent immobilisation due to e.g. post-surgical recovery or 

prolonged bed rest. 
o Hypersensitivity to the active substance (strontium ranelate) or any of the 

excipients. 
• PROTELOS should only be used with caution in: 

o Patients with significant risk factors for cardiovascular events such as 
hypertension, hyperlipidaemia, diabetes mellitus or smoking. 

o 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. 

• The treatment should be either discontinued or stopped in the following situations: 
o If the patient develops ischaemic heart disease, peripheral arterial disease, 

cerebrovascular disease or if hypertension is uncontrolled, the treatment should 
be stopped. 

o As soon as possible in the event of an illness or a condition leading to 
immobilization, the treatment should be discontinued. 

o If symptoms or signs of Stevens-Johnson Syndrome (SJS), Toxic Epidermal 
Necrolysis (TEN) or Drug Rash with Eosinophilia and Systemic Symptoms 
(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. If the 
patient has developed SJS, TEN or DRESS with the use of PROTELOS, 
PROTELOS must not be re-started. 

• Within the prescriber guide there will be a check-list to remind prescribers of the 
contraindications, warnings and precautions prior to prescribing and to support the 
regular monitoring of cardiovascular risk. 
 

The patient alert card shall contain the following key messages: 
• Importance of showing the patient alert card to any Health Care Professional involved in 

their treatment. 
• The contraindications to the treatment with PROTELOS. 

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• Key signs and symptoms of myocardial infarction, VTE and serious skin reactions. 
• When to seek urgent medical advice. 
• Importance of regularly monitoring cardiovascular risk. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

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A. LABELLING 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
PROTELOS 2 g granules for oral suspension 
Strontium ranelate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 2 g strontium ranelate. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains aspartame (E 951).  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension. 
7 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use 
 

 
 

 

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6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
If not used immediately after reconstitution, the preparation should be consumed within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/288/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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PROTELOS 2 g 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
PROTELOS 2 g granules for oral suspension 
Strontium ranelate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 2 g strontium ranelate. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains aspartame (E 951). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension. 
14 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use 
 

 
 

 

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6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
If not used immediately after reconstitution, the preparation should be consumed within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/288/002 
 

 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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PROTELOS 2 g 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
PROTELOS 2 g granules for oral suspension 
Strontium ranelate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 2 g strontium ranelate. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains aspartame (E 951). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension. 
28 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use 
 

 
 

 

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6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
If not used immediately after reconstitution, the preparation should be consumed within 24 hours. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/288/003 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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PROTELOS 2 g 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
PROTELOS 2 g granules for oral suspension 
Strontium ranelate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 2 g strontium ranelate. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains aspartame (E 951). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension. 
56 sachets 
84 sachets 
100 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use 

 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
If not used immediately after reconstitution, the preparation should be consumed within 24 hours. 
 

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9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/288/004 56 sachets 
EU/1/04/288/005 84 sachets (3 packs of 28) 
EU/1/04/288/006 100 sachets 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
PROTELOS 2 g 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Sachet 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
PROTELOS 2 g granules for oral suspension. 
Strontium ranelate. 
For oral use. 
 
 
2. METHOD OF ADMINISTRATION 
 

 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 g 
 
 
6. OTHER 
 
Read the package leaflet before use 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the patient 
 

PROTELOS 2 g granules for oral suspension 
Strontium ranelate 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or your pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet:  
1. What PROTELOS is and what it is used for 
2. What you need to know before you take PROTELOS 
3. How to take PROTELOS 
4. Possible side effects 
5. How to store PROTELOS 
6. Contents of the pack and other information 
 
 
1. What PROTELOS is and what it is used for 
 
PROTELOS is a medicine used to treat severe osteoporosis: 
- in postmenopausal women, 
- in adult men, 
at high risk of fracture, for whom other alternative treatments are not possible. In postmenopausal 
women, strontium ranelate reduces the risk of  fracture at the spine and at the hip. 
 
About osteoporosis 
Your body is constantly breaking down old bone and making new bone tissue. If you have 
osteoporosis, your body breaks down more bone than it forms so that gradually bone loss occurs and 
your bones become thinner and fragile. This is especially common in women after the menopause.  
Many people with osteoporosis have no symptoms and you may not even know that you have it. 
However, osteoporosis makes you more likely to have fractures (break bones), especially in your 
spine, hips and wrists. 
 
How PROTELOS works 
PROTELOS, which contains the substance strontium ranelate, belongs to a group of medicines used 
to treat bone diseases. 
PROTELOS works by reducing bone breakdown and stimulating rebuilding of bone and therefore 
reduces the risk of fracture. The newly formed bone is of normal quality. 
 
 
2. What you need to know before you take PROTELOS 
 
Do not take PROTELOS: 
- if you are allergic  to strontium ranelate or any of the other ingredients of PROTELOS (listed in 

section 6). 
- if you have or have had a blood clot (for example, in the blood vessels in your legs or lungs).  

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- if you are immobilised permanently or for some time such as being wheel-chair bound, or 
confined to bed or if you are to undergo an operation or recovering from an operation. The risk 
of vein thrombosis (blood clots in the leg or lungs) may be increased in the event of lengthy 
immobilisation. 

- if you have established ischaemic heart disease, or cerebrovascular disease, e.g. you have been 
diagnosed with a h eart attack, stroke, or transient ischaemic attack (temporary reduction of 
blood flow to the brain; also known as “mini-stroke”), angina, or blockages of blood vessels to 
the heart or brain.  

- if you have or have had problems with your blood circulation (peripheral arterial disease) or if 
you have had surgery on the arteries of your legs.  

- if you have high blood pressure not controlled by treatment.  
 
Warnings and precautions:  
Talk to your doctor or pharmacist before taking PROTELOS: 
- if you are at risk of heart disease, this includes  high blood pressure, high cholesterol, diabetes, 

smoking. 
- if you are at risk of blood clots.  
- if you have severe kidney disease. 
Your doctor will evaluate the conditions of your heart and blood vessels regularly, generally every 6 
to 12 months for as long you are taking PROTELOS. 
 
During treatment, if you experience an allergic reaction (such as swelling of the face, tongue or throat, 
difficulty in breathing or swallowing, skin rash), you must immediately stop taking PROTELOS and 
seek medical advice (see section 4).  
Potentially life-threatening skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis and 
severe hypersensitivity reactions (DRESS)) have been reported with the use of PROTELOS.  
The highest risk of occurrence of serious skin reactions is within the first weeks of treatment for 
Stevens-Johnson syndrome and toxic epidermal necrolysis and usually around 3-6 weeks for DRESS. 
If you develop a rash or serious skin symptoms (see section 4), stop taking PROTELOS, seek urgent 
advice from a doctor and tell him that you are taking this medicine. 
If you have developed Stevens-Johnson syndrome or toxic epidermal necrolysis or DRESS with the 
use of PROTELOS, you must not be re-started on PROTELOS at any time 
If you are of Asian origin, you may be at higher risk of skin reactions. 
The risk of these skin reactions in patients of Asian origin, particularly Han Chinese, may be 
predicted. Patients who have the HLA-A*33:03 and/or the HLA-B*58:01 genes are more likely to 
develop a serious skin reaction than those who do not have the genes.  
 Your doctor should be able to advise if a blood test is necessary before taking PROTELOS. 
 
Children and adolescents 
PROTELOS is not intended for use in children and adolescents (below the age of 18). 
 
Other medicines and PROTELOS: 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
You should stop taking PROTELOS if you have to take oral tetracyclines such as doxycycline or 
quinolones such as ciprofloxacin (two types of antibiotics). You can take PROTELOS again when 
you have finished taking these antibiotics. If you are unsure about this ask your doctor or pharmacist. 
If you are taking medicines containing calcium, you should leave at least 2 hours before you take 
PROTELOS. 
If you take antacids (medicines to relieve heartburn) you should take them at least 2 hours after 
PROTELOS. If this is not possible, it is acceptable to take the two medicines at the same time. 
If you need to have blood or urine tests to check your level of calcium, you should tell the laboratory 
that you are taking PROTELOS as it may interfere with some testing methods. 
 
PROTELOS with food and drink: 

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Food, milk and milk products reduce the absorption of strontium ranelate. It is recommended that you 
take PROTELOS in-between meals, preferably at bedtime at least two hours after food, milk or milk 
products or calcium supplements. 
 
Pregnancy and breast-feeding: 
Do not take PROTELOS during pregnancy or when you are breastfeeding. If you take it by accident 
during pregnancy or breastfeeding, stop taking it straight away and talk to your doctor. 
 
Driving and using machines: 
Protelos is unlikely to affect your ability to drive or use machines. 
 
PROTELOS contains aspartame (E951): 
If you suffer from phenylketonuria (a rare, hereditary disorder of the metabolism) talk to your doctor 
before you start to take this medicine. 
 
 
3. How to take PROTELOS 
 
The treatment should only be started by a doctor with experience in treating osteoporosis. 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
PROTELOS is for oral use. 
The recommended dose is one 2 g sachet a day. 
 
It is recommended that you take PROTELOS at bedtime, preferably at least 2 hours after dinner. You 
may lie down immediately after taking PROTELOS if you wish.  
 
Take the granules contained in the sachets as a suspension in a glass containing a minimum of 30 ml 
(approximately one third of a standard glass) of water. See instructions below. PROTELOS can 
interact with milk and milk products, so it is important that you mix PROTELOS only with water to 
be sure it works properly. 
 

 Empty the granules from the sachet into a glass; 
 

  Add water; 
 

  Stir until the granules are evenly dispersed in the water. 
 
Drink straight away. You should not leave more than 24 hours before you drink it. If for some reason 
you cannot drink the medicine straight away, make sure you stir it again before drinking.  
 
Your doctor may advise you to take calcium and vitamin D supplements in addition to PROTELOS. 
Do not take calcium supplements at bedtime, at the same time as PROTELOS. 
 

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Your doctor will tell you how long you should continue to take PROTELOS. Osteoporosis-therapy is 
usually required for a long period. It is important that you continue taking PROTELOS for as long as 
your doctor prescribes the medicine. 
 
If you take more PROTELOS than you should: 
If you take more sachets of PROTELOS than recommended by your doctor, tell your doctor or 
pharmacist. They may advise you to drink milk or take antacids to reduce the absorption of the active 
ingredient. 
 
If you forget to take PROTELOS: 
Do not take a double dose to make up for forgotten individual doses. Just carry on with the next dose 
at the normal time. 
 
If you stop taking PROTELOS: 
It is important that you continue taking PROTELOS for as long as your doctor prescribes the 
medicine. PROTELOS can treat your severe osteoporosis only if you continue to take it. 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If the following happens to you, stop using PROTELOS and talk to your doctor immediately: 
 
Common (may affect up to 1 in 10 people):  
− Heart attack: sudden crushing pains in your chest which may reach your left arm, jaw, stomach, 

back and/or shoulders. Other symptoms may be nausea/vomiting, sweating, shortness of breath, 
palpitations, (extreme) tiredness and/or dizziness. Heart attack may occur commonly in patients 
at high risk for heart disease. Your doctor will not prescribe PROTELOS for you if you are at 
particular risk.   

− Blood clots in veins: pain, redness, swelling in your leg, sudden chest pain or difficulty 
breathing. 

 
Rare (may affect up to 1 in 1000 people): 
− Signs of severe hypersensitivity reactions (DRESS): initially as flu-like symptoms and a rash on 

the face then an extended rash with a high temperature (uncommon), increased levels of liver 
enzymes seen in blood tests (uncommon) an increase in a type of white blood cell (eosinophilia) 
(rare) and enlarged lymph nodes (uncommon). 

 
Very rare (may affect up to 1 in 10,000 people): 
− Signs of potentially life-threatening skin rashes (Stevens-Johnson syndrome, toxic epidermal 

necrolysis): initially as reddish target-like spots or circular patches often with central blisters on 
the trunk. Additional signs may include ulcers in the mouth, throat, nose, genitals and 
conjunctivitis (red and swollen eyes). These potentially life-threatening skin rashes are often 
accompanied by flu-like symptoms. The rash may progress to widespread blistering or peeling 
of the skin. 

 
Other possible side effects 
 
Very Common (may affect more than 1 in 10 people):  
Itching, hives, skin rash, angioedema (such as swollen face, tongue or throat, difficulty in breathing or 
swallowing), bone, limb, muscle and/or joint pain, muscle cramps. 
 
Common:  

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 36 

Vomiting, abdominal pain, reflux, indigestion, constipation, flatulence, difficulty in sleeping, 
inflammation of the liver (hepatitis), swelling in limbs, bronchial hyperreactivity (symptoms include 
wheezing and shortness of breath and cough), increased level of a muscle enzyme (Creatine 
phosphokinase), increased levels of cholesterol. 
Nausea, diarrhoea, headache, eczema, memory trouble, fainting fit, pins and needles, dizziness, 
vertigo. However, these effects were mild and short-lived and usually did not cause the patients to 
stop taking their treatment. Talk to your doctor if any effects become troublesome or persist. 
 
Uncommon (may affect up to 1 in 100 people): 
Seizures, oral irritation (such as mouth ulcers and gum inflammation), hair loss, feeling confused, 
feeling unwell, dry mouth, skin irritation. 
 
Rare: 
Reduction in production of blood cells in the bone marrow.  
 
If you have stopped treatment due to hypersensitivity reactions, do not take PROTELOS again. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store PROTELOS 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the box and the sachet after EXP. 
The expiry date refers to the last day of that month. 
 
This medicinal product does not require any special storage conditions. 
 
Once reconstituted in water, the suspension is stable for 24 hours. However, it is recommended to 
drink the suspension immediately after preparation (see section 3). 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help  protect the environment. 
 
 
6. Contents of the pack and other information 
 
What PROTELOS contains 
- The active substance is strontium ranelate. Each sachet contains 2 g of strontium ranelate.  
- The other ingredients are aspartame (E 951), maltodextrin, mannitol (E 421). 
 
What PROTELOS looks like and contents of the pack 
PROTELOS is available in sachets containing yellow granules for oral suspension. PROTELOS is 
supplied in boxes of 7, 14, 28, 56, 84 or 100 sachets.  
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 37 

Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
Manufacturer(s) 
Les Laboratoires Servier Industrie 
905, route de Saran 
45520 Gidy 
France 
 
Anpharm Przedsiebiorstwo Farmaceutyczne S.A. 
03-236 Warszawa 
ul. Annopol 6B 
Poland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Lietuva 
UAB “SERVIER PHARMA” 
Tel: +370 (5) 2 63 86 28 
 

България 
Сервие Медикал ЕООД 
Тел.: +359 2 921 57 00 
 

Luxembourg/Luxemburg 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Česká republika 
Servier s.r.o. 
Tel: +420 222 118 111 
 

Magyarország 
Servier Hungaria Kft. 
Tel: +36 1 238 7799 

Danmark 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Malta 
Galepharma Ltd 
Tel: +(356) 21 247 082 

Deutschland 
Servier Deutschland GmbH 
Tel: +49 (0)89 57095 01 
 

Nederland 
Servier Nederland Farma B.V. 
Tel: +31 (0)71 5246700 
 

Eesti 
Servier Laboratories OÜ 
Tel:+ 372 664 5040 

Norge 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Eλλάδα 
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ 
Τηλ: +30 210 939 1000 
 

Österreich 
Servier Austria GmbH 
Tel: +43 (1) 524 39 99 
 

España 
Laboratorios Servier S.L. 
Tel: +34 91 748 96 30 
 

Polska 
Servier Polska Sp. z o.o. 
Tel: +48 (0) 22 594 90 00 
 

France 
Les Laboratoires Servier 
Tel: +33 (0)1 55 72 60 00 
 

Portugal 
Servier Portugal, Lda 
Tel.: +351 21 312 20 00 

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 38 

Hrvatska  
Servier Pharma, d. o. o.  
Tel.: +385 (0)1 3016 222  
 

România 
Servier Pharma SRL 
Tel: +40 21 528 52 80 

Ireland 
Servier Laboratories (Ireland) Ltd. 
Tel: +353 (0)1 6638110 

Slovenija 
Servier Pharma d.o.o.  
Tel.: +386 (0)1 563 48 11 

 
Ísland 
Servier Laboratories 
c/o Icepharma hf 
Sími: +354 540 8000 

 
Slovenská republika 
Servier Slovensko spol. s r.o. 
Tel.:+421 (0) 2 5920 41 11 

 
Italia 
Servier Italia S.p.A. 
Tel: +39 06 669081 

 
Suomi/Finland 
Servier Finland Oy 
P./Tel: +358 (0)9 279 80 80 
 

Κύπρος 
C.A. Papaellinas Ltd. 
Τηλ: +357 22741741 
 

Sverige 
Servier Sverige AB 
Tel: +46 (0)8 522 508 00 
 

Latvija 
SIA Servier Latvia 
Tel. +371 67502039 
 

United Kingdom 
Servier Laboratories Ltd 
Tel: +44 (0)1753 666409 

 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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http://www.ema.europa.eu/


 

39 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

Annex IV 

Scientific conclusions and grounds for the variation to the terms of the marketing authorisation 
 
 
 
 

 

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40 

Scientific conclusions 

Taking into account the PRAC Assessment Report for the non-interventional imposed PASS final 
study report for the medicinal product mentioned above, the scientific conclusions of CHMP are 
as follows:  

The PASS final study report submitted by the MAH complies with their obligation to perform a 
PASS to evaluate risk of serious cardiac disorders as imposed during the Article 20 procedure 
EMA/112925/2014. 

Therefore, in view of available data regarding the PASS final study report, the PRAC considered 
that changes to the conditions of the marketing authorization were warranted. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation 

On the basis of the scientific conclusions for the results of the study for the medicinal product 
mentioned above, the CHMP is of the opinion that the benefit-risk balance of this medicinal 
product is unchanged, subject to the proposed changes to the product information. 

The CHMP is of the opinion that the terms of the marketing authorisation of the medicinal 
product mentioned above should be varied. 

 

 
 

 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions and grounds for the variation to the terms of the marketing authorisation