OSSEOR .2 gr 28 sachets
OSSEOR .2 gr 28 sachets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each sachet contains 2 g Strontium ranelate.Za excipients, see section 6.1.
3 . PHARMACEUTICAL FORM
Granules for oral suspension
4 . CLINICAL FEATURES
Treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures (see section 5.1).
4.2 . Dosage and method of administration
The recommended daily dose is one 2 g sachet oral ednokratno.Poradi nature of the treated disease, strontium ranelate is intended for long term use.
Absorption of strontium ranelate is reduced by food, milk and derivative products and therefore PROTELOS should be given between meals. Given the slow absorption, PROTELOS should be taken at bedtime , at least two hours after eating (see sections 4.5 and 5.2). Granules in sachet should be dissolved in a glass of water. Although research in the application have demonstrated that strontium ranelate is stable in suspension for 24 hours after preparation , the suspension should be drunk immediately after being prepared .
Patients treated with strontium ranelate should receive vitamin D and calcium supplements if dietary intake is inadequate .
Use in elderly people is
The efficacy and safety of strontium ranelate have been established for a wide age group of women after menopause ( to incl. 100 years old) suffering from osteoporosis. No adjustment is necessary to age .
Use in renal impairment
There is no need for any dose adjustment in mild to moderate renal impairment (creatinine clearance 30-70 ml / min) ( see section 5.2). Strontium ranelate is not recommended in patients with severe renal impairment (creatinine clearance below 30 ml / min) ( see sections 4.4 and 5.2).
Use in hepatic impairment
As strontium ranelate is not metabolised , does not need any dose adjustment in patients with hepatic impairment.
Use in children and adolescents
The efficacy and safety of strontium ranelate have not been established in children and adolescents and use of these age groups is not recommended.
Hypersensitivity to the active substance or to any of the excipients .
4.4 Special warnings and precautions for use
In the absence of data on bone safety in patients with severe renal impairment treated with strontium ranelate , PROTELOS is not recommended in patients with creatinine clearance less than 30 ml / min ( see section 5.2). In accordance with good medical practice , periodic assessment of renal function in patients with chronic renal impairment. Continuation of treatment with PROTELOS in patients developing severe renal impairment should be assessed individually.
In the phase III placebo - kontrodiranite studies ranelate treatment was associated with an increase in the annual incidence of venous thromboembolism ( VTE), including pulmonary embolism (see section 4.8). The reason for this is not known. PROTELOS should be used with caution in patients at increased risk of VTE, including patients with a history of VTE. In the treatment of patients at risk , or developing risk of VTE, particular attention should be given to possible signs and symptoms of VTE and should be adequate preventive measures taken .
Strontium interferes with colorimetric methods for determining the concentration of calcium in blood and urine Therefore , in medical practice to use , inductively coupled plasma atomic emission spectrometry or atomic absorption spectrometry in order to perform accurate examination of the calcium concentration in blood and urine.
PROTELOS contains phenylalanine which may be harmful for people with phenylketonuria.
4.5 Drug 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, taking PROTELOS and such products should be separated by at least two hours ( see section 5.2).
In vivo clinical interaction study showed that the administration of aluminum and magnesium hydroxides either two hours before or together with strontium ranelate caused a slight decrease in the absorption of strontium ranelate ( 20-25 % decrease in AUC). At the same time , the absorption was almost unaffected when the antacid was given two hours after strontium ranelate . Therefore it is preferable antacids be taken 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.
As divalent cations can form complexes with oral tetracycline and quinolone antibiotics in the digestive tract, and thereby reduce their absorption , simultaneous administration of strontium ranelate with these medicinal products is not recommended . As a precautionary measure , PROTELOS treatment should be withheld during treatment with oral tetracycline or quinolone antibiotics .
No interaction was observed with supplements of vitamin D, taken peroralno.Pri clinical studies have not found any clinical interactions or relevant increase of blood strontium levels with medicinal products that are commonly prescribed together with PROTELOS in the target population . These include : non-steroidal anti-inflammatory drugs ( including aspirin ) , 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 antagonists , selective beta-2 adrenoceptor agonists , oral anti-coagulants , inhibitors of platelet aggregation , statins, fibrates and benzodiazepine derivatives .
4.6 Pregnancy and lactation
PROTELOS is intended for use by women after menopause.
We have no clinical data on pregnancies exposed to strontium ranelate . Animal studies have shown reversible bone effects in the offspring of rats and rabbits treated with large doses during pregnancy (see section 5.3). If PROTELOS is used inadvertently during pregnancy, treatment should be immediately spryano.Strontsiumat is excreted in milk . Strontium ranelate should not be given to nursing women .
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
PROTELOS has been studied in clinical trials , which involved almost 8,000 people. Long-term safety has been evaluated in postmenopausal women with osteoporosis treated for up to 56 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 enrollment , and 23% of the patients were between 80 and 100 years.
The overall incidence of adverse effects of strontium ranelate different from placebo and adverse events were usually mild and transient. The most common side effects are nausea and diarrhea , which are usually observed at the beginning of the treatment with no apparent difference in the groups below. Discontinuation of therapy was mainly due to nausea (1.3% and 2.2% respectively in the placebo and strontium ranelate ) .
Adverse reactions, defined as adverse events considered at least possibly attributable to strontium ranelate treatment in phase III studies are listed below using the following convention ( frequencies versus placebo) :
very common (> 1 /10), common (> 1/100 , <1 /10) times (> 1/1 , 000 to <1 /100) , rare (> 1/10 , 000, <1/1 , 000 ) very rare (< 1/10 , 000 ) .
Disorders of the nervous system
Common: headache (3.0 % vs. 2.4%)
Gastro - intestinal disorders
Common: nausea (6.6% vs. 4.3 %) , diarrhea (6.5 % vs. 4.6%) , loose stools (1.1% vs. 0.2 %)
Disorders of the skin and subcutaneous tissue
Common: dermatitis (2.1 % vs. 1.6%) , eczema (1.5% vs 1.2 %)
There were no differences in the nature of adverse events between treatment groups regardless of whether patients were aged below or above 80 at inclusion .
In Phase III studies, the annual incidence of venous thromboembolism (VTE ) observed over four years was approximately 0.7%, with a relative risk of 1,42 (CI 1,02; 1,98, p = 0.036 ) in patients treated with strontium ranelate compared to placebo (see section 4.4)
In phase III studies, over 4 years, disturbances of the nervous system were observed with greater frequency in patients treated with strontium ranelate , compared with those receiving placebo: disturbances in consciousness (2.5% versus 2 0%), memory loss ( 2.4% vs 1.9%) , and seizures (0.3% against 0.1%)
Evidence from laboratory studies
Reported transient occurring increases ( > 3 times the upper limit of normal) in creatine kinase ( CK) ( fraction of skeletal muscle ) at 1.0% and 0.4% respectively of the groups treated with strontium ranelate and placebo . In most cases, these values have been normalized spontaneously without change in treatment .
Good tolerance was shown in a clinical study investigating the repeated administration of 4 g strontium ranelate per day for 25 days in healthy postmenopausal women doses up to 11 g in healthy male volunteers did not cause any particular simptomi.V Following episodes of overdoses in clinical trials (up to 4 g / day for most - duration 147 days), there were no clinically relevant proyavi.Priemaneto milk or antacids may be helpful to reduce the absorption of the active substance . In cases of substantial overdose may be considered to induce vomiting to remove unabsorbed active substance .
5 . Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases - Other drugs affecting bone structure and mineralization
ATC code : M05BX03
In vitro , strontium ranelate :
increases bone formation in bone tissue culture and replication of osteoblast precursors and collagen synthesis in bone cell cultures , reduced bone resorption and decreased differentiation and resorbing activity of osteoclast This causes a rebalancing of bone turnover in favor of formation of kosttaAktivnostta strontium ranelate was studied in various non-clinical models. In particular, in intact rats, strontium ranelate increases trabecular bone mass , the number and thickness of trabeculae , this leads to the 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 . Bone from the iliac crest bone biopsies obtained after 60 months of treatment with strontium ranelate 2 g / day in phase III studies , no deleterious effects on bone quality or mineralization her
The combined effects of strontium distribution in bone ( see section 5.2) and increased X-ray absorption of strontium as compared to calcium, leading to increased 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 anti-fracture efficacy of treatment with PROTELOS measured BMD increased from baseline by 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, the biochemical markers of bone formation (bone specific alkaline phosphatase, and the C- terminal propeptide of procollagen type I) are increased , and those of bone resorption (serum C- telopeptide and N- crosslinked telopeptide of urine) decreased from the third month of treatment up to 3 years.
Secondary to the pharmacological effects of strontium ranelate slight decreases in serum calcium and parathyroid hormone ( PTH ) , an increase in the blood level of phosphorus and the activity of total alkaline phosphatase were observed without any clinical consequences
Osteoporosis is defined as BMD of the spine or hip 2.5 SD below the mean value of a normal young population. Postmenopausal osteoporosis combined with several risk factors, including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequences of osteoporosis are fractures. The risk of fracture is increased by the number of risk factors.
Treatment of postmenopausal osteoporosis :
Program PROTELOS anti-fracture studies based on two placebo- controlled trials - Phase III: SOTI study and TROPOS. SOTI involved 1,649 postmenopausal women with established osteoporosis (low lumbar BMD and prevalent vertebral fracture ) and a mean age of 70 years old. 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 the beginning of the study (23.1 % of the study population) . To treatment (2 g / day strontium ranelate or placebo) patients receiving concurrent adapted calcium and vitamin D in both prouchvaniya.OSEOR reduced the relative risk of new vertebral fractures by 41 % over 3 years in the study SOTI ( 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 loss of body height at least 1 cm), the relative risk was reduced by 38%. PROTELOS also decreased the number of patients with a height loss of at least 1 cm as compared to placebo. The assessment of quality of life in specific scale QUALIOST, and ball feel for the overall health of the overall SF- 36 scale indicated benefit of PROTELOS compared with placebo.
The efficacy of PROTELOS to reduce the risk of new vertebral fracture was confirmed by the study TROPOS, including osteoporotic patients without fractures at baseline . In patients aged over 80 years 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 a posteriori analysis of patients from the SOTI and TROPOS studies with baseline BMD of the lumbar spine and / or femoral neck BMD in the osteopenic range and without fracture, but there is at least I additional risk factor for fracture (N = 176) , PROTELOS reduces 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).
Was conducted a posteriori analysis of the subgroup of patients from the TROPOS study of particular medical interest and increased risk of fracture [defined by T score of femoral neck BMD <3 SD ( manufacturer's range corresponding to - 2.4 SD if applied NHANESIII) and age > 74 years (n = 1,977 , ie 40% »of the group studied by TROPOS)]. In this treatment group over 3 years PROTELOS reduces the risk of fracture of femur by 36% compared with the placebo group ( Table 2) .
5.2 Farmakokinetnchnn properties
Strontium ranelate is made up of 2 atoms of stable strontium and 1 molecule ranelic organic part permitting the - best compromise in terms of molecular weight , pharmacokinetics and tolerability of the drug. Mr. pharmacokinetics and strontium and ranelic acid were investigated in healthy young men and healthy postmenopausal women , as well as long-term exposure in postmenopausal women with osteoporosis , including many elderly women .
Due to its high polarity, the absorption , distribution and plasma protein binding of ranelic acid are low. No accumulation of ranelic acid and no detectable metabolism in animals and humans. Once absorbed ranelic acid is rapidly eliminated by the kidneys.
The absolute bioavailability of strontium is about 25% (range 19-27 %) after oral dose of 2 g of strontium ranelate . The maximum plasma concentration is reached 3 to 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 to 3 hours after a meal.