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עמוד הבית / פרוטלוס / מידע מעלון לרופא

פרוטלוס PROTELOS (STRONTIUM RANELATE)

תרופה במרשם תרופה בסל נרקוטיקה ציטוטוקסיקה

צורת מתן:

פומי : PER OS

צורת מינון:

גרנולות להכנת תרחיף פומי : GRANULES FOR ORAL SUSPENSION

Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

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 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   32.8%                     20.9%                     41% (27-52), p<0.001 over 3 years
New vertebral fracture   11.8%                     6.1%                      49% (26-64), p<0.001 over the 1st year
New clinical vertebral   17.4%                     11.3%                     38% (17-53), p<0.001 fracture over 3 years
TROPOS                   N=1823                    N=1817
New vertebral fracture   20.0%                     12.5%                     39% (27-49), p<0.001 over 3 years


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 

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).

Pharmacokinetic Properties

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 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
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

Older people
Population 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.

פרטי מסגרת הכללה בסל

א. התרופה האמורה תינתן לטיפול במקרים האלה: 1. חולות אוסטיאופורוזיס פוסט מנופאוזליות הזכאיות לטיפול על פי הקריטריונים הקיימים בסל לטיפול בביספוספונאטים או Raloxifene לאחר מיצוי הטיפולים הפומיים הקיימים בסל או החמרה מובהקת של אוסטיאופורוזיס בטיפול קבוע בביספוספונאטים או רלוקסיפן בשנתיים האחרונות; 2. אוסטיאופורוזיס בנשים פוסט מנופאוזליות לאחר שבר בצוואר הירך. ב. קיבל החולה טיפול ב-Zoledronic acid – לא יקבל טיפול ב-Densoumab או Strontium Ranelate 12 חודשים מהמנה האחרונה. ג. קיבל החולה טיפול ב-Denosumab – לא יקבל טיפול ב-Zoledronic acid או Strontium Ranelate 6 חודשים מהמנה האחרונה

מסגרת הכללה בסל

התוויות הכלולות במסגרת הסל

התוויה תאריך הכללה תחום קליני Class Effect מצב מחלה
אוסטיאופורוזיס בנשים פוסט מנופאוזליות לאחר שבר בצוואר הירך 10/01/2012
חולות אוסטיאופורוזיס פוסט מנופאוזליות 10/01/2012
שימוש לפי פנקס קופ''ח כללית 1994 לא צוין
תאריך הכללה מקורי בסל 10/01/2012
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142 09 31882 00

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