qanastek/EMEA-V3 huggingface dataset:
prevalent fracture at baseline Percentage of patients with new fracture Non-vertebral fractures Percentage of patients with non-vertebral fracture
ksur prevalenti fil- linja bażi Perċentwal ta ’ pazjenti bi ksur
n=1,970 4.4% n=2,852 8.1%
4. 4% n=2, 852
n=1,970 7.4% n=2,852 10.4%
7. 4% n=2, 852
All clinical fractures
li mhuwiex vertebrali Il- ksur kliniku kolluPerċentwal ta ’ pazjenti bi ksur kliniku
n=2,852 n=2,852
8. 1% n=2, 852
25%e
10. 4% n=2, 852
Percentage of patients with clinical fracture Abbreviations: n= number of patients; CI = Confidence Intervals a
(9%, 36%) 25% e
p < 0.0001; b p = 0.0004; c p = 0.0002; d p = 0.0020; e p = 0.0004
Taqsir: n= numru ta ’ pazjenti; IK = Intervalli ta ’ Kunfidenza ap p = 0. 0020; e p = 0. 0004
-Radiographic vertebral fractures
- Ksur vertebrali radjografiku
FABLYN significantly decreased the incidence of new radiographic vertebral fractures (excluding worsening of previous fractures) from 9.3% for placebo to 5.6% for FABLYN (relative risk reduction = 41%, p < 0.0001).
FABLYN naqqas l- inċidenza ta ’ ksur vertebrali radjografiku ġdid (eskluż ksur li diġà kien eżistenti qabel, u li mar għall- agħar) b’ mod sinifikanti minn 9. 3% għall- plaċebo għal 5. 6% għal FABLYN (tnaqqis relattiv tar- riskju = 41%, p < 0. 0001).
This decrease was observed through the first year and was maintained through 5 years.
Dan it- tnaqqis kien osservat matul l- ewwel sena u nżamm matul il- 5 snin.
In women with a prevalent vertebral fracture at baseline, FABLYN significantly reduced the incidence of new vertebral radiographic fractures from 14.2% for placebo to 8.7% for FABLYN (relative risk reduction = 42%, p = 0.0004).
F’ nisa bi ksur vertebrali prevalenti fil- linja bażi, FABLYN naqqas l- inċidenza ta ’ ksur vertebrali radjografiku ġdid b’ mod sinifikanti, minn 14. 2% għall- plaċebo għal 8. 7% għal FABLYN (tnaqqis relattiv tar- riskju = 42%, p = 0. 0004).
In women without any prevalent vertebral fractures at baseline, the incidence of new radiographic vertebral fractures was significantly reduced from 7.4% for placebo to 4.4% for FABLYN (relative risk reduction = 41%, p = 0.0002).
F’ nisa li ma kellhomx ksur vertebrali prevalenti fil- linja bażi, l- inċidenza ta ’ ksur vertebrali radjografiku ġdid naqset b’ mod sinifikanti, minn 7. 4% għall- plaċebo għal 4. 4% għal FABLYN (tnaqqis relattiv tar- riskju = 41%, p = 0. 0002).
Significantly fewer women experienced multiple radiographic vertebral fractures in the FABLYN treatment group versus the placebo group throughout 5 years of dosing (p < 0.0001).
11 Ammont inqas sewwa ta ’ nisa esperjenzaw ksur vertebrali radjografiku multiplu fil- grupp li kienu qegħdin jiġu kkurati b’ FABLYN kontra l- grupp li kienu qegħdin jiġu kkurati bil- plaċebo matul il- 5 snin ta ’ dożaġġ (p < 0. 0001).
Significantly fewer women treated with FABLYN experienced moderate or severe vertebral fractures (as determined by the Genant scale) compared to women treated with placebo (5.2% placebo-treated women versus 3.3% FABLYN-treated women; p = 0.0006).
Ammont inqas sewwa ta ’ nisa kkurati b’ FABLYN esperjenzaw ksur vertebrali moderat jew sever (kif determinat mill- iskala Genant) meta pparagunat man- nisa li ġew ikkurati bil- plaċebo (5. 2% tan- nisa kkurati bil- plaċebo kontra 3. 3% tan- nisa kkurati b’ FABLYN; p = 0. 0006).
10 -Non-vertebral fractures
- Ksur li mhuwiex vertebrali
FABLYN significantly decreased the incidence of non-vertebral fractures from 10.4% for placebo to 8.1% for FABLYN (relative risk reduction = 24%, p = 0.0020).
FABLYN naqqas, b’ mod sinifikanti, l- inċidenza tal- ksur li mhuwiex vertebrali, minn 10. 4% għall- plaċebo għal 8. 1% għal FABLYN (tnaqqis relattiv tar- riskju = 24%, p = 0. 0020).
This decrease was observed through the first year and was maintained through 5 years.
Dan it- tnaqqis ġie osservat matul l- ewwel sena u nżamm matul il- 5 snin li huma.
The reduction in the incidence of non-vertebral fractures was also observed in postmenopausal women with severe osteoporosis (defined as a baseline lumbar spine BMD T-score ≤ -2.5 + prevalent fracture or BMD T-score ≤ -3) (p = 0.0183).
It- tnaqqis fl- inċidenza ta ’ ksur li mhuwiex vertebrali kien osservat ukoll f’ nisa li diġà għaddew mill- menopawsa li jbatu minn osteoporożi severa (kif definita bħala linja bażi tal- ispina lumbari BMD T- score ≤ - 2. 5 + ksur prevalenti jew BMD T- score ≤ - 3) (p = 0. 0183).
-All clinical fractures
- Il- ksur kliniku kollu
FABLYN significantly decreased the incidence of all clinical fractures from 12.1% for placebo to 9.3% for FABLYN (relative risk reduction = 25%, p = 0.0004).
FABLYN naqqas l- inċidenza tal- ksur kliniku kollu b’ mod sinifikanti, minn 12. 1% għall- plaċebo għal 9. 3% għal FABLYN (tnaqqis relattiv tar- riskju = 25%, p = 0. 0004).
This decrease was observed through the first year and maintained through 5 years.
Dan it- tnaqqis kien osservat fl- ewwel sena u nżamm matul il- 5 snin li huma.
-Bone mineral density
- Id- densità tal- minerali fl- għadam
In a 3-year substudy of the PEARL study (n=760), FABLYN significantly increased BMD (compared to placebo) at lumbar spine (3.3%), total hip (3.0%), femoral neck (3.3%), greater trochanter (3.6%), intertrochanteric area (2.6%), Ward’ s triangle (5.9%) and forearm (1.8%) at 3 years.
Fi studju ta ’ 3 snin li jifforma parti mill- istudju PEARL (n=760), FABLYN żied il- BMD b’ mod sinifikanti (meta pparagunat mal- plaċebo) fl- ispina lumbari (3. 3%), fil- ġenbejn kollha (3. 0%), fl- għonq femorali (3. 3%), fil- trochanter il- kbir (3. 6%), fl- arja intertrochanteric (2. 6%), fit- triangolu Ward (5. 9%) u fid- driegħ mill- minkeb sal- polz jew sat- truf tas- swaba ’ (1. 8%) wara 3 snin.
FABLYN also significantly increased whole body bone mineral content (BMC), compared to placebo, at 3 years.
Wara 3 snin, FABLYN żied ukoll b’ mod sinifikanti l- ammont ta ’ minerali fil- ġisem kollu (BMC) meta pparagunat mal- plaċebo.
Significant increases in BMD were observed as early as 3 months for lumbar spine and total hip.
Sa minn wara 3 xhur biss minn meta nbeda l- istudju ġew osservati żidiet sinifikanti fil- BMD tal- ispina lumbari u tal- ġenbejn kollha.
An analysis was conducted of the subjects who were referred to their physician for consideration of treatment with an alternative osteoporosis medicinal product if one of the following was observed: a) ≥ 7% BMD loss at LS or ≥ 10% BMD loss at femoral neck at Month 12; b) ≥ 11% BMD loss at lumbar spine (LS) or ≥ 14% BMD loss at femoral neck at Month 24; c) ≥ 2 on-study radiographic vertebral fractures by Month 24.
Saru analiżi ta ’ dawk is- suġġetti li ġew referuti għand it- tabib tagħhom biex jikkunsidra li jagħtihom kura bi prodott mediċinali tal- osteoporożi ieħor jekk huwa jinnota wieħed mis- segwenti: a) telf ta ’ ≥7% tal- BMD tal- bażi tal- ispina lumbari jew telf ta ’ ≥10% tal- BMD tal- għonq femorali fit- 12- il Xahar; b) telf ta ’ ≥11% tal- BMD tal- ispina femorali (LS) jew telf ta ’ ≥14% tal- BMD tal - għonq femorali fl- 24 Xahar; c) ≥2 ksur vertebrali li jseħħ matul l- istudju radjografiku sa l- 24 Xahar.
These referrals were significantly less frequent in the FABLYN group (0.9%) than in the placebo group (3.3%).
Dawn ir- referenzi kienu inqas frekwenti b’ mod sinifikanti fil- grupp li kien ikkurat b’ FABLYN (0. 9%) milli fil- grupp li kien ikkurat bil- plaċebo (3. 3%).
Results from one-year trial in Asian subjects
Riżultati minn prova ta ’ sena f’ suġġetti Asjatiċi
The effects of FABLYN on BMD in postmenopausal Japanese, Korean and Taiwanese women with osteoporosis were also examined in a one-year, randomized, placebo-controlled, double-blind osteoporosis treatment trial.
L- effetti ta ’ FABLYN fuq il- BMD f’ nisa Ġappuniżi, Koreani, u Tajwaniżi li diġà għaddew mill- menopawsa li jbatu mill- osteoporożi kienu eżaminati wkoll fi prova dwar il- kura tal- osteoporożi li kienet randomized, kontrollata bil- plaċebo u double- blind.
The study population consisted of 497 women with osteoporosis as defined by low vertebral BMD (T-score ≤ 2.5).
Il- populazzjoni li fuqha kien qiegħed isir l- istudju kienet tikkonsisti f’ 497 mara bl- osteoporożi, kif jirriżulta mill- BMD vertebrali baxx tagħhom (Riżultat T ≤ 2. 5).
Women in this study had a median age of 63 years (range 44 to 79) and a median time since menopause of 13 years.
In- nisa li kienu qegħdin jipparteċipaw f’ dan l- istudju kellhom età medja ta ’ 63 sena (medda minn 44 sa 79 sena) u medja ta ’ 13- il sena minn meta kellhom il- menopawa.
All women in the study received calcium (600-1200 mg/ day) and Vitamin D (400-800 IU/ day).
In- nisa kollha li kienu qegħdin jipparteċipaw fl- istudju kienu qegħdin jirċievu l- kalċju (600- 1200 mg/ kuljum) u l- Vitamina D (400- 800 IU/ kuljum).
In this study, FABLYN significantly increased spine and hip (total hip and all subcomponents of the hip) BMD by 2 to 4%.
12 F’ dan l- istudju FABLYN żied, b’ mod sinifikanti, il- BMD tal- ispina u l- ġenbejn (il- ġenbejn kollha u l- komponenti li jagħmlu parti mill- ġenbejn) b’ minn 2 sa 4%.
It also reduced markers of bone turnover.
FABLYN ikkawża ukoll tnaqqis fil- markaturi tal- immudellar tal- għadam mill- ġdid.
Bone histomorphometry
Istomorfometrija tal- għadam
Bone formed during two years’ administration of lasofoxifene is of normal quality.
L- għadam li jifforma matul perjodu ta ’ sentejn li fih persuna tkun qiegħda tieħu lasofoxifene ikun ta ’ kwalità normali.
To assess bone quality, bone biopsies were obtained from 71 postmenopausal women enrolled in BMD trials after 2 years of treatment.
Biex tiġi evalwata l- kwalità tal- għadam, saru l- bijopsiji fuq 71 mara li diġà għaddew mill- menopawsa u li kienu qegħdin jipparteċipaw fi provi fuq il- BMD wara sentejn ta ’ kura b’ lasofoxifene.
There was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, woven bone or other abnormalities affecting the quality of the bone following lasofoxifene treatment.
Wara l- kura b’ lasofoxifene, ma kien hemm l- ebda evidenza ta ’ osteomalaċja, fibrożi tal- mudullun, tossiċità ċellulari, għadam temporanju li jifforma meta jkun hemm korriment u li ma jkunx b’ saħħtu ħafna jew ta ’ anormalitajiet oħra li jaffetwaw il- kwalità tal- għadam.
Effects on the endometrium:
Effetti fuq l- endometriju:
The following results of the effects of FABLYN on the endometrium through 5 years of exposure are reported from the PEARL study.
Ir- riżultati li ġejjin tal- effetti ta ’ FABLYN fuq l- endometriju matul l- ewwel 5 snin tal- esponiment ġew irrappurtati mill- istudju PEARL.
There was no difference between FABLYN- and placebo-treated women in the incidences of endometrial carcinoma and endometrial hyperplasia.
Fl- inċidenza tal- karċinoma fl- endometriju u l- iperplasija tal- endometriju, ma kien hemm l- ebda differenza bejn in- nisa li kienu kkurati b’ FABLYN u dawk li kienu kkurati bil- plaċebo.
11 Lasofoxifene may be associated with benign endometrial effects: endometrial cystic change viewed on ultrasound and histological benign cystic atrophy (a variant of atrophic endometrium), contributing to approximately 1.5 mm increase in mean endometrial thickness.
Lasofoxifene jista ’ jiġi assoċjat ma ’ effetti beninni tal- endometriju: bidla fiċ- ċesti tal- endometriju li tidher fl- eżami ultrasoniku u atrofija istoloġika bennina taċ- ċesti (varjant tal- atrofija tal- endometriju), li jikkontribwixxu għal żieda ta ’ bejn wieħed u ieħor 1. 5 mm fil- ħxuna medja tal- endometriju.
In clinical practice, these benign findings do not warrant further evaluation in women with no vaginal bleeding, in accordance with guidelines for postmenopausal women (see section 4.4).
Skont il- linji gwida għal nisa li diġà għaddew mill- menopawsa, fil- prattika klinika, dawn ir- riżultati beninni ma joħolqux il- ħtieġa li jsiru aktar evalwazzjonijiet fuq nisa li ma jkollhomx ħruġ ta ’ demm mill- vaġina (ara sezzjoni 4. 4).
The incidence of endometrial cystic change and endometrial thickness was analyzed in a subset of the study population (298 patients) with an annual transvaginal ultrasound (TVU) through 3 years.
L- inċidenza tal- bidla fiċ- ċesti tal- endometriju u fil- ħxuna tal- endometriju ġiet analizzata f’ parti mill- populazzjoni li kienet qiegħda tipparteċipa fl- istudju (298 pazjenta) permezz ta ’ eżami ultrasoniku transvaġinali annwali (TVU) matul 3 snin.
Placebo-treated women had a 1.9% incidence in cystic change over 3 years, whereas the FABLYN-treated women had a 20.4% incidence.
In- nisa li kienu qegħdin jiġu kkurati bil- plaċebo kellhom inċidenza ta ’ bidla fiċ- ċesti ta ’ 1. 9% matul 3 snin, filwaqt li n- nisa li kienu qegħdin jiġu kkurati bil- plaċebo kellhom inċidenza ta ’ 20. 4%.
All histology findings were benign.
Ir- riżultati kollha tal- istoloġija kienu beninni.
Placebo-treated women had a 0.7 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the FABLYN-treated women had a 1.4 mm mean increase.
In- nisa li kienu kkurati bil- plaċebo kellhom tnaqqis medju fil- ħxuna tal- endometriju ta ’ 0. 7 mm mil- linja bażi matul 3 snin, filwaqt li n- nisa li kienu kkurati b’ FABLYN kellhom żieda medja ta ’ 1. 4 mm.
The increase was observed at 12 months, and did not significantly increase through 3 years.
Iż- żieda kienet osservata wara 12- il xahar, u ma żdiditx b’ mod sinifikanti matul it- 3 snin.
In some cases, these findings were observed to resolve spontaneously on treatment.
F’ xi każijiet, dawn ir- riżultati ġew osservati bħala li ġew għan normal spontanjament waqt il- kura
In all women with a uterus at baseline, histologically benign endometrial polyps were reported in 34 of 2,302 (1.5%) FABLYN-treated women versus 18 of 2,309 (0.8%) placebo-treated women.
Fin- nisa kollha li kellhom l- utru fil- linja bażi, ġew irrappurtati polipi fl- endometriju li huma istoloġikament beninni f’ 34 minn 2302 (1. 5%) mara li kienu qegħdin jiġu kkurati b’ FABLYN meta pparagunat ma ’ 18 minn 2309 (0. 8%) mara li kienu qegħdin jiġu kkurati bil- plaċebo.
In a subset of the study population designed to look at endometrial histology (1,080 patients) with a TVU at 3 years, histologically benign endometrial polyps were reported in 20 of 366 (5.5%) FABLYN-treated women and 12 of 360 (3.3%) placebo-treated women.
F’ parti mill- populazzjoni li kienet qiegħda tipparteċipa fl- istudju fejn kienet qiegħda tiġi osservata l- istoloġija tal- endometriju (1080 pazjent) permezz ta ’ TVU wara 3 snin, ġew irrappurtati polipi fl- endometriju li huma istoloġikament beninni f’ 20 minn 366 (5. 5%) mara li kienu qegħdin jiġu kkurati b’ FABLYN u fi 12 minn 360 (3. 3%) mara li kienu qegħdin jiġu kkurati bil- plaċebo.
The overall incidence of vaginal bleeding was low (≤ 2.6% in all treatment groups).
L- inċidenza globali tal- ħruġ tad- demm mill- vaġina kienet baxxa (≤ 2. 6% fil- gruppi kollha li ngħataw kura).
Vaginal bleeding was reported in 74 (2.6%) FABLYN-treated women versus 37 (1.3%) placebo-treated women.
Il- ħruġ tad- demm mill- vaġina ġie rrappurtat f’ 74 (2. 6%) mara li kienu qegħdin jiġu kkurati b’ FABLYN meta pparagunat ma ’ 37 (1. 3%) mara li kienu qegħdin jiġu kkurati bil- plaċebo.
The number of subjects discontinuing treatment as a result of vaginal bleeding was low [FABLYN:
In- numru ta ’ suġġetti li waqqfu l- kura minħabba l- ħruġ ta ’ demm mill- vaġina kien baxx [FABLYN:
4 (0.1%), placebo:
4 (0. 1%), plaċebo:
The number of hysterectomies in the FABLYN-treated group (27/ 2,302 patients, 1.2%) and the placebo-treated group (24/ 2,309 patients, 1.0%) were similar.
13 In- numru ta ’ isterektomiji fil- grupp ta ’ nisa kkurati b’ FABLYN (27/ 2, 302 pazjenta, 1. 2%) u fil- grupp ta ’ nisa kkurati bil- plaċebo (24/ 2, 309 pazjenta, 1. 0%) kien simili.
To assess the effect of FABLYN on diagnostic uterine procedures (i. e., hysteroscopy, saline infused sonohysterogram, endometrial biopsy, polypectomy or dilation and curettage), an analysis was conducted on women without planned TVU surveillance (4,055 patients).
Biex jiġi stimat l- effett ta ’ FABLYN fuq il- proċeduri dijanjostiċi tal- utru (jiġifieri, il- proċedura li permezz tagħha wieħed ikun jista ’ jara fuq ġewwa tal- utru permezz ta ’ tubu li jiddaħħal mill- vaġina (isteroskopija), il- proċedura permezz ta ’ eżami ultrasoniku li permezz tiegħu wieħed jara jekk hemmx anormalitajiet fl- utru wara li jiddaħħal ilma bil- melħ fil- ġisem (saline infused sonohysterogram), bijopsija tal- endometriju, it- tneħħija ta ’ polipi b’ operazzjoni jew dilatazzjoni u t- tneħħija ta ’ xi formazzjoni morbuża mill- utru), saret analiżi fuq in- nisa mingħajr sorveljanza ppjanata fuq it- TVU (4, 055 pazjenta).
More FABLYN-treated patients (7.0%) had a diagnostic procedure compared to placebo-treated patients (2.7%).
Kien ammont ikbar ta ’ pazjenti kkurati b’ FABLYN (7. 0%) li kellhom proċedura dijanjostika meta pparagunati mal- pazjenti kkurati bil- plaċebo (2. 7%).
Diagnostic uterine procedures were performed in a greater number of FABLYN-treated patients as a result of vaginal bleeding (as mandated by the protocol) and asymptomatic endometrial findings (e. g., suspected uterine polyps, endometrial thickness).
Sar numru akbar ta ’ proċeduri dijanjostiċi tal- utru fuq pazjenti kkurati b’ FABLYN (7. 0%) minħabba ħruġ ta ’ demm mill- vaġina (kif indikat fil- protokoll) u minħabba riżultati tal- endometriju li ma jurux sintomi (eż, suspett ta ’ polipi fl- utru, il- ħxuna tal- endometriju).
Effects on breast:
Effetti fuq is- sider:
Over the 5 years of the PEARL study (involving 8,556 patients), FABLYN treatment compared to placebo reduced the risk of invasive breast cancer by 85% (placebo:
Matul il- 5 snin tal- istudju PEARL (li kien jinvolvi 8, 556 pazjenta), il- kura b’ FABLYN meta pparagunata mal- plaċebo, naqqset ir- riskju tal- kanċer tas- sider li jinfirex minn fejn oriġina għal tessuti f’ saħħithom b’ 85% (plaċebo:
20 (0.7%), FABLYN:
20 (0. 7%), FABLYN:
3 (0.1%); HR 0.15 (CI 0.04, 0.50)), the risk of all breast cancer by 79% (placebo:
3 (0. 1%); HR 0. 15 (CI 0. 04, 0. 50), ir- riskju tat- tipi kollha tal- kanċer tas- sider b’ 79% (plaċebo:
24 (0.9%), FABLYN:
24 (0. 9%), FABLYN:
5 (0.2%); HR 0.21 (CI 0.08, 0.55)), the risk of estrogen receptor (ER) positive invasive breast cancer by 83% (placebo:
5 (0. 2%); HR 0. 21 (CI 0. 08, 0. 55), ir- riskju tal- kanċer tas- sider li jinfirex u hu pożittiv għar- riċettur tal- estroġenu (RE) bi 83% (plaċebo:
18 (0.7%), FABLYN:
18 (0. 7%), FABLYN:
3 (0.1%); HR 0.17 (CI 0.05, 0.57)) and the risk of estrogen receptor (ER) positive breast cancer by 81% (placebo:
3 (0. 1%); HR 0. 17 (CI 0. 05, 0. 57) u r- riskju tal- kanċer tas- sider li hu pożittiv għar- riċettur tal- estroġenu b’ 81% (plaċebo:
21 (0.8%), FABLYN:
21 (0. 8%), FABLYN:
4 (0.1%); HR 0.19 (CI 0.07, 0.56)).
4 (0. 1%); HR 0. 19 (CI 0. 07, 0. 56).
FABLYN has no effect on the risk of ER negative breast cancer or ER negative invasive breast cancers.
FABLYN m’ għandux effett fuq ir- riskju tal- kanċer tas- sider li huma negattivi għar- RE jew tal- kanċer tas- sider li jinfirxu li huma negattivi għar- RE.
These observations support the conclusion that lasofoxifene has no intrinsic estrogen agonist activity in breast tissue.
Dawn l- osservazzjonijiet ikomplu jsaħħu l- konklużjoni li lasofoxifene m’ għandux attività intrinsika agonista fit- tessut tas- sider.
12 Effects on lipid metabolism and cardiovascular risk:
Effetti fuq il- metaboliżmu tal- lipidi u riskju kardjovaskulari:
The effect of FABLYN on the lipid profile was evaluated in a 3-year substudy of the PEARL study; the substudy enrolled 1,014 postmenopausal women.
L- effett ta ’ FABLYN fuq il- profil tal- lipidi ġie evalwat fi studju ta ’ 3 snin li kien jifforma parti mill- istudju PEARL; dan l- istudju kien jinvolvi 1014- il mara li diġà għaddew mill- menopawsa.
Relative to placebo, FABLYN significantly decreased total cholesterol, LDL cholesterol, LDL-associated apolipoprotein B-100, and high sensitivity C-reactive protein (median changes -10.4%, -15.8%, -11.8%, -12.5%, respectively); no significant changes versus placebo were seen for HDL cholesterol or VLDL cholesterol.
Meta mqabbel mal- plaċebo, FABLYN naqqas b’ mod sinifikanti l- kolesterol globali, il- kolesterol tat- tip LDL, apolipoprotein B- 100 assoċjat ma ’ l- LDL, u l- proteina C- reactive ta ’ sensittività għolja (il- medja tal- bidliet - 10. 4%, - 15. 8%, - 11. 8%, - 12. 5%, rispettivament); ma dehru l- ebda bidliet sinifikanti fil- kolesterol tat- tip HDL jew kolesterol tat- tip VLDL meta pparagunati mal- plaċebo.
Statistically significant increases were seen for apolipoprotein A-1, which is associated with HDL cholesterol, and serum triglycerides (median changes vs. placebo 6.1% and 4.9%, respectively).
Kien hemm żidiet li huma statistikament sinifikanti fil- każ ta ’ apolipoprotein A- 1, li hi assoċjata mal- kolesterol tat- tip HDL, u t- trigliċeridi fis- serum (il- medja tal- bidliet meta pparagunat mal- plaċebo kienet ta ’ 6. 1% u 4. 9%, rispettivament).
At 5 years in the overall study population (N=8,556), the incidence of major coronary events, including coronary death, non-fatal myocardial infarction, new ischemic heart disease, hospitalization for unstable angina, and revascularisation procedures, was significantly lower.
Wara 5 snin, fil- populazzjoni tal- istudju (N=8, 556), l- inċidenzi ta ’ każijiet koronarji maġġuri li jinkludu mwiet, infart mijokardjali li mhuwiex fatali, mard iskemiku tal- qalb ġdid, dħul l- isptar minħabba anġina mhux stabbli, u proċeduri ta ’ revaskularizzazzjoni, kienu inqas b’ mod sinifikanti.
There were 0.51 events/ 100 patient-years for FABLYN-treated patients compared to 0.75 events/ 100 patient-years in placebo-treated patients (HR 0.68; 95% CI 0.50, 0.93, p= 0.016).
Kien hemm 0. 51 każ/ 100 sena ta ’ pazjenta fl- każ ta ’ pazjenti kkurati b’ FABLYN meta pparagunati ma ’ 0. 75 każ/ 100 sena ta ’ pazjenta f’ pazjenti kkurati bil- palċebo (HR 0. 68; 95% CI 0. 50, 0. 93, p= 0. 016).
In the same study at 5 years, there was no increase in the risk of stroke including hemorrhagic, ischemic, embolic stroke, stroke type unspecified and transient ischemic attacks in FABLYN-treated patients.
Fl- istess studju, wara 5snin, ma kienx hemm żieda fir- riskju ta ’ attakk ta ’ puplesija li tinkludi attakk ta ’ puplesija li hu emorraġiku, iskemiku, u emboliku, attakk ta ’ puplesija li t- tip tiegħu mhuwiex speċifikat u attakki iskemiċi għaddiena f’ pazjenti li kienu kkurati b’ FABLYN.
There were 0.48 events/ 100 patient years in the placebo group and 0.36 events/ 100 patient years among FABLYN-treated patients (HR = 0.75; 95% CI 0.51, 1.10, p = 0.140).
Kien hemm 0. 48 każ/ 100 sena ta ’ pazjenta fil- grupp ta ’ pazjenti kkurati bil- plaċebo u 0. 36 każ/ 100 sena ta ’ pazjenta fil- pazjenti li kienu kkurati b’ FABLYN (HR = 0. 75; 95% CI 0. 51, 1. 10 p = 0. 140).
Effects on vulvar and vaginal atrophy (VVA):
14 Effetti fuq l- atrofija tal- vulva u tal- vaġina (VVA):
The efficacy of FABLYN in the treatment of VVA was investigated in two 12-week Phase 3 studies in postmenopausal women with moderate or severe signs and symptoms of VVA, regardless of osteoporosis status (involving 889 patients).
L- effikaċja ta ’ FABLYN fil- kura tal- VVA kienet investigata f’ żewġ studji ta ’ Fażi 3 li damu 12- il ġimgħa u saru fuq nisa li diġà għaddew mill- menopawsa li kellhom sinjali u sintomi ta ’ VVA moderati jew severi, u dan irrispettivament mill- istat tal- osteoporożi tagħhom (li involvew 889 pazjenta).
In both studies, it decreased the severity of the subject’ s most bothersome baseline VVA symptom, decreased vaginal pH, decreased the percentage of vaginal parabasal cells from the maturation index (MI) and increased the percentage of vaginal superficial cells from the MI.
Fiż- żewġ studji, FABLYN naqqas is- severità tas- sintomu l- aktar inkwetanti tal- VVA fil- linja bażi tas- suġġetti, naqqas il- pH vaġinali, naqqas il- perċentwal tal- iżgħar ċelluli epiteljali vaġinali mill- indiċi tal- maturazzjoni (IM) u żied il- perċentwal taċ- ċelluli superfiċjali vaġinali mill- IM.
Similar results for vaginal pH and MI were observed in the PEARL study.
Fl- istudju PEARL, ġew osservati riżultati simili dwar il- pH vaġinali u l- IM.
The disposition of lasofoxifene was evaluated in 758 subjects in conventional clinical pharmacology studies.
In natura ta ’ lasofoxifene ġiet evalwata f’ 758 suġġett fi studji kliniċi konvenzjonali tal- farmakoloġija.
Pharmacokinetic data from over 2,000 postmenopausal women including patients in selected osteoporosis clinical trials contributed to a population pharmacokinetic analysis.
Tagħrif farmakokinetiku li rriżulta minn aktar minn 2, 000 mara li diġà għaddew mill- menopawsa, inklużi pazjenti fi provi kliniċi magħżula tal- osteoporożi, ikkontribwixxa għal analiżi tal- populazzjoni farmakokinetika.
Lasofoxifene is slowly absorbed from the gastrointestinal tract with maximal plasma concentrations attained on average by approximately 6 hours after dosing.
Lasofoxifene jiġi assorbit bil- mod il- mod mis- sistema gastro- intestinali b’ konċentrazzjoni massima fil- plażma milħuqa f’ medja ta ’ bejn wieħed u ieħor 6 sigħat wara li tkun ingħatat id- doża.
Ingestion of a high fat meal does not change the oral bioavailability of lasofoxifene.
Il- fatt li persuna tiekol ikla li jkun fiha kontenut għoli ta ’ xaħam ma jbiddilx il- bijodisponibiltà orali ta ’ lasofoxifene.
FABLYN may be administered any time of day without regard to food or beverage intake.
FABLYN jista ’ jittieħed fi kwalunkwe ħin tal- ġurnata mingħajr ebda konsiderazzjoni jekk dan jittiħidx ma ’ l- ikel u x- xorb jew le.
The apparent volume of distribution (V/ F) of lasofoxifene in postmenopausal women is approximately 1,350 l.
Il- volum evidenti tad- distribuzzjoni (V/ F) ta ’ lasofoxifene f’ nisa li diġà għaddew mill- menopawsa huwa ta ’ bejn wieħed u ieħor 1, 350 l.
Lasofoxifene is highly bound to proteins in human plasma (> 99%).
Lasofoxifene jeħel ħafna mal- proteini fil- plażma tal- bniedem (> 99%).
Lasofoxifene binds to both albumin and α 1-acid glycoprotein; however, it does not affect the binding of either warfarin or propranolol.
Lasofoxifene jeħel kemm ma ’ l- albumina, kif ukoll ma ’ α 1 – glikoproteina tal- aċidu; madanakollu, dan ma jaffetwax it- twaħħil ta ’ warfarin jew ta ’ propranolol.
13 Metabolism:
Metaboliżmu:
Biotransformation and disposition of lasofoxifene in humans have been determined following oral administration of 14C-labeled lasofoxifene.
Il- bijotrasformazzjoni u n- natura ta ’ lasofoxifene fil- bniedem ġew stabbiliti wara li ttieħed lasofoxifene tikettat 14 C mill- ħalq.
Lasofoxifene is extensively metabolized in humans.
Lasofoxifene huwa mmetabolizzat ħafna fil- bniedem.
Five metabolic pathways of lasofoxifene have been identified: direct glucuronidation; direct sulfation; hydroxylation at the phenyl tetraline moiety (with subsequent conjugative metabolism of the catechol intermediates by methylation and glucuronidation); oxidation at the pyrrolidine ring; and phenyl hydroxylation.
Ġew identifikati ħames passaġġi minn fejn lasofoxifene jiġi mmetabolizzat: ditossifikazzjoni diretta mill- fwied fejn jinqabad il- glucuronic acid biex jitneħħa mill- ġisem; ditossifikazzjoni diretta mill- fwied fejn jinqabad il- kubrit biex jitneħħa mill- ġisem; – idrossilazzjoni mal- parti phenyl tertaline tal- molekula (b’ metaboliżmu successiv konjugattiv ta ’ intermedjarji ta ’ catechol bil - proċess ta ’ methylation u glucuronidation); ossidazzjoni fiċ- ċirku pyrrolidine; u phenyl idrossilazzjoni.
Three metabolites of lasofoxifene were detected in plasma: the direct glucuronide conjugate, the glucuronide of a hydroxylated metabolite, and the methylated catechol.
Instabu 3 metaboliti ta ’ lasofoxifene fil- plażma; l- akkopjat dirett ta ’ glucuronide, il- glucuronide ta ’ metabolit idrossilat, u methylated catechol.
The binding affinities of the major circulating metabolites of lasofoxifene were at least 31-fold and 18-fold less than those of lasofoxifene for the estrogen receptor alpha and the estrogen receptor beta, respectively, indicating that these metabolites are unlikely to contribute to the pharmacologic activity of lasofoxifene.
L- affinitajiet tat- tweħħil tal- metaboliti prinċipali ta ’ lasofoxifene li jiċċirkulaw kienu ta ’ mill- inqas 31 darba u 18- il darba inqas minn dawk ta ’ lasofoxifene għar- riċettur tal- estroġenu alfa u r- riċettur tal- estroġenu beta, rispettivament, u dan jindika li dawn il- metaboliti x’ aktarx li ma jikkontribwixxux għall- attività farmakoloġika ta ’ lasofoxifene.
Oxidation, by multiple cytochrome P450s including CYPs 2D6 and 3A4/ 5, and conjugation of lasofoxifene are the two primary mechanisms of elimination of lasofoxifene from the systemic circulation.
L- ossidazzjoni, permezz taċ- ċitokroma P450 multipla, inklużi CYPs 2D6 u 3A4/ 5, u l- konjugazzjoni ta ’ lasofoxifene, huma ż- żewġ mekkaniżmi prinċipali tal- eliminazzjoni ta ’ lasofoxifene miċ- ċirkolazzjoni sistemika.
The apparent oral clearance (CL/ F) of lasofoxifene in postmenopausal women is approximately 6.6 l/ hr.
It- tneħħija evidenti ta ’ lasofoxifene mill- ħalq (CL/ F) f’ nisa li diġà għaddew mill- menopawsa hija ta ’ bejn wieħed u ieħor 6. 6 l/ siegħa.
Elimination:
15 Eliminazzjoni:
Lasofoxifene has a half-life of approximately 6 days.
Lasofoxifene għandu half- life ta ’ bejn wieħed u ieħor 6 ijiem.
Lasofoxifene and its metabolites are primarily excreted in feces, with a minor component of urinary excretion of active substance-related material.
Lasofoxifene u l- metaboliti tiegħu jitneħħew fil- biċċa l- kbira tagħhom mill- iskart tal- ġisem, u jkun hemm tneħħija żgħira ta ’ materjal relatat mas- sustanza attiva permezz tal- awrina.
Following oral administration of 14C-labeled lasofoxifene in solution to humans, approximately 72% of the radioactive dose was recovered by day 24 (approximately 66% in feces and 6% in urine).
Wara li ttieħed lasofoxifene tikettat 14 C mill- ħalq permezz ta ’ soluzzjoni, fil- bniedem instabet bejn wieħed u ieħor 72% tad- doża radjuattiva sa l- 24 ġurnata (bejn wieħed u ieħor 66% fl- iskart tal- ġisem u 6% fl- awrina).
Less than 2% of the administered dose was recovered in the urine as unchanged lasofoxifene.
Inqas minn 2% tad- doża mittieħda nstabet fl- awrina bħala lasofoxifene mhux mibdul.
Linearity/ non-linearity:
Linearità/ nuqqas ta ’ linearità:
Lasofoxifene exhibits linear pharmacokinetics over a wide dose range following single-dose (up to 100 mg) and multiple-dose (up to 20 mg once daily) administration.
Lasofoxifene juri farmakokinetika lineari fuq skala ta ’ doża wiesgħa wara li tkun ingħatat doża singola (sa 100 mg) u doża multipla (sa 20 mg darba kuljum).
Steady-state pharmacokinetics of lasofoxifene are consistent with expectations from its single-dose pharmacokinetics.
Il- farmakokinetika ta ’ koncetrazzjoni fissa ta ’ lasofoxifene hija konsistenti ma ’ dak li kien mistenni mill- farmakokinetika ta ’ doża waħda.
At steady state, the half-life of lasofoxifene in postmenopausal women is approximately 6 days, resulting in small fluctuations in concentrations over the 24-hour dosing interval.
Fi steady state, il- half- life ta ’ lasofoxifene f’ nisa li diġà għaddew mill- menopawsa, huwa ta ’ bejn wieħed u ieħor 6 ijiem, u fuq l- intervall ta ’ dożaġġ ta ’ 24 siegħa jkun hemm varjazzjonijiet żgħar fil- konċentrazzjonijiet.
Paediatric:
Użu pedjatriku:
The pharmacokinetics of lasofoxifene have not been evaluated in a paediatric population.
Il- farmakokinetika ta ’ lasofoxifene għadha ma ġietx evalwata fil- populazzjoni pedjatrika.
No clinically meaningful differences in lasofoxifene pharmacokinetic were observed over the age range of 40 to 80 years of age based on the results of a population pharmacokinetic analysis.
Skont ir- riżulatati ta ’ analiżi farmakokinetika tal- populazzjoni, ma ġew osservati l- ebda differenzi li huma klinikament sinifikanti fil- farmakokinetika ta ’ lasofoxifene fil- medda ta ’ żmien ta ’ bejn l- 40 u t- 80 sena.
No dose adjustment for FABLYN is necessary in elderly patients.
M’ hemmx bżonn ta ’ aġġustament tad- doża ta ’ FABLYN fil- każ ta ’ pazjenti anzjani.
In a population pharmacokinetic analysis, no discernible difference in lasofoxifene pharmacokinetics was detected in different racial groups.
F’ analiżi farmakokinetika tal- populazzjoni, ma dehret l- ebda differenza fil- farmakokinetika ta ’ lasofoxifene fi gruppi ta ’ razez differenti.
This analysis included 2,049 postmenopausal women consisting of 85.5% Caucasian, 8.6% Hispanic, 3.4% Asian, and 1.9% African American.
Din l- analiżi kienet tinkludi 2049 mara li diġà għaddew mill- menopawsa li kienu jikkonsistu f’ 85. 5% tan- nisa Kawkażi (ta ’ ġilda bajda), 8. 6% tan- nisa ta ’ razza tal- Amerikana Latina, 3. 4% tan- nisa Asjatiċi, u 1. 9% tan- nisa Afroamerikani.
The results of a phase 1 study in Japanese and Caucasian women was consistent with the population pharmacokinetic analysis and showed no discernible difference in lasofoxifene pharmacokinetics in these two populations.
Ir- riżultati ta ’ studju ta ’ fażi 1 fuq nisa Ġappuniżi u Kawkażi kienu konsistenti ma ’ l- analiżi farmakokinetika tal- populazzjoni u ma wrew l- ebda differenza fil- farmakokinetika ta ’ lasofoxifene f’ dawn iż- żewġ populazzjonijiet.
14 Gender:
Sess:
Since FABLYN is indicated for use only in postmenopausal women, no assessment of the effect of gender on lasofoxifene pharmacokinetics has been made.
Peress li FABLYN huwa indikat biss għall- użu min- nisa li diġà għaddew mill- menopawsa, ma saret l- ebda stima dwar l- effett tas- sess tal- persuna fuq il- farmakokinetika ta ’ lasofoxifene.
Hepatically impaired patients:
Pazjenti b’ indeboliment tal- fwied:
Lasofoxifene was studied, as a single 0.25 mg dose, in healthy subjects and subjects with mild or moderate hepatic impairment.
Lasofoxifene ġie studjat bħala doża waħda ta ’ 0. 25 mg f’ suġġetti f’ saħħithom u f’ suġġetti li jbatu minn indeboliment tal- fwied ħafif jew moderat.
Plasma lasofoxifene exposure was approximately the same in healthy subjects as in subjects with mild hepatic impairment (Child-Pugh Class A) and was modestly increased (38%) in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects.
L- esponiment fil- plażma b’ lasofoxifene kien bejn wieħed u ieħor l- istess f’ suġġetti f’ saħħithom u f’ suġġetti li jbatu minn indeboliment tal- fwied ħafif (Child- Pugh Klassi A) u żdied b’ ammont mhux kbir (38%) f’ suġġetti li jbatu minn indeboliment tal- fwied moderat (Child- Pugh Klassi B) meta pparagunat ma ’ suġġetti f’ saħħithom.
These differences are not considered to be clinically meaningful.
Dawn id- differenti mhumiex meqjusa bħala li huma ta ’ rilevanza klinika.
No dose adjustment for FABLYN is necessary for patients with mild or moderate hepatic insufficiency.
M’ hemmx bżonn ta ’ aġġustament tad- doża ta ’ FABLYN fil- każ ta ’ pazjenti li jbatu minn insuffiċjenza tal- fwied ħafifa jew moderata.
Subjects with severe hepatic impairment have not been studied (see section 4.4).
Ma sarux studji fuq suġġetti li jbatu minn indeboliment tal- fwied sever (ara sezzjoni 4. 4).
Renally impaired patients:
16 Pazjenti b’ indeboliment renali:
Since less than 2% of lasofoxifene is recovered in urine as unchanged active substance, a study in subjects with renal insufficiency was not conducted.
Peress li inqas minn 2% ta ’ lasofoxifene jinstab fl- awrina bħala sustanza attiva mhux mibdula, ma sarx studju fuq suġġetti li jbatu minn insuffiċjenza renali.
In a population pharmacokinetic analysis, there were no clinically meaningful differences in lasofoxifene pharmacokinetics between postmenopausal women with estimated creatinine clearance as low as 32 ml/ min and those with normal creatinine clearance.
F’ analiżi farmakokinetika tal- populazzjoni, ma nstabu l- ebda differenzi li huma klinikament rilevanti fil- farmakokinetika ta ’ lasofoxifene bejn nisa li diġà għaddew mill- menopawsa li għandhom it- tneħħija tal- krejatinina stimata bħala li hi baxxa anke sa 32 ml/ min, u dawk li għandhom tneħħija tal- krejatinina normali.
No dose adjustment for FABLYN is necessary for patients with mild or moderate renal insufficiency (see section 4.4).
M’ hemmx bżonn ta ’ aġġustament tad- doża ta ’ FABLYN fil- każ ta ’ pazjenti li jbatu minn insuffiċjenza renali ħafifa jew moderata (ara sezzjoni 4. 4).
Lasofoxifene was not genotoxic in any of the battery of tests applied.
Lasofoxifene ma kienx ġenotossiku fl- ebda grupp ta ’ testijiet li saru.
In two-year carcinogenicity studies conducted in rats (≥ 1 mg/ kg/ day; 7 times systemic exposure following a human dose of 0.5 mg/ day based on plasma AUC) an increased incidence of renal tubular adenoma and carcinoma in males and granulosa cell tumours of the ovary in females was noted.
Fi studji karċinoġeniċi sussegwenti li damu għaddejjin sentejn li saru fuq il- firien (≥1 mg/ kg/ kuljum; esponiment sistemiku ta ’ 7 darbiet aktar wara doża ta ’ 0. 5 mg/ kuljum li tingħata lill- bniedem ibbażata fuq l- AUC tal- plażma) ġiet osservata żieda fl- inċidenza ta ’ adenoma tubulari renali u tal- karċinoma fl- irġiel u tumuri granulożi ċellulari fl- ovarji fin nisa.
In the corresponding 2-year study in mice (≥ 2 mg/ kg/ day; less than systemic exposure following a human dose of 0.5 mg/ day based on plasma AUC), there was an increased incidence of adrenal cortical adenoma and carcinoma, interstitial cell tumors of the testis, benign and malignant ovarian tumors and benign uterine glandular polyps.
Fl- istudju l- ieħor ta ’ sentejn fil- ġrieden (≥2 mg/ kg/ kuljum; inqas mill- esponiment sistemiku wara doża ta ’ 0. 5 mg/ kuljum li tingħata lill- bniedem bbażata fuq l- AUC tal- plażma), kien hemm żieda fl- inċidenza ta ’ adenoma adrenali kortikali u tal- karċinoma, tumuri ta ’ bejn iċ- ċelloli tat- testis, tumuri ovarji beninni u malinni u qarnit glandolari beninn tal- utru.
Although all of these tumours are believed to be the result of rodent-specific hormonal mechanisms, their relevance for humans is currently unknown.
Għalkemm hu mifhum li dawn it- tipi ta ’ tumuri huma relatati ma ’ mekkaniżmu tal- ormoni li hu speċifiku għall- annimali gerriema, ir- relevanza tagħhom ghal- bniedem għada mhux magħrufa.
Based on 3- and 5-year human data in the clinical trials, the incidence of cancer during treatment with lasofoxifene was not higher than for placebo.
Fi studji kliniċi ta ’ 3 snin u 5 snin, li saru fuq il- bnedmin, l- inċidenza tal- kanċer waqt il- kura b’ lasofoxifene ma ’ kienitx għola min dik tal - plaċebo.
Lasofoxifene was not teratogenic in rats up to a dose of 10mg/ kg (approximately 53 times the AUC in humans) or rabbits up to a dose of 3 mg/ kg (below the level of systemic exposure in humans).
Lasofoxifene ma kienx teratoġeniku fil- firien sa doża ta ’ 10 mg/ kg (bejn wieħed u ieħor 53 darba aktar mill- AUC fil- bniedem) jew fil- fniek sa doża ta ’ 3 mg/ kg (taħt il- livell ta ’ esponiment sistemiku fil- bniedem).
Increased incidence of imperforate anus, hypoplastic tail, edema and limb flexures noted in fetuses of pregnant rats dosed at 100 mg/ kg (approximately 400 times the AUC in humans) were associated with increased embryo-fetal lethality and generalized failure to thrive.
Żidiet fl- inċidenzi fejn it- toqba tal- musrana d- dritta kienet mingħajr ftuħ normali, fejn id- denb ma kienx żviluppat kif sippost, fejn kien hemm nefħa kkważata minn akkumulazzjoni ta ’ ilma fil- ġisem u fejn kien hemm riġlejn jew dirgħajn mgħawġin, li kienu nnutati fil- fetujiet ta ’ firien tqal li ngħataw doża ta ’ 100 mg/ kg (bejn wieħed u ieħor 400 darba aktar mill- AUC fil- bniedem) ġew assoċjati ma ’ żieda fl- imwiet tal- embriji- feti b’ konsegwenza ta ’ vvelenar u mal- inkapaċità ġenerali tagħhom li jgħixu.
In fertility studies conducted in rats with lasofoxifene, slight effects on male reproductive performance occurred at ≥ 10 mg/ kg/ day (approximately 42 times the AUC in humans) as evidenced by decreases in copulation index, implantation sites, and fetuses sired.
Fi studji fuq il- fertilità li saru b’ lasofoxifene fuq il- firien, seħħew effetti żgħar fuq l- imġiba ta ’ riproduzzjoni tal- far maskil meta kien qed jingħata doża ta ’ ≥10 mg/ kg/ kuljum (bejn wieħed u ieħor 42 darba aktar mill- AUC fil- bniedem), kif jidher mit- tnaqqis fl- indiċi tal- kopulazzjoni, il- post tal- implantazzjoni, u l- fetujiet li rriżultaw mit- tgħammir.
Reduced fertility, and an increase in pre- and post-implantation loss leading to reduced litter size and prolonged gestation were observed in females treated at ≥ 0.01 mg/ kg/ day (below the level of systemic exposure in humans).
It- tnaqqis fil- fertilità, u ż- żieda fit- telf ta ’ qabel u wara l- implantazzjoni li jwasslu għal tnaqqis fin- numru ta ’ frieħ li jitwieldu u għal perjodu tat- tqala itwal ġew osservati f’ firien nisa li ngħataw ≥0. 01 mg/ kg/ kuljum (taħt il- livell ta ’ esponiment sistemiku fil- bniedem).
In a prenatal and postnatal study in rats, at ≥ 0.01 mg/ kg/ day lasofoxifene delayed and/ or disrupted parturition, increased pup mortality at birth, altered the achievement of developmental milestones, and reduced growth.
Fi studju li sar fuq il- ġrieden qabel u wara t- tqala, l- għoti ta ’ lasofoxifene ta ’ ≥0. 01 mg/ kg/ kuljum tawwal u/ jew fixkel il- proċess tat- twelid, żied ir- rata tal- imwiet tal- frieħ mat- twelid, biddel l- ilħuq ta ’ objettivi ta żvilupp basici, u naqqas l- iżvilupp.
Overall, the reproductive and developmental effects observed in animals are consistent with the SERM class of compounds.
B’ mod ġenerali, l- effetti li kienu osservati fuq is- sistema riproduttiva u fuq l- iżvilupp fl- annimali huma konsistenti mal- klassi tas- SERM.
Lactose anhydrous
Lactose anhydrous
Microcrystalline cellulose
Microcrystalline cellulose
Croscarmellose sodium
Croscarmellose sodium
Silica, colloidal anhydrous
Silica, colloidal anhydrous
Magnesium stearate
Magnesium stearate
Tablet coating:
Il- qoxra ta ’ barra tal- pillola:
Sunset yellow FCF aluminium lake (E110)
FCF aluminium lake (E110) ta ’ lewn isfar kulur inżul ix- xemx
Lactose monohydrate
Lactose monohydrate
Titanium dioxide (E171)
Titanium dioxide (E171)
FABLYN film-coated tablets are supplied in PVC blisters with aluminum foil backing or HDPE bottles with polyethylene/ aluminum foil lined polypropylene child-resistant closures.
Il- pilloli miksija b’ rita FABLYN huma fornuti f’ folji tal- PVC bin- naħa ta ’ wara magħmul mill- fojl tal- alumijum, jew fi fliexken tal- HDPE ta ’ densità għolja b’ għotjin li ma jinfetħux mit- tfal infurrati bil- polyethylene/ fojl tal- alumijum.
Blister packs of 7, 28 or 30 tablets and bottles of 90 tablets.
Pakketti b’ folji ta ’ 7, 28 jew 30 pillola u fliexken ta ’ 90 pillola.
6.6 Special precautions for disposal
18 6. 6 Prekawzjonijiet speċjali li għandhom jittieħdu meta jintrema
United Kingdom
Ir- Renju Unit
< {DD/MM/YYYY} > < {DD month YYYY} >
< {JJ/ XX/ SSSS} > < {JJ xahar SSSS} >
17 ANNEX II
19 ANNESS II
Germany
Ġermanja
The Marketing Authorisation Holder (MAH) shall ensure that, prior to launch, all healthcare professionals who are expected to prescribe FABLYN or order gynaecological ultrasound of patients treated with FABLYN, are provided with access to risk minimisation educational programme.
Id- Detentur ta ’ L- Awtorizazzjoni għat- tqegħid fis- suq għandu jassigura li qabel ma l- prodott jitqiegħed fuq is- suq, kull professjonist tas- saħħa li mistenni jippreskrivi FABLYN jew li jistaqsi għal- ultrasound ġinekoloġiku f’ pazjenti kkurati bil- FABLYN, ikollu aċċess għal programm edukattiv fuq it- tnaqqis tar- riskju.
The programme materials shall be provided via the following means:
Il- materjal ta ’ dan il- programm għandu jiġi pprovdut f’ dawn il- forom:
• Web-based • On CD • Printed on paper
• Fuq sit elettroniku • Fuq CD • Pprintjat fuq karta
The programme shall convey the following key messages:
Il- programm għandu jwassal dawn il- messaġġi primarji
• FABLYN increases risk of venous thromboembolism (VTE). • The approaches recommended for mitigation of risk of venous thromboembolism based on the SmPC, including contraindication of FABLYN in patients with active or past history of VTE. • FABLYN causes morphologic changes, particularly the cystic atrophy of endometrium.
21 • FABLYN iżid ir- riskju ta ’ trombo- emboliżmu fil- vini (VTE) • Il proċess irrakomandat sabiex jitnaqqas ir- riskju ta ’ trombo- emboliżmu fil- vini, bbażat fuq l- SmPC li jinkludi kontra- indikazzjoni ta ’ FABLYN f’ pazjenti li jbatu jew ġieli batew fil- passat b’ każijiet ta ’ VTE. • FABLYN jikkawża tibdil morfoloġiku, partikolarment atrofija taċ- ċesti tal- endometriju.
It results in increased mean endometrial thickness. • Based on the clinical trials, the morphologic changes caused by FABLYN are benign and do not require further investigation unless vaginal bleeding occurs. • References to authoritative international guidelines relevant for uterine surveillance. • The need to stop treatment with FABLYN and investigate when unexplained uterine bleeding occurs.
Dan jirriżulta żieda fil- ħxuna medja tal- endometriju. • Meta tqis studji klinici, dan it- tibdil morfoloġiku ikkaġunat b’ FABLYN huwa beninn u m ’ għandux bżonn aktar investigazzjonijiet sakemm ma jkunx hemm ħruġ ta ’ demm mill- vaġina. • Għandu jkun hemm referenza għal- linji gwida ta ’ awtorita ’ internazzjonali ta ’ rilevanza għal- sorveljanza tal- utru. • Il- bżonn li titwaqqaf il- kura b’ FABLYN u jkun hemm investigazzjoni meta jkun hemm ħruġ ta ’ demm mill- vaġina li mhux normali.
19 The programme shall include the full text of the SmPC.
Il- programm għandu jinkludi l- kitba kollha tal- SmPC.
This programme should focus on interpretation of endometrial biopsy of women treated with FABLYN.
Dan il- programm għandu jiffoka fuq l- interpretazzjoni ta ’ bijopsija tal- endometriju ta ’ nisa kkurati b’ FABLYN.
Pharmacovigilance system
Is- sistema tal- farmakoviġilanza.
The MAH must ensure that the system of pharmacovigilance, as described in version version 1.1 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and whilst the product is on the market.
L- MAH għandu jassigura li s- sistema tal- farmakoviġilanza kif miftiehem f’ verzjoni 1. 1 ippreżentata fis- sezzjoni 1. 8. 1 ta ’ l- Applikazzjoni għall- Awtorizazzjoni għat- tqegħid fis- suq, qed taħdem qabel u waqt li l- prodott ikun fis- suq.
Risk Management Plan
Pjan ta ’ Mmaniġġjar tar- Riskju
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 1.4 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the CHMP.
L- MAH jikkommetti ruħu sabiex iwettaq l- istudji u l- attivitajiet farmakoviġilanti addizzjonali li jinsabu imniżżla fil- pjan tal- farmakoviġilanza, kif miftihem f’ verżjoni 1. 4 tal- Pjan Dwar l- Immaniġġar tar- Riskju (RMP) li ġie ppreżentat f’ Modulu 1. 8. 2 ta ’ l- Applikazzjoni għall- Awtorizzazzjoni għat- tqegħid fis- suq u aġġornamenti sussegwenti oħra tal- RMP aċċettati mis- CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
Skond il- linja gwida CHMP li titratta dwar is- Sistemi ta ’ l- Immaniġjar tar- Riskju għall- prodotti mediċinali magħmula għall- użu mill- bniedem, il- RMP aġġornat għandu jiġi ssottomess flimkien mar- Rapport Perjodiku ta’ Aġġornamenti dwar is- Sigurtà (PSUR).
• When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities • Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached • At the request of the EMEA
• meta jkun hemm informazzjoni ġdida li tista ’ taffetwa l- Ispeċifikazzjoni dwar is- Sigurtà applikabbli bħalissa, Pjan tal- Farmakoviġilanza jew attivitajiet relatati mat- tnaqqis tar- riskju • fi żmien 60 ġurnata mid- data meta jseħħ avveniment importanti (relatat ma ’ farmakoviġilanza jew ma ’ tanqqis tar- riskju) • fuq talba ta ’ l- EMEA
20 ANNEX III
22 ANNESS III
22 PARTICULARS TO APPEAR ON THE OUTER PACKAGING
24 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
CARTON FOR BOTTLE PACK (90 film-coated tablets)
IL- KARTUNA TAL- PAKKETT TAL- FLIXKUN (90 pillola miksija b’ rita)
FABLYN 500 microgram film-coated tablets
FABLYN 500 mikrogramma pilloli miksija b’ rita
Each tablet contains lasofoxifene tartrate, equivalent to 500 microgram lasofoxifene.
Kull pillola fiha lasofoxifene tartrate, ekwivalenti għal 500 mikrogramma lasofoxifene.
Contains lactose
Fih il- lattosju
See the package leaflet for further information.
Għal aktar informazzjoni ara l- fuljett ta ’ tagħrif.
90 film-coated tablets
90 pillola miksija b’ rita
Sealed pack.
Pakkett issiġillat.
Do not use if box has been opened.
Tużax jekk il- kaxxa tkun miftuħa.