ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
CONBRIZA 20 mg film-coated tablets
2.
Each film-coated tablet contains bazedoxifene acetate equivalent to 20 mg bazedoxifene.
Excipient: each film-coated tablet contains 142.8 mg lactose monohydrate
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to off-white, capsule-shaped, film-coated tablet debossed on one side with “WY20”.
4.
CONBRIZA is indicated for the treatment of postmenopausal osteoporosis in women at increased risk
of fracture. A significant reduction in the incidence of vertebral fractures has been demonstrated;
efficacy on hip fractures has not been established.
When determining the choice of CONBRIZA or other therapies, including oestrogens, for an
individual postmenopausal woman, consideration should be given to menopausal symptoms, effects
on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1).
Posology
The recommended dose of CONBRIZA is one tablet once daily, at any time of day, with or without
food (see section 5.2).
Doses higher than 20 mg are not recommended because there is no demonstrable increased efficacy
and higher doses may be associated with additional risk (see section 5.1).
Supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.
Oral use.
Special Populations
Renal impairment
Bazedoxifene has not been sufficiently evaluated in patients with severe renal impairment; caution
should be used in this population (see sections 4.4 and 5.2).
No dose adjustment is required for mild or moderate renally impaired patients.
2
Hepatic impairment
Safety and efficacy of bazedoxifene have not been evaluated in patients with hepatic impairment; use
in this population is not recommended (see sections 4.4 and 5.2).
Elderly patients
No dose adjustment is necessary based on age (see section 5.2).
Paediatric population
Bazedoxifene is not indicated for use in paediatric patients.
Hypersensitivity to the active substance or to any of the excipients.
Active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary
embolism, and retinal vein thrombosis.
CONBRIZA is only for use in postmenopausal women. Bazedoxifene must not be taken by women of
child-bearing potential (see sections 4.6 and 5.3).
Unexplained uterine bleeding.
Patients with signs or symptoms of endometrial cancer; safety in this patient group has not been
adequately studied.
Use of CONBRIZA is not recommended in women at an increased risk for venous thromboembolic
events. CONBRIZA is associated with an increased risk of venous thromboembolism (VTE). In
clinical trials, the highest rate of VTE was observed during the first year of treatment, with a relative
risk of 2.69 compared to placebo. After 3 years the relative risk was 1.63 and after a 5 year study
period the relative risk was 1.50 (see sections 4.8 and 5.1). The risk factors associated with VTE cases
in clinical trials included: advanced age, obesity, immobilisation, surgery, major trauma and
malignancy. It should be discontinued prior to and during prolonged immobilisation (e.g.,
post-surgical recovery, prolonged bed rest), and therapy should be resumed only after the patient is
fully ambulatory. In addition, women taking CONBRIZA should be advised to move about
periodically during prolonged travel.
Bazedoxifene has not been studied in premenopausal women. Its safety in premenopausal women has
not been established, and its use is not recommended.
There is no evidence of endometrial proliferation. Any uterine bleeding during CONBRIZA therapy is
unexpected and should be fully investigated.
Bazedoxifene has not been studied in women with triglyceride levels 300 mg/dl (3.4 mmol/litre). It
may increase serum triglyceride levels; therefore, caution should be exercised in patients with known
hypertriglyceridaemia (see section 5.1).
The safety of CONBRIZA in patients with breast cancer has not been studied. No data are available
on the concomitant use with agents used in the treatment of early or advanced breast cancer.
Therefore, bazedoxifene is not recommended for treatment or prevention of breast cancer.
3
Bazedoxifene has not been sufficiently evaluated in patients with severe renal impairment; caution
should be used in this population.
Patients with hepatic impairment showed a 4.3-fold increase in area under the curve (AUC) [on
average] compared with controls. Use in this population is not recommended (see sections 4.2 and
5.2).
CONBRIZA contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
In a 30-day study, bazedoxifene increased hormone-binding globulin concentrations, including
corticosteroid-binding globulin (CBG), sex hormone-binding globulin (SHBG) and
thyroxine-binding globulin (TBG).
Bazedoxifene undergoes little or no cytochrome P450 (CYP)-mediated metabolism. Bazedoxifene
does not induce or inhibit the activities of major CYP isoenzymes.
In vitro
data suggest that
bazedoxifene is unlikely to interact with co-administered medicinal products via CYP-mediated
metabolism.
There were no significant pharmacokinetic interactions between bazedoxifene and the following
medicinal products: ibuprofen, atorvastatin, azithromycin, or an antacid containing aluminium and
magnesium hydroxide. Based on
in vitro
bazedoxifene plasma protein binding characteristics, drug
interactions with warfarin, digoxin and diazepam are unlikely.
CONBRIZA is only for use in postmenopausal women. It is contraindicated in women of
child-bearing potential (see section 4.3). There are no data from the use of bazedoxifene in pregnant
women. Studies in rabbits have shown reproductive toxicity (see section 5.3). The potential risk for
humans is unknown.
It is not known whether bazedoxifene is excreted in human milk. Bazedoxifene is not intended for use
in breast-feeding women.
Studies in rats have shown adverse effects on fertility (see section 5.3). The potential risk for humans
is unknown.
No studies on the effects on the ability to drive or use machines have been performed. However, in
clinical trials, somnolence was reported as an adverse reaction, and patients should be advised on the
potential effect on driving and using machines.
Summary of the safety profile
The safety of CONBRIZA has been evaluated in two multicentre, double-blind, randomised, placebo-
and active-control, Phase 3 trials: 7,492 evaluable postmenopausal women in a three-year
osteoporosis treatment trial (1,886 women received bazedoxifene 20 mg; 1,872 women received
bazedoxifene 40 mg; 1,849 women received raloxifene; 1,885 women received placebo) and 1,583
evaluable postmenopausal women in a 2-year osteoporosis prevention trial (321 women received
bazedoxifene 10 mg; 322 women received bazedoxifene 20 mg; 319 women received bazedoxifene
40 mg; 311 women received raloxifene; 310 women received placebo).
4
The majority of adverse reactions occurring during the clinical trials were mild to moderate in
severity and did not lead to discontinuation of therapy.
The most frequent drug-related adverse reactions in double-blind, randomised studies were hot flushes
and muscle spasms (includes leg cramps).
Tabulated list of adverse reactions
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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).
Immune system disorders
Common: Hypersensitivity
Nervous system disorders
Common: Somnolence
Eye disorders
Rare:
Retinal vein thrombosis*
Vascular disorders
Very common: Hot flushes
Uncommon:
Deep vein thrombosis*
Superficial thrombophlebitis
Respiratory, thoracic and mediastinal disorders
Uncommon:
Pulmonary embolism*
Gastrointestinal disorders
Common: Drymouth
Skin and subcutaneous tissue disorders
Common: Urticaria
Musculoskeletal, connective tissue and bone disorders
Very common: Muscle spasms (includes leg cramps)
General disorders and administration site conditions
Common: Peripheraloedema
Investigations
Common:
Increased blood triglycerides, increased alanine aminotransferase; increased
aspartate aminotransferase
5
Description of selected adverse reactions
*In the osteoporosis treatment trial in 7,492 evaluable subjects (mean age=66 years), the
bazedoxifene-treated women had an increased risk of venous thromboembolism (deep vein
thrombosis, pulmonary embolism and retinal vein thrombosis). The rate per 1,000 women-years
through the 3-year study period was 2.86 in the bazedoxifene 20 mg group and 1.76 in the placebo
group, and through the 5-year study period was 2.34 in the bazedoxifene 20 mg group and 1.56 in the
placebo group. The rate of VTE was highest in the first year with a relative risk of 2.69. After 3 years
the relative risk was 1.63 and after a 5 year study period the relative risk was 1.50 (see section 5.1). ).
Other venous thromboembolic events could also occur.
In the case of overdose, there is no specific antidote, and treatment should be symptomatic.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective estrogen receptor modulator, ATC code: G03XC02.
Mechanism of action
Bazedoxifene belongs to a class of compounds known as selective estrogen receptor modulators
(SERMs). Bazedoxifene acts as both an oestrogen-receptor agonist and/or antagonist, depending upon
the cell and tissue type and target genes. Bazedoxifene decreases bone resorption and reduces
biochemical markers of bone turnover to the premenopausal range. These effects on bone remodeling
lead to an increase in bone mineral density (BMD), which in turn contributes to a reduction in the risk
of fractures. Bazedoxifene functions primarily as an oestrogen-receptor antagonist in uterine and
breast tissues.
Clinical efficacy
The efficacy of bazedoxifene was established in two multicentre, double-blind, randomised, placebo-
and active-control, Phase 3 trials: 3-year osteoporosis treatment trial and a 2-year osteoporosis
prevention trial.
In the osteoporosis treatment study, 7,492 postmenopausal women (mean age of 66 years; range 50 to
85 years and a mean time of 19.5 years since menopause) received bazedoxifene (20 or 40 mg daily),
raloxifene (60 mg daily), or placebo to evaluate the incidence of new vertebral fractures over 3 years
(3-year core study). The 3-year core study was extended for 2 additional years resulting in total
treatment duration of up to 5 years (5-year study) while the blind study was maintained. A total of
3,146 subjects continued into the 2-year extension (bazedoxifene 20 mg: n=1,047,
bazedoxifene40/20 mg: n=1,041, placebo: n=1,058). The bazedoxifene 40 mg dose was decreased to a
20 mg dose after approximately 4 years. The raloxifene group was discontinued during the 2-year
extension. All subjects were to receive 1,200 mg of elemental calcium and 400 IU of vitamin D daily.
This study included mostly Caucasian (87.3%) subjects who were either osteoporotic without baseline
vertebral fracture (BMD T-score at lumbar spine [LS] or femoral neck [FN] between -2.5 and -4.0) or
osteoporotic, with at least 1 mild baseline vertebral fracture. The mean LS and FN T-scores at
baseline were -2.4 and -1.7, respectively.
There was a significant reduction in the incidence of new vertebral fractures after 3 years of treatment
with bazedoxifene 20 mg and raloxifene 60 mg compared to placebo. The reduction in the incidence
6
of vertebral fracture was similar among bazedoxifene and raloxifene treatment groups. The treatment
effect was similar among those with and without prevalent vertebral fractures (Table 1).
Table 1: Effect of bazedoxifene on risk of vertebral fractures after 3 years of treatment
Number of subjects
Absolute
risk
reduction
Relative risk
reduction
(95% CI)
Bazedoxifene
20 mg
Placebo
Total number of subjects
n=1,724
n=1,741
Number (%)
a
of subjects with
new vertebral fracture
35 (2.34%)
59 (4.07%)
1.73%
42%
b
(11%, 62%)
Subjects with no baseline
fracture
n=757
n=760
Number (%)
a
of subjects with ≥1
new vertebral fracture
13 (1.98%)
20 (3.13%)
1.15%
35%
c
Subjects with 1 baseline
fracture
n=967
n=981
Number (%)
a
of subjects with ≥1
new vertebral fracture
22 (2.63%)
39 (4.80%)
2.17%
45%
d
(6%, 68%)
a
Kaplan-Meier rate estimates
b
p-value=0.015
c
p-value=0.22
d
p-value=0.035
After 5 years of treatment, the incidence of new vertebral fractures remained lower in the
bazedoxifene 20 mg group (4.49%) compared to placebo (6.85%) with a relative risk reduction of
36% (p=0.014).
The incidence of non-vertebral osteoporosis-related fractures was similar among bazedoxifene 20 mg
(5.68%), raloxifene 60 mg (5.87%), and placebo (6.26%) groups. In a post-hoc analysis, the 10-year
fracture probability as an index of baseline fracture risk was determined. The mean 10-year fracture
probability of a major osteoporotic fracture for the entire study population was 11%. In subjects
treated with bazedoxifene, the incidence of fractures was related to the baseline fracture risk: the
higher the fracture risk, the greater the benefit with bazedoxifene treatment. In subjects with 10-year
fracture probabilities at or above 16%, bazedoxifene was associated with a significant decrease in the
risk of all clinical fractures.
In a post-hoc analysis, the relative risk of non-vertebral fractures in bazedoxifene-treated subjects
decreased with increased fracture probability. In subjects with a fracture probability of 20% or greater
(n = 618), the risk of non-vertebral fractures in bazedoxifene-treated subjects was decreased by 55%
(95% CI: 18-76) compared to placebo-treated subjects.
The increase in LS BMD compared with placebo with bazedoxifene 20 mg and raloxifene 60 mg was
significant at 6 months (1.02% and 1.29%, respectively) and was maintained through 3 years (1.32%
and 2.08%, respectively). The effect of bazedoxifene on BMD at other skeletal sites was similar. The
increases in BMD relative to placebo remained significant at all skeletal sites throughout the 5 years
of treatment with bazedoxifene.
Discontinuation from the study was required when excessive bone loss or incident vertebral fractures
occurred. Such discontinuation was statistically significant more frequently in the placebo group
(4.0%) than in the bazedoxifene 20 mg (2.8%) or raloxifene 60 mg (2.1%) groups.
7
The prevention study (1,583 subjects; mean age, 58 years; mean years since menopause, 11)
compared BMD effects of bazedoxifene (10, 20, or 40 mg daily), raloxifene (60 mg daily), and
placebo. All subjects received calcium supplementation daily; most received 600 mg calcium (e.g.,
Caltrate) daily, while some received up to 1,200 mg daily. This study included subjects who had a
LS or FN neck BMD T-score no less than -2.5. The median T-score ranged from -0.6 to -1.4,
depending on the skeletal site.
BMD was preserved in bazedoxifene 20 mg and raloxifene 60 mg-treated subjects, while significant
loss in BMD was observed in patients receiving placebo. The increase in LS BMD with bazedoxifene
20 mg and raloxifene 60 mg, compared with placebo, was significant at 6 months (1.14% and 1.26%,
respectively) and was maintained through 2 years (1.41% and 1.49%, respectively). The effect of
bazedoxifene on BMD at other skeletal sites was similar.
Clinical safety
Assessment of bone histomorphometry and bone turnover
In the osteoporosis treatment study in 7,492 postmenopausal women (mean age = 66 years), 121 bone
biopsies were obtained from iliac crest after the administration of fluorochrome label from the
subjects in bazedoxifene, raloxifene and placebo groups (bazedoxifene 20 mg = 28; bazedoxifene
40 mg = 29, raloxifene 60 mg = 32, placebo = 32) after approximately 2 or 3 years of treatment.
Histological assessment of bone biopsies from all treatment groups revealed formation of normal
lamellar bone in all treated subjects. There was no evidence of osteomalacia, peritrabecular or marrow
fibrosis, cellular toxicity or woven bone in any of the bone-biopsy specimens in any of the treatment
groups. Histomorphometric assessment revealed normal mineralisation, as evidenced by the presence
of normal osteoid thickness, normal mineralisation lag time, and mineral apposition rate.
In the osteoporosis treatment study, bazedoxifene 20 mg and raloxifene 60 mg therapy resulted in a
significant reduction of serum markers of bone resorption (C-telopeptide) and bone formation
(osteocalcin), when compared to placebo, indicating a reduction in bone turnover. Median reductions
from baseline over 25% for C-telopeptide and osteocalcin were observed with bazedoxifene therapy.
Similar reductions in the rate of bone turnover have been observed in the osteoporosis prevention
study.
Effects on lipid metabolism and cardiovascular system
In the osteoporosis treatment study after 3 years of treatment, bazedoxifene 20 mg and raloxifene
60 mg exhibited significant reductions in serum total cholesterol, low-density lipoprotein (LDL)
cholesterol and a significant increase in high-density lipoprotein (HDL) cholesterol compared to
placebo. The median percent change from baseline of total cholesterol, LDL cholesterol and HDL
cholesterol with bazedoxifene 20 mg were –3.75%, –5.36% and 5.10%, respectively, and were similar
to that observed with raloxifene 60 mg. The effect on triglycerides in the bazedoxifene 20 mg and
raloxifene 60 mg groups was similar to placebo. This lipid profile was maintained throughout the 5
years of treatment. The treatment effect on lipids was similar in the osteoporosis prevention study.
The clinical relevance of these changes has not been established.
In the osteoporosis treatment trial in 7,492 subjects (mean age = 66 years), the bazedoxifene-treated
women had an increased risk of VTE (deep vein thrombosis, pulmonary embolism and retinal vein
thrombosis) (see section 4.8). The highest rate of VTE per 1,000 women-years of follow up was
observed during the first year: 4.64 in the bazedoxifene 20 mg group and 1.73 in the placebo group
(relative risk 2.69).The rate per 1,000 women-years at 3 years was 2.86 in the bazedoxifene 20 mg
group and 1.76 in the placebo group (relative risk 1.63). The rate per 1,000 women-years at 5 years
was 2.34 in the bazedoxifene 20 mg group and 1.56 in the placebo group (relative risk 1.50).
Cerebrovascular Effects
In the 3 year core study the rate per 1,000 women-years for ischaemic strokes was similar between the
20 mg bazedoxifene (1.98) and placebo (2.2) groups and higher in the 40 mg bazedoxifene (2.72)
group. The rate per 1,000 women years for transient ischaemic attacks (TIA) was similar between the
8
20 mg bazedoxifene (1.1) and placebo (0.88) groups and higher in the 40 mg bazedoxifene (1.59)
group.
After 5 years of treatment the rate per 1,000 women-years for ischaemic strokes was similar between
20 mg bazedoxifene (1.87) and placebo (2.02). The rate per 1,000 women years for TIA was higher
for 20 mg bazedoxifene (0.94) compared to placebo (0.62).
Effects on the uterus
In the osteoporosis treatment study, transvaginal ultrasonography (TVU) showed minimal changes in
endometrial thickness in placebo (-0.08 mm, n=131), bazedoxifene 20 mg (-0.07 mm, n=129), and
raloxifene 60 mg (0.16 mm, n=110) treated groups after 2 years. At 3 years, there were no cases of
endometrial cancer and 1 case (0.1%) of endometrial hyperplasia in the bazedoxifene 20 mg-treated
subjects. There was 1 case (0.1%) of endometrial cancer, 1 case of sarcoma (0.1%), and 1 case (0.1%)
of endometrial hyperplasia in the raloxifene 60 mg-treated subjects. There were 3 cases (0.2%) of
endometrial cancer and 1 case (0.1%) of endometrial hyperplasia in the placebo group. Endometrial
polyps were diagnosed in 10 subjects in the bazedoxifene 20 mg, 17 subjects in the raloxifene 60 mg,
and 11 subjects in the placebo treatment groups through month 36.
After 5 years of treatment, the endometrial thickness in the bazedoxifene 20 mg group did not change
and remained similar to placebo; there were no cases of endometrial cancer in the bazedoxifene 20 mg
group compared to 6 cases in the placebo group (p<0.05).
In the osteoporosis prevention study, TVU showed minimal changes from baseline in endometrial
thickness in placebo (-0.24 mm, n=154), bazedoxifene 20 mg (-0.06 mm, n=158) and raloxifene
60 mg (0.01 mm, n=154) treated groups after 2 years. No cases of hyperplasia or endometrial
malignancy were identified in any bazedoxifene- or raloxifene-treated subjects.
Effects on the breast
In the osteoporosis treatment study, the incidence of breast-related adverse events in the bazedoxifene
group was similar to placebo at 3 years. There were 5 cases of breast cancer per 4,591 person-years of
follow-up in the bazedoxifene 20 mg group (1.09 per 1,000), 7 cases of breast cancer per 4,526
person-years of follow-up in the raloxifene 60 mg group (1.55 per 1,000), and 8 cases of breast cancer
per 4,604 person-years of follow-up in the placebo group (1.74 per 1,000). After 5 years of treatment,
there were 9 cases of breast cancer in the bazedoxifene 20 mg group (1.40 per 1,000 women-years)
and 10 cases in the placebo group (1.56 per 1,000 women-years).
In the osteoporosis prevention study, the incidence of breast-related adverse events (breast tenderness,
pain, breast cancer, benign breast neoplasm) in the bazedoxifene 20 mg and raloxifene 60 mg groups
was similar to placebo.
In the breast-density study, an ancillary study of the osteoporosis treatment study, 444
postmenopausal women (mean age = 59 years) with osteoporosis from all 4 treatment groups, were
evaluated for mammographic breast density changes at 24 months. Mean changes in mammographic
breast density in the bazedoxifene 20 mg group were significantly reduced from baseline (-1.45
percentage points, p<0.05) while no changes were observed in the placebo group (-0.15 percentage
points).
5.2 Pharmacokinetic properties
The mean pharmacokinetic parameters of bazedoxifene after multiple doses in healthy
postmenopausal ambulatory women who were naturally postmenopausal or who had undergone
bilateral oophorectomy are summarized in Table 2.
9
Table 2. Mean ± SD pharmacokinetic parameters
of bazedoxifene (n=
23)
C
max
(ng/ml)
t
max
(h)
t
½
(h)
AUC
(ng
h/ml)
Cl/F
(l/h/kg)
Multiple dose
20 mg/day
6.2 ± 2.2
1.7 ± 1.8 28 ± 11
82 ± 37
4.1 ± 1.7
Absorption
Bazedoxifene is rapidly absorbed with a t
max
of approximately 2 hours and exhibits a linear increase in
plasma concentrations for single doses from 0.5 mg up to 120 mg and multiple daily doses from 1 mg
to 80 mg. The absolute bioavailability of bazedoxifene is approximately 6%.
When single doses of 20 mg bazedoxifene were administered with a high-fat meal, C
max
and AUC
increased by 28% and 22%, respectively. An additional study evaluating the effects of a standardized
medium-fat meal on the pharmacokinetics of bazedoxifene at steady-state showed a 42% and 35%
increase in C
max
and AUC, respectively, when 20 mg bazedoxifene was administered with food.
Because these changes are not considered clinically relevant, bazedoxifene can be administered
without regard to meals.
Distribution
Following intravenous administration of a 3 mg dose of bazedoxifene, the volume of distribution is
14.7 ± 3.9 l/kg. Bazedoxifene is highly bound (98% - 99%) to plasma proteins
in vitro
.
Metabolism
The metabolic disposition of bazedoxifene in postmenopausal women has been determined following
oral administration of 20 mg of radio-labelled bazedoxifene. Bazedoxifene is extensively metabolised
in women. Glucuronidation is the major metabolic pathway. Little or no cytochrome P450-mediated
metabolism is evident. Bazedoxifene-5-glucuronide is the major circulating metabolite. The
concentrations of this glucuronide are approximately 10-fold higher than those of unchanged active
substance in plasma.
Elimination
Bazedoxifene is eliminated with a half-life of approximately 30 hours. Steady-state concentrations are
achieved by the second week of once-daily administration. The apparent oral clearance of
bazedoxifene is approximately 4 to 5 l/h/kg. The major route of excretion of radio-labelled
bazedoxifene is the faeces, and less than 1% of the dose is eliminated in urine.
Special populations
Hepatic insufficiency
The disposition of a single 20 mg dose of bazedoxifene was compared in patients with hepatic
impairment [Child-Pugh Class A (n=6), B (n=6), and C (n=6)] and subjects with normal hepatic
function (n=18). On average, patients with hepatic impairment showed a 4.3-fold increase in AUC
compared with controls. Safety and efficacy have not been evaluated further in patients with hepatic
insufficiency. Use in this patient population is not recommended (see sections 4.2 and 4.4).
Renal insufficiency
Limited clinical data (n=5) are available in subjects with moderate renal impairment
(CrCl 50 ml/min). A single 20 mg dose of bazedoxifene was administered to these subjects.
Negligible amounts of bazedoxifene were eliminated in urine. Impaired renal function showed little or
no influence on bazedoxifene pharmacokinetics, and no dosing adjustment is required.
Elderly patients
10
The pharmacokinetics of a 20 mg single-dose of bazedoxifene were evaluated in a study in 26 healthy
postmenopausal women. On average, compared to women 51 to 64 years of age (n=8), women 65 to
74 years of age (n=8) showed a 1.5-fold increase in AUC, and women 75 years of age (n=8) showed
a 2.3-fold increase in AUC. This increase was most likely attributed to age-related changes in hepatic
function. No dose adjustment is necessary based on age.
Paediatric patients
The pharmacokinetics of bazedoxifene have not been studied in the paediatric population.
Race
No pharmacokinetic differences based on ethnic group were observed.
5.3 Preclinical safety data
In rabbit studies, abortion and an increased incidence of heart (ventricular septal defect) and skeletal
system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull)
anomalies in the foetuses were present at maternally toxic doses of 0.5 mg/kg/day (1.5 times the
human exposure). Treatment of rats at maternally toxic doses 1 mg/kg/day (0.3 times the human
exposure) resulted in reduced numbers of live foetuses and/or reductions in foetal body weights. No
foetal developmental anomalies were observed.
Female rats were administered daily doses of 0.3 to 30 mg/kg (0.03 to 8 times the human exposure)
prior to and during mating with untreated males. Oestrous cycles and fertility were adversely affected
in all bazedoxifene-treated female groups.
The effects of bazedoxifene treatment on bone, uterus, and mammary gland were assessed in
ovariectomized rats (0.15 to 1.5 mg/kg/day) and non-human primates [
Cynomolgus macaques
] (0.2 to
25.0 mg/kg/day). In rats, treatment with bazedoxifene for approximately one year partially prevented
the effects of ovariectomy on numerous skeletal parameters (bone mineral content, bone mineral
density, and architecture). Additionally, uterine wet weights were reduced compared with untreated
animals and histologic evaluation demonstrated little to no difference from the untreated controls. In
monkeys, treatment with bazedoxifene for 18 months resulted in the partial preservation of cortical
and cancellous bone mass as determined by BMD measurements. The partial preservation of bone
mass was achieved by reductions in the ovariectomy-induced increases in bone turnover, evaluated by
biochemical markers of bone turnover and histomorphometric indices measured in cancellous and
cortical bone. Importantly, in both species, the administration of bazedoxifene had no deleterious
effects on bone quality. Like the rodent results, bazedoxifene treatment in non-human primates
resulted in uterine and mammary gland atrophy without other histological differentiation from
untreated animals.
Repeated-dose studies in normally cycling rodents and cynomolgus monkeys revealed a marked
stimulation of ovarian follicle growth without ovulation, leading to partly haemorrhagic-ovarian cysts
and markedly elevated estradiol levels. This pharmacological effect of bazedoxifene can also be
expected in pre-menopausal women, but is considered clinically irrelevant in post-menopausal
women.
In 6-month carcinogenicity studies in transgenic mice, there was an increased incidence of benign,
ovarian granulosa-cell tumours in female mice given 150 or 500 mg/kg/day. Systemic exposure
(AUC) to bazedoxifene in these groups was 35 and 69 times that in postmenopausal women
administered 20 mg/day for 14 days.
In a 2-year carcinogenicity study in rats, an increased incidence of benign, ovarian granulosa-cell
tumours was observed in female rats at dietary concentrations of 0.03 and 0.1%. Systemic exposure
(AUC) of bazedoxifene in these groups was 2.6 and 6.6 times that observed in postmenopausal
women administered 20 mg/day for 14 days.
11
The observation of benign, ovarian granulosa-cell tumours in female mice and rats administered
bazedoxifene is a class effect of SERMs, related to its pharmacology in rodents when treated during
their reproductive lives, when their ovaries are functional and responsive to hormonal stimulation.
Bazedoxifene was not genotoxic or mutagenic in a battery of tests, including
in vitro
bacterial reverse
mutation assay,
in vitro
mammalian cell forward mutation assay at the thymidine kinase (TK±) locus
in L5178Y mouse lymphoma cells,
in vitro
chromosome aberration assay in Chinese hamster ovary
(CHO) cells, and
in vivo
mouse micronucleus assay.
Bazedoxifene caused corticomedullar nephrocalcinosis and enhanced spontaneous chronic
progressive nephropathy (CPN) in male rats. Urine parameters were pathologically changed. In
long-term studies renal tumours (adenomas and carcinomas) were observed at all doses tested, most
likely as a consequence of this chronic renal damage. In the 2-year carcinogenicity study,
bazedoxifene, administered orally in the diet to rats at dosages of 0, 0.003%, 0.01%, 0.03%, or 0.1%,
resulted in exposures, based on surface area (mg/m
2
) of approximately 0.6 to 23 times and 0.9 to 31
times in males and females, respectively, the clinical dose of 20 mg. Since chronic progressive
nephropathy and corticomedullar nephrocalcinosis are most likely rat-specific nephropathies, these
findings are presumably not relevant for humans.
In an 18-month bone efficacy study in aged ovariectomized cynomolgus monkeys, bazedoxifene,
administered orally to monkeys at dosages of 0, 0.2, 0.5, 1, 5, or 25 mg/kg/day, resulted in exposures,
based on surface area (mg/m
2
) of approximately 0.2 to 24 times the clinical dose of 20 mg. Renal cell
carcinomas were observed in this study. These tumours are considered as spontaneous renal cell
carcinomas that are known to occur in nonhuman primates and are unlikely to be relevant to humans.
6.
6.1 List of excipients
Tablet core:
Lactose monohydrate
Microcrystalline cellulose
Pregelatinised starch (maize)
Sodium starch glycolate
Sodium lauryl sulfate
Colloidal anhydrous silica
Magnesium stearate
Ascorbic acid
Film coating:
Hypromellose
Titanium dioxide (E171)
Macrogol 400
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
12
6.4 Special precautions for storage
Do not store above 25C.
6.5 Nature and contents of container
PVC/Aclar blister packs of 7, 28, 30, 84, and 90 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
8.
EU/1/09/511/001
EU/1/09/511/002
EU/1/09/511/003
EU/1/09/511/004
EU/1/09/511/005
9.
Date of first authorisation: 17 April 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/.
13
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Wyeth Medica Ireland
Little Connell
Newbridge
County Kildare
Republic of Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Pharmacovigilance System
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.5 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.
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).
In addition, an updated RMP should be submitted
• 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 European Medicines Agency
The MAH will submit 6-monthly PSURs unless otherwise specified by the CHMP.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
None
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON TEXT
1.
CONBRIZA 20 mg film-coated tablets
Bazedoxifene
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains bazedoxifene acetate equivalent to 20 mg bazedoxifene.
3.
LIST OF EXCIPIENTS
Also contains lactose.
See leaflet for further information.
4.
7 film-coated tablets
28 film-coated tablets
30 film-coated tablets
84 film-coated tablets
90 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
18
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25ºC.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/09/511/001 28 tablets
EU/1/09/511/002 30 tablets
EU/1/09/511/003 84 tablets
EU/1/09/511/004 90 tablets
EU/1/09/511/005 7 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CONBRIZA
19
MINIMUM PARTICULARS TO APPEAR ON BLISTERS AND STRIPS
BLISTER
1.
CONBRIZA 20 mg film-coated tablets
Bazedoxifene
2.
Pfizer Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
CONBRIZA 20 mg film-coated tablets
Bazedoxifene
Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What CONBRIZA is and what it is used for
2.
Before you take CONBRIZA
3.
How to take CONBRIZA
4.
Possible side effects
5.
How to store CONBRIZA
6.
Further information
1.
WHAT CONBRIZA IS AND WHAT IT IS USED FOR
CONBRIZA is a medicine that belongs to a group of non-hormonal medicines called Selective
Estrogen Receptor Modulators (SERMs). It is used for the treatment of osteoporosis in women after
they have reached menopause, when they are at an increased risk of fractures. It works by slowing or
stopping the thinning of bone in these women.
2.
BEFORE YOU TAKE CONBRIZA
Do not take CONBRIZA
if you are allergic (hypersensitive) to bazedoxifene or any of the other ingredients of
CONBRIZA (see section 6).
if you have or have had a blood clot (for example, in the blood vessels in your legs, lungs, or
eyes).
if you are pregnant or could still become pregnant. This medicine may cause harm to your
unborn child if taken during pregnancy.
if you have any unexplained vaginal bleeding. This must be investigated by your doctor.
if you have active uterine cancer.
Take special care with CONBRIZA
as it may increase your risk of getting blood clots. While very infrequent, these clots can cause
serious medical problems, disability or death. Speak with your doctor to see if you are at
increased risk for blood clots.
if you are immobile (unable to move) for some time, such as being wheel-chair bound, sitting for
a prolonged period of time or having to stay in bed while recovering from an operation or
illness. If you are traveling on long trips, you should walk around or exercise your legs and feet
at regular intervals. This is because sitting for a long time in the same position may prevent
good blood circulation and may increase your risk of blood clots. If you need to remain
22
immobile for an extended period of time or are scheduled to have surgery, it is important for
you to talk to your doctor about ways you can reduce the risk of blood clots.
if you are pre-menopausal. CONBRIZA has only been studied in women who have reached
menopause, and therefore is not recommended.
if you have had increased levels of triglycerides (a type of fat found in your blood) in the past.
if you have liver or severe kidney problems.
if you have any vaginal bleeding while you take CONBRIZA, you should speak with your
doctor.
if you are suffering from breast cancer, as there is insufficient experience with this medicine use
in women with this disease.
The above are some reasons why this product may not be suitable for you. If any of them apply to
you, talk to your doctor before you take the medicine.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
CONBRIZA is for use only by postmenopausal women. It must not be taken by women who are
pregnant or who could still have a baby. Do not take CONBRIZA if you are breast-feeding, because it
is not known whether it is excreted in mother's milk.
Driving and using machines
If you feel drowsy after taking CONBRIZA, you should avoid driving or operating machines.
Important information about some of the ingredients of CONBRIZA
This medicine contains lactose (a type of sugar). If you have been told by your doctor that you have
an intolerance to some sugars, contact your doctor before taking this medicinal product.
3.
HOW TO TAKE CONBRIZA
Always take CONBRIZA exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. You should continue taking this medicine as long as your doctor tells
you to. In order for CONBRIZA to treat osteoporosis, it must be taken daily.
The usual dose is one tablet by mouth daily. Taking more than one tablet daily is not more
effective and may carry additional risks.
You can take the tablet at any time of the day, with or without food.
CONBRIZA should be taken with an adequate amount of calcium and vitamin D. Consult your
doctor to see if your dietary calcium and vitamin D intake is adequate and whether you need
calcium and vitamin D supplementation. If you take supplemental calcium and/or vitamin D, it
may be taken at the same time as this medicine.
If you take more CONBRIZA than you should
Tell your doctor or pharmacist.
23
If you forget to take
CONBRIZA
If you forget to take a tablet, take it as soon as you remember. However, if it is almost time to take
your next dose of CONBRIZA, skip the dose you missed and only take your next scheduled dose. Do
not take a double dose to make up for a forgotten tablet.
If you have any further questions on the use or stopping the use of this product, ask your doctor or
pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, CONBRIZA can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data)
Very common
side effects:
Muscle spasms (includes leg cramps)
Hot flushes
Common
side effects:
Allergic reaction (including hypersensitivity and urticaria)
Dry mouth
Increase in blood triglycerides (fat found in your blood)
Increase in liver enzymes
Swelling of the hands, feet and legs (peripheral oedema)
Drowsiness
Uncommon
side effects:
Blood clot in the leg
Blood clot in the lungs
Rare side
effects:
Blood clot in the eye (retinal vein)
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
24
5.
HOW TO STORE CONBRIZA
Keep out of the reach and sight of children.
Do not use CONBRIZA after the expiry date, which is stated on the carton and blister after EXP. The
expiry date refers to the last date of that month.
Do not store above 25C.
6.
FURTHER INFORMATION
What CONBRIZA contains
The active substance is bazedoxifene. Each film-coated tablet contains bazedoxifene acetate
equivalent to 20 mg bazedoxifene.
The other ingredients are lactose monohydrate, microcrystalline cellulose, pre-gelatinised starch
(maize), sodium starch glycolate, sodium lauryl sulfate, colloidal anhydrous silica, magnesium
stearate, ascorbic acid, hypromellose, titanium dioxide (E171) and macrogol 400.
What CONBRIZA looks like and contents of the pack
CONBRIZA is supplied as a white to off-white, capsule-shaped, film-coated tablet marked with
“WY20”. They are packed in PVC/Aclar blisters and are available in packs of 7, 28, 30, 84 or 90
tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
Manufacturer: Wyeth Medica Ireland, Little Connell Newbridge, County Kildare, Ireland.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Luxembourg/Luxemburg
Pfizer S.A./N.V.
Tél/Tel: +32 (0)2 554 62 11
Kύπρος
Wyeth Hellas (Cyprus Branch) AEBE
T: +357 22 817690
Česká Republika
Pfizer s.r.o.
Tel: +420-283-004-111
Magyarország
Pfizer Kft
Tel: +36 1 488 3700
Danmark
Pfizer ApS
Tlf: +45 44 201 100
Malta
Vivian Corporation Ltd.
Tel: +35621 344610
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Nederland
Wyeth Pharmaceuticals B.V.
Tel:+31 23 567 2567
25
България/Eesti/Latvija/Lietuva/
/Slovenija
Wyeth-Lederle Pharma GmbH
Teл/Tel/Tãlr: +43 1 89 1140
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
Pfizer Hellas A.E.
Τηλ.: +30 210 6785 800
Polska
Pfizer Polska Sp. z o.o.
Tel:+48 22 335 61 00
España
Pfizer, S.A.
Télf: +34914909900
Norge
Pfizer AS
Tlf: +47 67 526 100
France
Pfizer
Tél: +33 (0)1 58 07 34 40
Portugal
Laboratórios Pfizer, Lda.
Tel: (+351) 21 423 55 00
Ireland
Wyeth Pharmaceuticals
Tel: +353 1 449 3500
Slovenská Republika
Pfizer Luxembourg SARL,
organizačná zložka
Tel: + 421 2 3355 5500
Ísland
Icepharma hf
Simi: +354 540 8000
Suomi/Finland
Pfizer Oy
Puh/Tel: +358 (0)9 430 040
Italia
Pfizer Italia S.r.l.
Tel: +39 06 33 18 21
Sverige
Pfizer AB
Tel:+46 (0)8 550 520 00
România
Pfizer Romania S.R.L
Tel: +40 (0) 21 207 28 00
United Kingdom
Wyeth Pharmaceuticals
Tel: +44 845 367 0098
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
-----------------------------------------------------------------------------------------------------------------------------
26
Source: European Medicines Agency
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