Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Malignant Neoplasms
Additions
and/or revisions underlined:
…
Breast
Cancer
OSPHENA
60 mg has not been adequately studied in women with breast cancer; therefore,
it should not be used in women with known or suspected breast cancer.
The
Women’s Health Initiative (WHI) substudy of daily conjugated estrogen (CE)
(0.625 mg)-alone provided information about breast cancer in estrogen-alone
users. In the WHI estrogen alone substudy, after an average follow-up of 7.1
years, daily CE alone was not associated with an increased risk of invasive
breast cancer [relative risk (RR) 0.80] compared to placebo.
After a mean follow-up of 5.6 years, the
WHI substudy of daily CE (0.625 mg) plus medroxyprogesterone acetate (MPA) (2.5
mg) reported an increased risk of invasive breast cancer in women who took
daily CE plus MPA compared to placebo. In this substudy, prior use of estrogen-
alone or estrogen plus progestin therapy was reported by 26 percent of the
women. The relative risk of invasive breast cancer was 1.24 and the absolute
risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared
with placebo. Among women who reported prior use of hormone therapy, the
relative risk of invasive breast cancer was 1.86, and the absolute risk was 46
versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo.
Among women who reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases
per 10,000 women-years for CE plus MPA compared with placebo. In the same
substudy, invasive breast cancers were larger, were more likely to be node
positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus
MPA (2.5 mg) group compared with the placebo group. Metastatic disease was
rare, with no apparent difference between the two groups. Other prognostic
factors, such as histologic subtype, grade and hormone receptor status did not
differ between the groups.
Consistent
with the Women’s Health Initiative (WHI) clinical trials, observational studies
have also reported an increased risk of breast cancer for estrogen plus
progestin therapy and a smaller, but still increased, risk for estrogen-alone
therapy after several years of use. One large meta-analysis of prospective
cohort studies reported increased risks that were dependent upon duration of
use and could last up to >10 years after discontinuation of estrogen plus
progestin therapy and estrogen-alone therapy. Extension of the WHI trials also
demonstrated increased breast cancer risk associated with estrogen plus
progestin therapy. Observational studies also suggest that the risk of breast
cancer was greater, and became apparent earlier, with estrogen plus progestin
therapy as compared to the risk with estrogen-alone therapy. However, these
studies have not found significant variation in the risk of breast cancer among
different estrogen plus progestin combinations, doses, or routes of
administration.
The
use of estrogen-alone and estrogen plus progestin has been reported to result
in an increase in abnormal mammograms requiring further evaluation.
All
women should receive yearly breast examinations by a healthcare provider and
perform monthly breast self-examinations. In addition, mammography examinations
should be scheduled based on patient age, risk factors, and prior mammogram
results.
Approved Drug Label (PDF)
Boxed Warning
WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS
(Additions
and/or revisions are underlined)
OSPHENA is
an estrogen agonist/antagonist with tissue
selective effects. In the endometrium, OSPHENA has estrogen agonistic
effects. There is
a potential increased risk of endometrial
cancer in a woman with a uterus
who uses unopposed estrogens.
Adequate diagnostic measures, including directed and random endometrial sampling
when indicated, should
be undertaken to rule out malignancy in postmenopausal women with
undiagnosed persistent or recurring
abnormal genital bleeding.
Cardiovascular Disorders
In
the clinical trials for OSPHENA (duration of treatment up to 15 months), the
incidence rates of thromboembolic and hemorrhagic stroke were 1.13 and 3.39 per thousand women years, respectively in the OSPHENA 60 mg treatment group and 3.15 and 0 with placebo. The
incidence of DVT was
2.26 per thousand women years (2
reported cases) in the OSPHENA 60 mg treatment
group and 3.15 per thousand women years
(1 reported case) with placebo. OSPHENA should be
prescribed for the shortest duration
consistent with treatment
goals and risks for
the individual woman.
There is
a reported increased risk of stroke
and deep vein thrombosis (DVT) in postmenopausal
women (50 to 79 years of
age) who received daily oral conjugated
estrogens (CE) [0.625 mg]-alone
therapy over 7.1 years
as part of the Women’s
Health Initiative (WHI).
5
Warnings and Precautions
5.1 Cardiovascular Disorders
(Additions
and/or revisions are underlined)
Risk factors for cardiovascular
disorders, arterial vascular
disease (for example, hypertension, diabetes mellitus,
tobacco use, hypercholesterolemia,
and
obesity) and/or
venous thromboembolism (VTE) (for example,
personal history or family
history of VTE, obesity,
and systemic lupus erythematosus),
should be managed appropriately.
Stroke
In the clinical trials
for
OSPHENA (duration of treatment up to 15 months), the incidence rates of
thromboembolic and hemorrhagic stroke were 1.13 and 3.39 per
thousand women years, respectively in OSPHENA 60 mg treatment group and 3.15 and
0 per
thousand women years
in placebo.
Should thromboembolic or
hemorrhagic stroke occur or be
suspected, OSPHENA should be discontinued
immediately.
In
the WHI estrogen-alone substudy, a
statistically significant increased risk of stroke was
reported in women 50 to 79 years of age receiving daily
CE (0.625 mg)-alone compared to women in the same age group receiving
placebo (45
versus 33 per ten thousand women-years).
The increase in risk was demonstrated
in year 1 and persisted.
Coronary Heart Disease
In the OSPHENA clinical trials, two cases of
myocardial infarction (MI) occurred in women receiving 60 mg
of ospemifene.
In the WHI estrogen-alone substudy, no overall effect
on coronary heart disease (CHD) events (defined
as nonfatal MI, silent MI, or CHD
death) was reported in women
receiving estrogen-alone compared to placebo.
Venous
Thromboembolism
In the OSPHENA clinical trials, two cases of
DVT occurred in women receiving OSPHENA 60 mg. Should a
VTE occur or be suspected, OSPHENA should be discontinued immediately.
If feasible, OSPHENA
should be discontinued at least
4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism,
or during periods of prolonged
immobilization.
In
the WHI estrogen-alone substudy, the
risk of VTE
(DVT and PE), was increased for women receiving
daily CE (0.625 mg)-alone
compared to placebo (30
versus 22 per ten thousand women- years), although
only
the increased risk of DVT reached statistical
significance (23 versus 15 per ten
thousand women-years). The increase in VTE risk was
demonstrated during the first
2 years.
5.2 Malignant Neoplasms
(Additions
and/or revisions are underlined)
Endometrial Cancer
OSPHENA is
an estrogen
agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has agonistic
effects. In the
OSPHENA clinical trials (60 mg treatment group),
no cases of endometrial cancer were seen with exposure up to 52 weeks. There was a single case of simple
hyperplasia without atypia. Endometrial thickening equal to 5 mm or greater was seen in the OSPHENA up to 52 weeks treatment groups at
a rate of 101.4 per
thousand women vs. 20.9 per thousand women
for placebo. The incidence of any type
of proliferative (weakly plus
active plus disordered) endometrium was
26.3 per thousand women in the OSPHENA up to 52 weeks
treatment groups vs. 0 per thousand women for placebo.
Uterine polyps occurred
at an incidence of 19.6 per thousand women
in the OSPHENA up to 52 weeks treatment groups
vs. 8.3 per thousand women for placebo.
…
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions
and/or revisions are underlined)
…
The safety of OSPHENA
has been assessed in ten phase 2/3
trials (N=2209) with doses
ranging from 5 to 90 mg per day.
The duration of treatment in these studies ranged from
6 weeks
to 15 months. The majority
of women (N=1683) had treatment exposure up to 12 weeks, 847 had
up to 52 weeks (1 year) of exposure.
The incidence rates of thromboembolic and hemorrhagic stroke were 1.13
per thousand women years
(1 reported case of thromboembolic
stroke) and 3.39 per thousand women years (3
reported cases of hemorrhagic stroke), respectively in OSPHENA 60 mg treatment group and 3.15 (1 case of thromboembolic
stroke) and 0 per
thousand women years, respectively in placebo. There were 2 reported cases
of DVT
among the 1459 women in the OSPHENA 60 mg treatment group
and 1 case of DVT among the 1136 women in
the placebo group.
Table 1
lists adverse reactions occurring
more frequently in the
OSPHENA 60 mg treatment
group than in placebo and at a frequency greater than or equal to
1% in the 12-week, double-blind, placebo-controlled
clinical trials.
Table 2 lists adverse reactions occurring
more frequently in the
OSPHENA 60 mg treatment
group than in placebo and at a frequency greater than or equal to 1% in all clinical trials up to 52-weeks.
(Tables
in this subsection has been added; please refer to label)
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
The following adverse
reactions have been identified during post-approval use of ospemifene. Because these reactions are reported voluntarily from a
population of uncertain size, it is not possible
to reliably estimate
their frequency or establish a causal relationship
to drug exposure.
Neoplasms
Benign, Malignant and Unspecified (incl
cysts and polyps); endometrial hyperplasia, endometrial cancer
Immune System Disorders: allergic conditions including
hypersensitivity, angioedema Nervous System Disorders: headache
Vascular Disorders:
deep vein thrombosis, thrombosis, pulmonary
embolism
Skin
and Subcutaneous Tissue Disorders: rash, rash erythematous, rash generalized, pruritus, urticaria
7
Drug Interactions
7.1 Estrogens and Estrogen Agonist/Antagonist
(Additions and/or revisions are underlined)
Do not use OSPHENA concomitantly with estrogens and estrogen agonists/antagonists. The safety of concomitant
use of OSPHENA with estrogens and estrogen
agonists/antagonists has not been
studied.
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions are underlined)
Risk
Summary
Not
Recommended During Pregnancy
OSPHENA is contraindicated
in women who are or may become pregnant. If this drug is used
during pregnancy, or if a woman becomes
pregnant while taking
this drug, she should be apprised of the potential
hazard to a fetus.
Based
on animal
data, OSPHENA is likely to
increase the risk of adverse outcomes during pregnancy and
labor. Adverse findings at maternally toxic doses included embryofetal
lethality in rats and rabbits, and
neonatal mortality and difficult
labor in rats. The
reproductive effects observed
are consistent with and
are
considered to be related
to estrogen receptor activity
of OSPHENA.
The background risk
of major
birth defects and miscarriage for the indicated population is unknown. However,
the background risk in the U.S. general population
of major birth defects is 2 to 4%, and of miscarriage is 15 to 20% of
clinically recognized pregnancies.
Data
Animal Data
The effects of
ospemifene on embryo-fetal development were studied
in rats (0.1, 1, or 4 mg/kg/day) and
rabbits (3, 10, or 30 mg/kg/day)
when treated from
implantation through organogenesis
[Gestation Day (GD) 6-16 in the rat and GD6-18 in the rabbit. In rabbits, there was
an
increase in the incidence of total resorptions
at 30 mg/kg/day (10
times the human exposure based
on body surface area mg/m2)]. Drug-induced malformations were not
observed in either rats or rabbits.
The effects of ospemifene on pre- and
postnatal development were studied in pregnant
rats (0.01, 0.05, and 0.25 mg/kg/day)
treated from implantation (GD6) through lactation (Lactation Day (LD) 21).
Pregnant rats given
0.05 or 0.25 mg/kg/day ospemifene
(0.8% to 4% the human exposure based on body surface
area mg/m2),
had a significantly prolonged
and difficult gestation, increased post- implantation loss, increased number of dead pups at birth, and
an increased incidence
of postnatal loss. Ospemifene did not induce adverse effects in the surviving offspring of pregnant rats at drug exposures
up to 4% the human exposure.
8.3 Lactation
(Additions and/or revisions are underlined)
Risk Summary
It
is not known whether OSPHENA is excreted in human breast milk. There are no data on
the effects of
OSPHENA on the breastfed child or
the effects on milk production. Do not breastfeed while taking OSPHENA. Ospemifene was excreted in rat milk.
Data
In a
nonclinical study, ospemifene was excreted in rat milk
and detected at concentrations
higher than that in maternal plasma.
8.5 Geriatric Use
(Additions and/or revisions are underlined)
Of the 2209 OSPHENA-treated women
enrolled in the ten phase 2/3 trials of OSPHENA, >19 percent were 65
years of age or older. No clinically meaningful differences in safety or
effectiveness were observed between these women and younger women less than 65
years of age.
8.7 Hepatic
Impairment
(Additions and/or revisions are underlined)
The pharmacokinetics of ospemifene has not
been studied in women with severe hepatic impairment (Child-Pugh Class C);
therefore, do not use OSPHENA in women with severe hepatic impairment. …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved labeling (Patient
Information).
Hypersensitivity
Reactions
Inform postmenopausal women
who have had hypersensitivity reactions to OSPHENA, such as
angioedema, urticaria, rash, pruritus,
that they should not take OSPHENA.
Vaginal Bleeding
Inform postmenopausal women
of the importance of reporting unusual vaginal
bleeding to their healthcare providers as soon as possible.
Hot Flashes or Flushes
OSPHENA may initiate or
increase the occurrence of hot
flashes in some women
Other
PATIENT INFORMATION
(Extensive
changes, please refer to the label)
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